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Gaucher disease …
- Updated 05.15.2024
- Released 12.28.1993
- Expires For CME 05.15.2027
Gaucher disease
Introduction
Overview
Gaucher disease is a storage disorder caused by mutations in the GBA1 gene, which codes for lysosomal acid beta-glucocerebrosidase (glucocerebrosidase), resulting in accumulation of glucosylceramide (glucocerebroside). Type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) Gaucher disease are in a phenotypic continuum of neurologic abnormalities with variable courses. Sudden unexpected death and unusual behavior may occur in Gaucher type 3, particularly in Egyptian patients. Enzyme replacement therapy has no effect on the neurologic complications of the disease. CSF glycoprotein nonmetastatic B (GPNMB) may be used to quantify neurologic involvement in Gaucher disease. Mutations in the GBA1 gene are the most common genetic risk factor for adult-onset, isolated Parkinson disease; multiple system atrophy; and dementia with Lewy bodies. Substrate reduction therapy, pharmacological chaperone therapy, and gene therapy for neuronopathic Gaucher disease are currently being tested or are in the advanced planning stages.
Key points
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• Neuronopathic Gaucher disease has a very wide clinical spectrum--from congenital and early infantile Gaucher disease type 2 to very mild with horizontal supranuclear gaze palsy as the only neurologic abnormality and normal or even superior intelligence. | |
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• Current treatment for the non-neuronopathic and for the chronic neuronopathic forms of the disease includes enzyme replacement, which targets only the non-neurologic aspects of the disease. | |
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• Substrate synthesis reduction has shown to be effective in controlling the non-neurologic aspects of Gaucher disease, and the approach is being tried in Gaucher disease type 3 patients. | |
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• Adult-onset, isolated Parkinson disease; multiple system atrophy; and dementia with Lewy bodies are not features of neuronopathic Gaucher disease. Rather, GBA1 mutations are a risk factor for developing these neurodegenerative diseases. |
Historical note and terminology
The first example of Gaucher disease was documented in a patient with hepatosplenomegaly. The case was described in the doctoral thesis of Philippe C E Gaucher (1854-1918) (69).
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Alternative metabolic pathway of glucosylceramide (GlcCer) accumulation due to glucocerebrosidase (GCase) deficiency (1)
The expression of GCase varies from one cell type to another and depends on the tissue. In a mouse model of GCase deficiency (red cross), GlcCer is transformed via an alternative ceramidase pathway into glucosylsphingosine (red...
The disorder was diagnosed as an epithelioma of the spleen.
The characteristic appearance of storage in reticuloendothelial cells was noted as early as 1907 by German pathologist Felix Marchand (1846-1928) (114). The first step toward the description of the chemistry of the material accumulating in these cells evolved from the identification of its "lipoid" character by morphologists. Later, Viennese pathologist Emil Epstein (1875-1951) demonstrated that spleens from Gaucher patients yielded considerable amounts of an alcohol-soluble substance (55). (Epstein, a Jew, was dismissed from the teaching staff of the medical faculty of the University of Vienna in 1938, an effect of the annexation of Austria by the German Reich under "National Socialism.")
In 1924, Austrian medical analytical chemist Hans Lieb (1887-1979), working then as an unpaid Medical-Chemical Institute at the University of Graz (Medizinisch-Chemischen Institutes der Universität Graz), characterized this material as a cerebroside akin to the compounds described earlier by German-born British physician and biochemist Johann Ludwig Wilhelm Thudichum (known in Britain as John Louis William Thudichum; 1829-1901) (170; 107); Lieb was later promoted to full professor of applied medicinal chemistry, was appointed head of the Medical-Chemical Institute, and on three occasions was elected dean of the medical faculty.
German-born British physician and biochemist Johann Ludwig Wilhelm Thudichum (aka, John Louis William Thudichum) (1829-1901)
Thudichum isolated and characterized numerous compounds of the brain, such as cephalin, sphingomyelin, galactose, lactic acid, and sphingosine. In 1884, he explained his findings in a publication titled "A Treatise on the Chemi...
In 1925, American pathologist William Bloom (1899-1972) wrote a long paper comparing the pathology of Gaucher disease and Niemann disease, for which he reviewed two cases of Gaucher disease (19; 157).
The correct identification of the sugar in the sphingolipid compound was not achieved until 1934, when French gynecologist Henriette Aghion (1906-1986) demonstrated that the lipid accumulating in the tissues of patients with Gaucher disease was a glucosyl, not a galactosyl, a derivative of ceramide (04).
The discovery of the lysosome as an organelle in 1955 by Belgian cytologist and biochemist Christian de Duve (1917-2013) and colleagues changed the definition of the storage disorders, earning de Duve a Nobel Prize in physiology or medicine in 1974. Within a short time, the first lysosomal storage disorder was described and was shown to be due to a deficiency of acid alpha-1,4-glucosidase (alpha-glucosidase) in a patient with Pompe disease (79). Other storage disorders quickly became recognized as diseases resulting from the lack of a degradative capacity—notably a lysosomal enzyme—with the expected lysosomal accumulation of substrate (80; 47). The accumulation of acid beta-glucocerebrosidase (glucocerebroside) was already well known in patients with Gaucher disease. Attention was focused on the possibility that the material accumulated because of a specific deficiency in its degradative pathway, leading to the description of the enzyme deficiency; in the mid-1960s, American biochemist Roscoe Owen Brady (1923-2016) and his colleagues at the U.S. National Institutes of Health identified the enzymatic defects in Gaucher disease (25; 26; 27; 28; 135; 24; 65).
It had been recognized that a variety of clinical disorders were related to glucocerebroside storage. Although these subtypes were originally thought to be distinguished by the relative amount of residual enzyme present (158; 189), this has been shown to be incorrect.
The discovery of the enzyme deficiency led to the development of several approaches to understand the biology of the lysosomes and to the development of enzyme replacement therapy to replace the missing gene product.
With the advent of alglucerase enzyme replenishment therapy (ERT) in 1991, the manufacturer (Genzyme Corporation) created the International Cooperative Gaucher Group (ICGG) Gaucher Registry to collect longitudinal observational "real word" information about Gaucher disease in heterogeneous patient populations to study the impact of phenotypes and genotypes on the natural history of Gaucher disease in untreated patients and to study treatment outcomes (184).
Note on nomenclature. This summary follows the current guidelines for gene and protein nomenclature and for mutation description. Please see Gene and mutation nomenclature for those guidelines. The enzyme, acid beta-glucocerebrosidase (GBA) is often referred to as glucocerebrosidase in the literature. The description of mutations in the older literature refers to the processed protein after excision of the 39 amino acid leader peptide. The current guidelines for mutation nomenclature stipulate that numbering begins with the leader peptide.
Clinical manifestations
Presentation and course
The presenting signs and symptoms of Gaucher disease vary throughout childhood (187).
Timeline of presenting signs and symptoms of Gaucher disease throughout childhood
(a) Dysphagia, apnea, difficulty with secretions. (b) Progressive. (c) Avascular necrosis, osteopenia, pathologic fractures. Presenting signs and symptoms of Gaucher disease are summarized Gary and colleagues; some would only b...
Common features include coagulopathy, hepatosplenomegaly, fatigue, bone pain, and frequent infections; frequent infections are common in childhood, whereas the others are typical of adolescence (117).
Prevalence and age at occurrence of the five most frequently reported symptoms in patients with Gaucher disease
(n = 19) (Source: Mengel E, Gaedeke J, Gothe H, et al. The patient journey of patients with Fabry disease, Gaucher disease and mucopolysaccharidosis type II: a German-wide telephone survey. PLoS One 2020;15[12]:e0244279. Creati...
Based on clinical signs and symptoms, Gaucher disease has been divided into three subtypes: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, chronic neuronopathic (101). All three types of Gaucher disease are caused by a deficiency of acid beta-glucocerebrosidase that results in the accumulation of glucocerebroside within the cells of the reticuloendothelial system. The principal differences between the subtypes are the presence of neurologic manifestations caused directly by glucocerebrosidase deficiency. Neuronopathic Gaucher disease is defined as the presence of neurologic involvement in a patient with biochemically proven Gaucher disease for which there is no explanation other than Gaucher disease (176). Because symptoms in all three types may begin in infancy, and the discrimination of subtypes depends on the evolution of clinical manifestations, especially nervous system involvement, this classification is more appropriate than one that includes reference to age of onset (ie, "adult," "infantile," and "juvenile" forms of Gaucher disease). The assignment of type, especially in children, should be made only after a careful examination for the presence and progression of related neurologic abnormalities or if a genotype study shows the presence of the N370S allele that typically is associated with Gaucher disease type 1.
Type 1: Chronic non-neuronopathic Gaucher disease. The age of onset and the severity of symptoms within this subtype vary widely and are not completely explained by the genotype. The diagnosis is frequently made later in life because of a lack of apparent clinical manifestations.
Although exceptions occur, painless splenomegaly with thrombocytopenia, anemia, and leukopenia are the usual initial signs. In many patients, these complications are not life threatening and may go unrecognized for years.
Visceral features. Although hepatomegaly is often noted at the time splenomegaly is observed, the liver may not become enlarged until later in the course of the disease. Moderate hepatic dysfunction is discerned by elevated levels of liver enzymes in serum. Histologically, all patients have some degree of hepatic fibrosis (92). Hepatic failure can occur in untreated patients. Portal hypertension leading to esophageal varices is a recognized complication, occurring in patients with severe type 1 and type 3 disease.
Hematological features. Patients may have platelet counts below 50,000 without an accompanying bleeding diathesis. Conversely, some patients with Gaucher disease who have a normal prothrombin time, partial thromboplastin time, and platelet count (greater than 100,000) may have abnormal clotting times, excessive bruising, and unexpected perioperative bleeding. This variability in hematological features necessitates an individualized approach that may require the administration of platelets and fresh frozen plasma prior to and after surgical procedures.
Skeletal features. Complex degenerative skeletal changes are the leading cause of disability in patients with type 1 disease; these may include marrow infiltration, bone pain, osteopenia, fragility fractures, and recurrent avascular osteonecrosis (15).
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Diffuse bone marrow signal abnormality throughout the left femur consistent with avascular osteonecrosis
In a patient with Gaucher disease type 1 (GBA1 genotype p.Asn409Ser/c.217delC mutations), MRI revealed diffuse bone marrow signal abnormality throughout the left femur consistent with avascular osteonecrosis. (Source: ...
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Avascular osteonecrosis in right femur of a patient with Gaucher disease
A few months after initial MRI, the patient developed avascular osteonecrosis in the right femur. (Source: Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set f...
Some degree of osteopenia and osteolysis occurs in all patients, although the extent of bone disease is variable (190; 89).
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Intermediate-magnification photomicrograph of Gaucher disease and necrotic bone
Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [...
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High-magnification photomicrograph of Gaucher disease and necrotic bone
Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [...
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Very-high-magnification photomicrograph of Gaucher disease and necrotic bone
Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [...
Radiologic abnormalities are typically extensive.
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Radiographic imaging of skeletal manifestations in Gaucher disease (1)
Generalized osteopenia and lytic areas in iliac wings and mid shafts of both femora. Pathological fractures both upper femora. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gau...
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Radiographic imaging of skeletal manifestations in Gaucher disease (2)
Generalized osteopenia and lytic areas in mid shafts of both femora and tibiae. Erlenmeyer flask deformity of both femurs, also known as metaphyseal flaring. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for...
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Radiographic imaging of skeletal manifestations in Gaucher disease (3)
Generalized osteopenia and lytic areas in humeri. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attributio...
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Radiographic imaging of skeletal manifestations in Gaucher disease (4)
Gross expansion and coarse trabeculation of the left femur. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons ...
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Radiographic imaging of skeletal manifestations in Gaucher disease (5)
Extensive osteonecrosis of the right femoral head, which shows marked flattening with complete loss of joint space. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher diseas...
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Radiographic imaging of skeletal manifestations in Gaucher disease (6)
Prominent thoracic kyphosis and exaggerated lumbar lordosis with minimal lumbar curve. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;1...
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Radiographic imaging of skeletal manifestations in Gaucher disease (7)
H-shaped vertebrae of the thoracic spine consistent with osteonecrosis. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creat...
Patients rarely have neither radiographic nor scintigraphic evidence of bone involvement. Most affected individuals have a substantial burden of bone disease that is progressive and leads to clinical presentation. Others have such severe involvement that they are confined to a wheelchair early in life because of pain, pathologic fractures, or skeletal instability. Many patients experience episodic pain in the hips, legs, back, and shoulders, referred to as "bone crises," lasting from days to months.
Splenectomy is associated with increased risks of osteonecrosis and fragility fractures (43). Controlling for gender, the hazard or risk of having a first osteonecrosis event after presentation of Gaucher disease is greater in patients who had splenectomy (hazard ratio of 3.32 [95% CI 1.74–5.00; p < 0.001]) (43).
Similarly, controlling for gender, the hazard or risk of having a first fragility fracture after presentation of Gaucher disease was also greater in patients who had splenectomy (hazard ratio of 2.83 [95% CI 1.33–5.99; p = 0.01]) (43).
The hazard or risk of having a first osteonecrosis event after presentation of Gaucher disease is significantly lower after starting enzyme replacement therapy (ERT) than before (hazard ratio of 0.20; 95% CI 0.11–0.38; p < 0.001) (43).
Cumulative hazard for first osteonecrosis event according to treatment status
Horizontal axis shows time in years after presentation of Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Cr...
In a study by D'Amore and colleagues, the effects of substrate reduction therapy (SRT) and bone marrow transplantation (BMT) were difficult to assess due to the small sample size (nine and two patients received substrate reduction therapy or bone marrow transplantation as first treatment, respectively) (43). Of the two patients with bone marrow transplantation, one had their first episode of osteonecrosis after the procedure.
Pulmonary features. Pulmonary hypertension is a relatively common complication found in approximately a third of Gaucher disease patients, a direct consequence of acid beta-glucocerebrosidase storage that is worsened in splenectomized patients by the accumulation of storage cells in the lung. Fortunately, most cases are mild and subclinical with pulmonary artery pressures below 25 mmHg. The rare cases with severe pulmonary hypertension typically improve with enzyme therapy (105).
Ophthalmological abnormalities. Rare ophthalmological abnormalities may involve the vitreous, retina, cornea, uvea, and conjunctiva (50). Vitreous opacities are the most common and seen mostly in patients with Gaucher type 3 and sometimes require vitrectomy to ameliorate visual acuity.
Type 2: Acute neuronopathic Gaucher disease. In contrast to the variability seen within type 1 Gaucher disease, type 2 is somewhat more uniform in its presentation (61). It has no ethnic predilection. The average age of onset is three months, and the presenting sign is usually massive hepatosplenomegaly.
Neurologic abnormalities. Neurologic complications develop by 3 to 6 months of age. The presenting signs usually indicate involvement of cranial nerve nuclei and pyramidal tracts. A triad of clinical findings is very suggestive of the disease: (1) rigidity of the neck and trunk (which can progress to neck retroflexion and to frank opisthotonus); (2) bulbar signs (particularly poor suck and swallow reflexes with dysphagia and aspiration); and (3) oculomotor paresis (or bilateral fixed strabismus, particularly a convergent squint). These signs may be associated with microcephaly, trismus, hypertonia, hypokinesia, progressive spasticity, hyperreflexia, Babinski signs, and other pathologic reflexes. Seizures may occur. As neurologic deterioration proceeds, the child usually becomes apathetic and motionless. Death occurs either from apnea or aspiration pneumonia at an average age of nine months, with a range of 1 month to 2 years.
This form of Gaucher disease exhibits alterations in epidermal ultrastructure, which may provide an early and specific diagnostic tool (33).
Neonatal Gaucher disease. A rare form of Gaucher disease presents with hydrops fetalis and so-called "collodion skin" (congenital ichthyosis) (168; 161; 111).
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Facial cutaneous abnormalities of "collodion baby" due to perinatal Gaucher disease type 2
The infant’s epidermal detachment ("collodion baby") is characteristic of perinatal Gaucher disease type 2. (Source: Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a ca...
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Limb cutaneous abnormalities of "collodion baby" due to perinatal Gaucher disease type 2
The infant’s epidermal detachment ("collodion baby") is characteristic of perinatal Gaucher disease type 2. (Source: Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a ca...
A review of the clinical and hematological features of neonatal Gaucher disease found that this type is typically diagnosed based on postmortem pathological findings, with familial history suspected in 22% (118). Contrary to what is observed in type 2 disease, 22% of neonatal cases have dysmorphic features characterized by low-set ears, small nose with flat bridge, and anteverted nares. In a molecular analysis of 31 patients with this type of Gaucher disease, homozygosity for a recombinant allele that included the mutation p.Leu483Pro (formerly Leu444Pro) was associated with early lethality (161).
The characteristics of the clinical phenotype and the pregnancy are somewhat different between those newborns and fetuses affected by non-immune hydrops fetalis, in whom prematurity, fetal demise, and neonatal distress are prominent features. Hepatosplenomegaly is suspected prenatally in most cases with non-immune hydrops fetalis. Cardiomegaly has also been observed in some fetuses with Gaucher disease associated with non-immune hydrops fetalis (118).
Neonatal Gaucher disease should be distinguished from types 1 and 2. Type 1 cases are also diagnosed before 2 years of age and may have rapid progression in bone, liver, and spleen manifestations. CNS involvement must be established as an associated finding prior to making a diagnosis of type 2 disease.
Type 3: Subacute or chronic neuronopathic Gaucher disease. The clinical features of Gaucher disease type 3, apart from those referable to the nervous system, are common to Gaucher disease type 1. Patients may have a combination of systemic and neurologic abnormalities, including mild systemic disease with a progressive neurologic course, or severe skeletal and hematological abnormalities with a nonprogressive neurologic course. Hepatosplenomegaly is often the presenting feature rather than the neurologic abnormalities. In well-documented and biochemically proven cases, there is marked variation in age of onset and severity of organ involvement.
Neurologic abnormalities. A neurologic hallmark of Gaucher disease type 3 (and type 2) is marked slowing of horizontal saccades, sometimes labeled saccade initiation failure or oculomotor apraxia (176; 18). Vertical saccades are also slow, but to a lesser extent, and this deficit lags the slowing of horizontal saccades. Other oculomotor abnormalities include decreased gain of smooth pursuit and of the vestibulo-ocular reflex (30).
Other neurologic manifestations may include various degrees of intellectual disability or dementia, ataxia, dystonia (especially nuchal and facial), and, more rarely, tonic-clonic or complex partial seizures, or progressive myoclonic epilepsy.
Patients who are otherwise stable medically and neurologically, and who are on long-term enzyme replacement therapy, may develop partial complex seizures of temporal lobe origin that should not be confused with progressive myoclonic encephalopathy (07; 134).
There is significant variation in neurologic pattern among different ethnicities; for example, an oppositional behavioral abnormality is seen in Egyptian patients with Gaucher disease type 3 (02). Egyptian patients may also be more susceptible to sudden unexpected death, often with epilepsy, which has otherwise been rarely observed among patients with Gaucher disease (01). Certain GBA1 mutations are associated with myoclonic encephalopathy (eg, N188S), whereas L444P/L444P rarely, if ever, is (134; 102).
A group of patients with a neurodegenerative course and cardiac valvular calcification and stenosis are homozygous for the mutation in the acid beta-glucocerebrosidase (GBA1) gene (p.Asp409His, now annotated as NM_000157.3: c.1342G > C; p.Asp448His) (37; 103). These cases have been classified as type 3c. The neurologic features occur at an older age but are no different than those of typical type 3 disease.
The neuronopathic phenotypes appear to be part of a continuum of disease severity, and some patients may have intermediate phenotypes between types 2 and 3 (20; 72). Other reported cases have novel features that may defy easy categorization (88; 103).
The Gaucher/Parkinson disease phenotype. GBA1 mutations are a strong genetic risk factor for synucleinopathies (Parkinson disease and Lewy body dementia) (144; 154). Patients with Gaucher disease and parkinsonism have typical Lewy bodies in hippocampal regions susceptible to Gaucher-related neurodegeneration (191).
A large international collaborative study of 16 centers found significantly higher odds of 5.4 for any GBA1 mutation among 5691 patients with Parkinson disease compared with 4898 controls (154). Moreover, patients with a GBA1 mutation presented earlier with Parkinson disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Although the centers varied in their ability to detect GBA1 mutations, all 16 centers could detect two particular GBA mutations: L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients (n=780) and 3% of controls (n=387), whereas among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, demonstrating that limited mutation screening may identify less than half of the mutant alleles.
A prospective cohort study of patients with Gaucher disease and GBA1-mutation carriers found that, over a 2-year period, GBA-mutation-positive individuals show deterioration in clinical markers consistent with the prodrome of Parkinson disease (16).
Even patients with Gaucher disease type 1 (ie, chronic non-neuronopathic Gaucher disease) are at a higher risk of developing Parkinson disease (31).
Although loss of function of acid β-glucocerebrosidase caused by GBA1 mutations presumably contributes to the increased risk of synucleinopathies, the pathophysiological mechanism is not clear (66). Even in the absence of GBA1 mutations, patients with Parkinson disease have lower glucocerebrosidase activity in peripheral blood (06) and in the substantia nigra (70; 36), suggesting that loss of glucocerebrosidase function, whether due to genetic or nongenetic causes, contributes to the pathogenesis of Parkinson disease. Proposed mechanisms include (1) apoptosis induced by a bidirectional pathogenic loop between glucocerebrosidase deficiency and α-synuclein (116); and (2) endoplasmic reticulum stress in susceptible neurons caused by glucocerebrosidase deficiency (113). In addition, patients with Parkinson disease carry a significant burden of other rare lysosomal storage disorder gene variants, implying that multiple genetic hits may act in combination to degrade lysosomal function, thereby enhancing Parkinson disease susceptibility (142).
Prognosis and complications
Death in patients with Gaucher type 1 who have never received enzyme replacement therapy occurred at a median age of 66 years and was often caused by liver disease, septicemia, malignancies, and suicide (185).
So-called "Gaucher cells" are macrophages that become full of unprocessed glucocerebroside in patients with Gaucher disease. Gaucher cells accumulate primarily in the spleen, liver, and bone marrow, causing organ inflammation and dysfunction.
Visceral involvement.
The lymphoreticular system. Painless splenomegaly is usually the earliest sign in all types of Gaucher disease. Even when the spleen is not palpable by physical examination, it usually can be demonstrated to be enlarged by diagnostic imaging techniques. The rate of enlargement of the spleen is helpful in judging the rate of progression of the disease. The preferred modality for measuring organ volume is volumetric MRI (34). The rate of splenic enlargement is often consistent for each case. Changes in that rate have been associated with malignancy or other intercurrent disease. Spontaneous rupture of the spleen is uncommon. Most cases develop hypersplenism manifested by pancytopenia and a bleeding diathesis. Red cell and platelet survival time is shortened. Splenectomy should be limited to those patients having severe bleeding diathesis, high-output cardiac failure, or mechanical interference of bowel, diaphragm, or kidney. The spleen is enlarged and firm, with pathological findings of infarcts, fibrosis, and distortion of the splenic architecture. Splenic infarction can cause abdominal pain and should be considered in the differential diagnosis of an acute abdomen in patients with Gaucher disease. The red pulp of the spleen is replaced by white collections of Gaucher cells. The surface and body of the spleen may contain dark-purple nodules that are foci of extramedullary hematopoiesis. Splenectomy is almost always followed by correction of cardiac and hematologic abnormalities. However, splenectomy poses a risk for severe, overwhelming sepsis that can be fatal within a day. For these reasons enzyme replacement therapy is the treatment of choice.
In some patients, lymph nodes may be enlarged and contain Gaucher cells. The thymus, Peyer patches in the intestine, and the pharyngeal tonsils are frequently affected.
Liver. Despite the frequent occurrence of hepatomegaly and abnormal liver function tests in Gaucher disease, hepatic failure occurs infrequently. In contrast to other lipidoses (eg, Niemann-Pick disease), hepatocytes are not involved in storage. Gaucher cells are seen within the sinusoids. In the more severely affected cases with cirrhosis, fibrosis distorts the architecture, forming small regenerating nodules that are infiltrated by Gaucher cells. Marked portal hypertension and consequent complications (eg, ascites and esophageal varices) are common in severe disease. The enlarged liver may contain sites of extramedullary hematopoiesis. Recurrent bleeding from esophageal varices has been successfully treated with a combination of aggressive medical management and sclerotherapy. Jaundice is a serious adverse prognostic sign in this disease and represents either intercurrent infectious hepatitis or hepatic failure. In cases with liver involvement, early intervention with enzyme replacement therapy is indicated. Hepatic transplantation is required in patients with end-stage liver disease.
Skeletal manifestations. In patients with Gaucher types 1 and 3, skeletal abnormalities on x-ray occur in 50% to 75% of patients and include expansion of the cortex in the distal femur (Erlenmeyer flask deformity), fractures, and other abnormalities of the acetabulum and head and neck of the femur. Prosthetic hip replacement is often necessary for patients to remain ambulatory. In some cases, the hip lesions may be confused with Legg-Calve-Perthes disease. Destruction of vertebral bodies may produce collapse, gibbus formation, and spinal cord or nerve root dysfunction.
Bone pain and bone crises. Bone infarction causes so-called "bone crises." This process affects the femoral heads and distal femur more frequently than other bones. Episodes are usually self-limited and typically last approximately 2 weeks but may be protracted over many months. During the first days of crisis, patients may require hospitalization to control pain. Bed rest is always indicated until the episode is completely resolved. Typically, a region of osteosclerosis, bone deformity, or pathologic fracture develops. Although the infarcted region can become secondarily infected, producing osteomyelitis, bone crises should be treated conservatively unless infection is highly suspected. Instrumentation of infarcted bone should be avoided unless clearly indicated because instrumentation may cause secondary infection and development of a sinus tract. Gallium scans may be helpful in distinguishing infarction from osteomyelitis, whereas x-rays and technetium scans are usually not helpful.
Adequate calcium intake should be maintained. If urinary calcium is low, the diet should be fortified with calcium and vitamin D. In addition, the storage of glucocerebroside in tissue macrophages may alter the generation of competent osteoclasts and result in a failure to maintain a healthy bone matrix.
A rare occurrence in type 1 disease is the extraosseous extension of Gaucher cells to the surrounding soft tissues, a condition that may mimic a malignant process (137). Because the incidence of several malignancies, including lymphoproliferative disorders, is increased in Gaucher disease (152), a biopsy may be required for an accurate differential diagnosis.
The hypothesis that bone crises are the result of progressive vascular compromise produced directly by occlusion of vessels by Gaucher cells is not supported by scintigraphic or histologic studies. In fact, perfusion scans of bones are often enhanced. Vascular occlusion by Gaucher cells would not explain the combination of osteopenia, osteonecrosis, and osteosclerosis seen in the disorder. Other vascular complications, such as premature stroke, myocardial infarction, or renal failure, are not features of the disease, making a simple vascular occlusive process a less attractive explanation of the skeletal involvement. Metabolic and endocrinologic studies suggest an imbalance in calcium homeostasis; however, the entire skeleton is not affected uniformly. On the contrary, the lesions consist of collections of Gaucher cells scattered throughout the bone substance. Bone complications probably result from a toxic process around these foci, which then leads secondarily to edema, vascular compromise, and infarction. One study reported a correlation between the severity of type 1 disease and serum levels of macrophage derived cytokines. This correlation suggests that a cytokine imbalance may have a role in the pathophysiology of the bone lesions (83). From existing information, it is not likely that infarction is incited by vascular occlusion by Gaucher cells, but rather by the vascular compromise alluded to above.
Progressive kyphosis (sometimes with scoliosis) without any vertebral body abnormality is commonly observed in patients with Gaucher type 3. It is very rarely seen in patients with Gaucher type 1. Correction and stabilization of the kyphosis is required, and Harrington rods are often placed towards the end of the growth period (late adolescence). The mechanism of this phenomenon is unknown, but studies in a zebrafish model suggest a developmental abnormality of bone (199).
Growth retardation and delay in skeletal maturation occurs in children but is normalized by enzyme replacement therapy (95).
Other organic systems. In the kidney, Gaucher cells can be found in the cortex, medulla, or glomeruli. Renal function in Gaucher patients is usually normal. In a few cases, proteinuria or hematuria has been reported. The cause of these signs is uncertain, but they have been attributed to the infiltration of Gaucher cells.
Focal collections of Gaucher cells are found within Peyer patches and the lamina propria of the gastrointestinal tract. Patients may complain of bloating, cramps, and diarrhea. Abnormal uptake of calcium may be one of several factors affecting bone in the disorder.
The cherry-red spot that appears in the macula in some sphingolipidoses and mucolipidoses does not occur in Gaucher disease; however, white patches containing Gaucher cells have been seen in the vitreous and retina of some Gaucher type 3 patients, and they can develop while the patient is on enzyme replacement therapy (146). A case has been reported in which loss of vision due to uveitis in type 1 disease could be reversed by enzyme replacement therapy (21). There have been many reports suggesting that patients with Gaucher disease are at increased risk of developing malignancies, particularly hematopoietic tumors. A large study of 1525 patients found 2- to 3-fold risks of non-Hodgkin lymphoma, malignant melanoma, and pancreatic cancer in patients with Gaucher disease but no significant association between Gaucher disease and cancer in general or with other specific malignancies, such as multiple myeloma (104).
Because of the different clinical courses of patients with Gaucher disease, researchers have tried to develop a laboratory test that would both discriminate subtype and be useful in determining prognosis. Genotype analysis gives some guidance in this area but is not completely satisfactory. Most individuals with even one p.Asn409Ser allele do not have neurologic involvement, whereas almost all patients with the p.Leu483Pro allele have neurologic involvement. Differences in epidermal cells may provide a means to differentiate type 2 neuronopathic Gaucher disease from types 1 and 3 Gaucher disease (62; 153). Disorganized lamellar membranes in the epidermal stratum corneum are present in type 2 patients but not in type 3 patients (85; 33).
Garvey and colleagues observed that the amplitude of stretch-evoked somatosensory evoked potentials in patients with type 3 Gaucher disease positively correlated with the degree of cognitive deficit and, therefore, with neurologic disease burden (67). It is possible that measurement of somatosensory evoked potentials may be useful to monitor the response of future therapies aimed at correcting the neuropathology of Gaucher disease.
Clinical vignette
Case 1. A 5-year-old girl experienced a bladder infection that became obvious when she suddenly began to have toileting accidents. The infection was treated with sulfa drugs and cleared up initially but reoccurred 6 months later. Primary care evaluation disclosed splenomegaly and a low platelet count. She was diagnosed with a platelet disorder and treated with prednisone. Several days into the steroid treatment, her platelet count was found to be very low, and a bone marrow biopsy was performed. The biopsy showed Gaucher cells. Follow-up testing showed enzyme assay of 2 (NR 12-17) and genotype p.Asn409Ser/p.Leu483Pro.
Follow-up and discussion. The p.Asn409Ser mutation is only associated with type 1 Gaucher disease. When p.Asn409Ser occurs with a second different mutation like p.Leu483Pro, the disease sometimes presents earlier in life. This patient had two brothers, and because neither of them had symptoms of Gaucher disease, they did not have genetic testing. When a genetic condition, such as Gaucher disease, is known in a family, the brothers and sisters of a person with the condition are at higher risk for having the same condition and for being carriers. For this reason, it is important for parents to educate all of the children in an affected family about the condition. Many parents want and need help with this process. Genetic counseling is recommended for each family member when he or she becomes an adult (or before if indicated).
Case 2. At 4 months of age, the parents of an infant boy noted "something not quite right with his eye movement" and mentioned this to their pediatrician at his 6-month well baby visit. At this visit, the pediatrician noticed splenomegaly and heard a report from the parents that the boy had a choking episode during which he became cyanotic and was taken to the ER. Developmentally, the infant was meeting expected milestones and at 6 months was sitting, reaching for and grasping objects, and responding to his name. The pediatrician ordered a panel of metabolic tests including acid beta-glucocerebrosidase.
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Physical examination | |
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• Liver approximately two times normal size | |
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Laboratory findings | |
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• Platelet count 125,000 | |
Follow-up and discussion. The boy was treated with enzyme replacement therapy at a dose of 120 U/kg every 2 weeks. He did well for several months; he was walking well and saying a few words. Eventually, he failed to progress and began having more frequent choking episodes. He died during the night at age 22 months.
Case 3. A 20-month-old Caucasian boy presented with the following history: at his 12-month well-child checkup, the pediatrician noted hepatosplenomegaly. The hepatosplenomegaly was unchanged on follow-up at 15 months. At 18 months he was seen because of irritability and fever that had persisted for approximately 1 month. At that time, increased hepatosplenomegaly and cervical lymphadenopathy were noted. He was admitted to the hospital, at which time he also had hoarseness and diarrhea. He was evaluated for possible malignancy with results that included the following: chest x-ray, normal; abdominal x-ray, hepatosplenomegally; fragmented right femoral epiphysis; cervical lymph node biopsy, normal; bone marrow aspirate, Gaucher cells.
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Physical examination | |
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• 85 cm, 10.5 kg | |
Follow-up and discussion. Over the next few months, it became apparent from examination and parents’ observations that he had horizontal supranuclear gaze palsy with compensatory head thrusting. Treatment with enzyme replacement therapy was initiated at a dose of 60 U/kg every 2 weeks. Years later at age 11 years, he had no progression of the slow looping saccadic eye movements and no organomegaly or obvious bone disease; he played baseball and football, was an A and B student, and had the lead in the school play during the previous academic year.
Case 4. A girl was born to unrelated, healthy parents after an uneventful pregnancy and delivery (81). Bilateral esotropia was noted in early infancy, and she was referred to an ophthalmologist at her 4-month check-up. Recurrent dysphagia and cyanosis started at 11 months of age. Hypotonia, growth arrest, and psychomotor retardation were recognized by 12 months of age. At 15 months of age, she was evaluated for acutely worsening stridor and cyanosis. Bronchoscopic examination revealed laryngeal spasms, which required endotracheal intubation. She had bilateral ptosis, esotropia, and marked hepatosplenomegaly; liver and spleen were palpable 5 cm below the costal margins. Blood gas analysis excluded metabolic acidosis. Blood tests showed thrombocytopenia (103 × 109/L) and marginally elevated aspartate transaminase. NH3, alanine aminotransferase, and creatine kinase levels were unremarkable. Serum angiotensin-I converting enzyme and acid phosphatase levels were increased to 76.2I U/L (reference range 8.3–21.4) and 7150 (reference range 120–420), respectively. Echocardiography showed no abnormality. Bone marrow aspiration identified Gaucher cells. Within a few days after admission, opisthotonic postures occurred repeatedly, with or without sensory stimulation. Serial cranial MRIs found no degenerative brain lesions. Genetic testing identified compound heterozygous pathogenic variants p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1.
Infusion of imiglucerase (60 units/kg every other week) and oral administration of ambroxol (3 mg/kg/day) was started from day 20 after admission. The dose of ambroxol was increased by 3 mg/kg every 2 to 4 weeks to reach the target doses (30 mg/kg/day) (126).
After starting imiglucerase and ambroxol therapy, she began to roll over in 1 week and to sit unaided in 2 weeks. Over this interval, spasticity and opisthotonus disappeared. Platelet counts increased to 150-200 × 109/L within 2 months of starting treatment. Because of prolonged dysphagia and laryngospasm, tracheosatomy was performed on hospitalization day 9. Given her chronic dyspepsia, the imiglucerase dose was increased to 80 units/kg every other week from 19 months of age. She then underwent laryngotracheal separation to control recurrent airway infections at 27 months of age and esophageal hiatal hernia repair at 3.5 years of age.
Serial monitoring of molecular markers supported the efficacy of treatment: (1) increased angiotensin-I converting enzyme levels declined from 76.2 U/L on admission to 50.5 U/L in 1 month and to 20.5 U/L at 2.5 years of age; (2) tartrate-resistant acid phosphatase 5b (TRACP-5b) was initially as high as 7150 mU/dL (reference range 120–420) but declined to 1770 mU/dL during treatment; and (3) serum glucosylsphingosine (Lyso-Gb1) declined from 721 ng/mL at the beginning of treatment to 130 ng/mL after 5 months of treatment.
At 3.75 years of age, she was walking independently, and her cognitive function had reached a developmental age of 12 to 16 months. Her health-related quality of life score markedly improved from before treatment to 2 years after starting ambroxol therapy.
Biological basis
Etiology and pathogenesis
Gaucher disease in the spectrum of glycosphingolipid diseases. Glycosphingolipids are composed of a sphingosine, a fatty acid chain (these two forming a ceramide) and a carbohydrate moiety (17).
The fatty acid attached to the sphingosine may vary in chain length, degree of unsaturation, or hydroxylation (17). Glycosphingolipids include ceramide, cerebrosides (galactosylceramide and glucosylceramide), lactosylceramides, and gangliosides.
The biosynthetic and degradation pathways of glycosphingolipids in the brain are complex and incorporate metabolic loci for Fabry disease, metachromatic leukodystrophy, Krabbe disease, Gaucher disease, Sandhoff disease, Sialidosis, Tay Sachs disease/Sandhoff disease/GM2 gangliosidosis AB variant, and GM1 gangliosidosis.
Biosynthetic and degradation pathways of glycosphingolipids in the brain
This diagram shows the metabolic loci for Fabry disease, metachromatic leukodystrophy, Krabbe disease, Gaucher disease, Sandhoff disease, Sialidosis, Tay Sachs disease/Sandhoff disease/GM2 gangliosidosis AB variant, and GM1 gan...
Glucosylceramides and galactosylceramides are hydrolyzed respectively by glucocerebrosidase (also named glucosylceramidase; the GBA gene encoding lysosomal glucocerebrosidase is associated with Gaucher disease) and galactosylceramidase (encoded by the GALC gene; that deficiency causes Krabbe disease) to regenerate ceramides.
Ceramides are further deacetylated to sphingosines that can be broken down or recycled for sphingolipid synthesis by the salvage pathway.
Genetics of Gaucher disease. Gaucher disease is a lysosomal storage disease that is transmitted as an autosomal recessive trait.
Pedigree for family DEM4599 with Gaucher disease segregating as an autosomal recessive trait
Circles represent females and squares males. Filled symbols indicate affected family members and clear symbols unaffected members. Double lines in the pedigree represent a consanguineous marriage. Asterisks indicate individuals...
Gaucher disease results from homozygous or compound heterozygous mutations in the gene encoding acid beta-glucosidase (GBA; OMIM 606463) on chromosome 1q22.
The wide spectrum of clinical severity in patients with Gaucher disease, particularly in Gaucher type 3 patients, is often explained by the presence of genetic modifiers. An interesting effort used animal models to identify such genes (100). The authors identify a number of variants that modify the lifespan of the affected mouse. The most interesting was Grin2b, which codes for NR2B subunit of the N-methyl-D-aspartate receptor. Pharmacological blocking of the N-methyl-D-aspartate receptor using memantine led to a significant prolongation of the Gaucher mouse model (100). Effort to identify genetic modifiers in patients with Gaucher type 3 is underway.
The precise genetic and biochemical reasons for the manifestations of the disease and the phenotypic differences among patients are not completely understood. There is little doubt that additional genetic modifiers of Gaucher disease cause marked differences in the presentation of signs and symptoms related to bone marrow, liver, spleen, lung, bone, brain, and other systems involved in the disease (71).
Acid beta-glucocerebrosidase. In addition to the 5' and 3' untranslated regions, the cDNA of the GBA gene contains 1548 base pairs encoding human acid beta-glucocerebrosidase. The molecular weight of acid beta-glucocerebrosidase calculated from the 536 amino acids deduced from the cDNA sequence is 59,716, which is in good agreement with that estimated by SDS-polyacrylamide of the product of in vitro translation of human placental mRNA (57; 56). Five potential glycosylation sites (Asp-X-Ser/Thr) were identified. Quantitative carbohydrate analysis indicates that only four are glycosylated (166). This has been confirmed by direct analysis of the amino acid sequence (B Martin, unpublished data). In addition to the amino acid sequence of the structural protein, the reading frame of the cDNA codes for 39 additional amino acids upstream of the amino terminus. This signal polypeptide contains a hydrophobic core, consisting of Gly-Leu-Leu-Leu-Leu and, in addition, has glycine at the peptidase cleavage site. These features are consistent with the properties of signal peptides of other translocated proteins. Furthermore, the cDNA sequence confirms the presence of a 2-kd signal sequence identified by pulse-labeling studies. More than 300 mutations of the GBA gene have been described as a cause of Gaucher disease, including missense or nonsense mutations as well as splice mutations, deletions, and complex gene rearrangements.
Biochemical abnormalities in Gaucher disease.
Metabolic block and storage substance. With all lysosomal storage diseases, an enzyme deficiency results in the accumulation of its substrate in the lysosome. In particular, Gaucher disease is caused by a deficiency of glucocerebrosidase (GCase; or β-glucosidase). β-Glucocerebrosidase, a member of the glycoside hydrolase family 30, has three distinct domains (I-III) (108).
Domain I forms a three-stranded anti-parallel β-sheet; this domain contains two disulfide bridges that are necessary for correct folding, and a glycosylated residue (Asn19) that is required for catalytic activity in vivo. Domain II consists of two β-sheets that resemble an immunoglobulin fold. Domain III is homologous to a TIM barrel (triose-phosphate isomerase barrel, or alpha/beta barrel), a highly conserved domain among glycoside hydrolases, consisting of 8 α-helices and 8 parallel β-strands that alternate along the peptide backbone.
Domain III harbors the active site, which binds the substrate glucocerebroside in proximity to the catalytic residues E340 and E235.
Glucocerebrosidase, which is activated by saposin C, is responsible for the lysosomal degradation of glucosylceramide (Glc-Cer; also called glucocerebroside) (60). Glucocerebrosidase maturation occurs in the Golgi apparatus from which it is delivered to lysosomes with the assistance of lysosomal integral membrane protein-2 (LIMP-2) molecule.
The deficiency of glucocerebrosidase in Gaucher disease leads to accumulation of glucosylceramide, as well as glucosylsphingosine (lyso-Gb1) (160; 03; 141). The accumulation of glucosylceramide causes formation of fibrillar aggregates in macrophages, giving the cytoplasm the appearance of “crumpled tissue paper” (60). Such dysfunctional "Gaucher cells" infiltrate various organs (eg, bone marrow, spleen, and liver).
In glucocerebrosidase deficiency, glucosylceramide can also be metabolized by an alternative metabolic pathway involving acid ceramidase, resulting in the formation of glucosylsphingosine, which is less hydrophobic (60). Glucosylsphingosine is metabolized by a cytoplasmic enzyme, the so-called "second glucocerebrosidase," which is encoded by the GBA2 gene and functions at neutral pH. This second glucocerebrosidase converts glucosylsphingosine into sphingosine, which is then phosphorylated, producing sphingosine-1-phosphate. Accumulation of glucosylsphingosine can cause neuronal dysfunction and death, whereas high levels of sphingosine can be toxic to bone. Glucosylsphingosine is absent in the brains of healthy individuals but can be detected in the brains of patients with Gaucher disease-related neurologic lesions. Glucosylsphingosine is markedly increased in neuronopathic Gaucher disease, especially Gaucher disease type 2.
Saposin C, the activator of glucocerebrosidase, is derived from the cleavage of prosaposin–precursor protein into four homologous proteins (saposins A-D) (60). These mature saposins support the activity of lysosomal hydrolases in sphingolipid degradation. Saposin C mutations can produce biochemical phenotypes mimicking Gaucher disease.
Glucosylsphingosine concentrations are markedly elevated in the brains of type 2 and 3 Gaucher disease patients, and to a lesser extent in patients with Gaucher disease type 1 (127; 133; 48).
Glucocerebroside is a compound of ceramide and glucose. The glucose moiety is esterified to the C-1 of ceramide in a beta-glucosidic linkage. The compound is similar in structure and properties to the group of sugar-containing lipids isolated from the brain by Thudichum (169; 170).
Cerebrosides are composed of ceramide esterified to a variety of different substituents at C-1. This carbon may participate in reactions with phosphorylcholine to produce the sphingomyelins, an unsubstituted monosaccharide or oligosaccharide to produce the neutral glycosphingolipids, or an oligosaccharide containing one to four molecules of sialic acid to produce the gangliosides. The common unit among these compounds is ceramide. Ceramide is derived from a long-chain base named sphingosine (D(+)-erythro-1,3-dihydroxy-2-amino-4-transoctadecene, or C18 sphingosine). This lipid is joined by an amide bond at C-2 to a long-chain fatty acid to form ceramide. The fatty acid chain length varies. In general, the neutral glycosphingolipids and sphingomyelins contain C20 and C24 fatty acids, whereas the gangliosides contain C18 fatty acids. It is from sphingosine that the group of disorders of lipid catabolism obtains its name (ie, sphingolipidoses) because the accumulating lipid compounds are derived from it.
Glucocerebroside is at the end of the glycosphingolipid catabolic pathway. The higher glycosphingolipids and gangliosides are degraded in a stepwise fashion by specific acid hydrolases, resulting in the formation of glucocerebroside, which is normally degraded to ceramide and glucose by acid beta-glucocerebrosidase. The compounds that contribute to the pool of glucocerebroside in peripheral organs are globoside, globotriose, and lactosylceramide. These are derived from the degradation of membranes, the major source of which is white blood cells (96).
The glucocerebroside found in spleen, liver, kidney, plasma, and red cells contains fatty acids with chain length of approximately C22 to C24 (61). The glucocerebroside in the brains of patients with type 2 disease is composed primarily of C18 (stearic acid) (163; 128). This conclusion has been confirmed and extended to type 3 cases (127; 39). These data have been interpreted to mean that the glucocerebroside accumulating in brain derives from gangliosides within the brain itself. This is consistent with the known fatty acid content of gangliosides. Some of the glucocerebroside, in certain type 3 cases, may be derived from sources outside the central nervous system. This may have important consequences because levels of plasma and tissue glucocerebroside increase following splenectomy in Norrbottnian cases (ie, a neuronopathic form of Gaucher disease that is relatively prevalent in Norrbotten, Sweden caused by a single mutation in exon 10 of the glucocerebrosidase gene) (128; 44; 150; 172).
Although the level of plasma glucocerebroside has been shown to increase following splenectomy in some Norrbottnian cases, this has not been reported in cases of other subtypes of the disease.
Glucosylceramide forms fibrillar aggregates that accumulate in macrophages forming so-called Gaucher cells that have a characteristic "crumpled tissue paper" appearance (23; 160). Gaucher cells result from the transformation of macrophage cells and correspond to a distinct "M2" subpopulation from an alternative differentiation pathway. The M2 subpopulation has anti-inflammatory, immunomodulatory, and tissue repair properties (160).
Alternative pathway. As was identified in a mouse model of glucocerebrosidase deficiency, glucosylceramide is also the substrate of an alternative pathway, which is favored in cases of glucocerebrosidase deficiency (ie, Gaucher disease) (121; 160).
Alternative metabolic pathway of glucosylceramide (GlcCer) accumulation due to glucocerebrosidase (GCase) deficiency (1)
The expression of GCase varies from one cell type to another and depends on the tissue. In a mouse model of GCase deficiency (red cross), GlcCer is transformed via an alternative ceramidase pathway into glucosylsphingosine (red...
In the alternate pathway, a ceramidase transforms glucosylceramide into glucosylsphingosine (or lyso-glucosylceramide), which then diffuses into fluids due to its reduced hydrophobicity. The enzymatic deficit of glucocerebrosidase is multifactorial, resulting from intrinsic enzymatic dysfunction as well as abnormalities during transport and delivery of the enzyme to the lysosomes. In particular, enzyme misfolding during passage through the endoplasmic reticulum can lead to premature degradation by the proteasome (145; 193; 160).
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Alternative metabolic pathway of glucosylceramide (GlcCer) accumulation due to glucocerebrosidase (GCase) deficiency (2)
Protein maturation takes place in the Golgi apparatus; the transport and delivery of GCase to lysosomes require a particular molecule, LIMP-2, which allows GCase to reach the lysosome where the acidic pH breaks the molecular li...
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Alternative metabolic pathway of glucosylceramide (GlcCer) accumulation due to glucocerebrosidase (GCase) deficiency (3)
LIMP-2 is a lysosomal membrane protein (LMP) whose highly glycosylated intra-lysosomal part protects the lysosome’s membrane. LIMP-2 anomalies can induce a phenotype rather than GD3 (Gonzalez A, Valeiras M, Sidransky E, Tayebi ...
Other biochemical abnormalities in Gaucher disease. Levels of acid phosphatase, angiotensin-converting enzyme, lysosomal hydrolases, lysozyme, and immunoglobulins are elevated in the plasma of patients with Gaucher disease (173; 130; 109; 182; 156; 122; 87; 143). Chitotriosidase is a particularly sensitive indicator of macrophage storage in patients with Gaucher disease (84).
The severity of neurologic symptoms is associated with glycoprotein nonmetastatic B levels (200). The same was found in a mouse model of Gaucher disease. GPNMB may prove to be a useful marker to quantify neuropathology in patients with Gaucher disease and treatment efficacy in future treatment trials (200).
Organ involvement in Gaucher disease.
Clotting cascade. Because of liver involvement, patients may have prolonged partial thromboplastin, prothrombin, and bleeding times. In addition, increased amounts of plasma glucocerebroside may interfere with the clotting cascade (22).
Reticuloendothelial system. A study of the gene expression profile in Gaucher disease showed enhanced expression of genes associated with inflammatory reactions in the affected spleen (124). In particular, the transcript abundance of the cDNAs representing cysteine proteinases (cathepsins B, K, and S) was greatly increased. These proteins are known to participate in tissue modeling, antigen presentation, and in the case of cathepsin K, bone matrix destruction. Glycolipid storage in the cells of the reticuloendothelial tissue may induce an inflammatory response characterized by the recruitment of proinflammatory cytokines and other cells of the immune system. In turn, extensive tissue damage would ensue, particularly in the liver, spleen, and bones.
Brain involvement in Gaucher disease type 1. Patients with Gaucher disease type 1 do not have clinical symptoms or signs referable to the nervous system. In this group, anatomic and biochemical examinations of the brain have been infrequent. Hippocampal gliosis has been found in brains of otherwise neurologically normal patients with Gaucher disease type 1 (191).
Pathologic features of neuronopathic phenotypes. In Gaucher disease types 1, 2, and 3, perivascular Gaucher cells have been observed within the Virchow-Robin spaces (46; 191).
In type 2 patients' brains, free Gaucher cells have been demonstrated within the parenchyma accompanied by gliosis and microglial nodules. These changes are present but much less frequently in type 3 patients' brains. Neuronal storage of lipid has been suggested in several reports, but this has not been confirmed ultrastructurally in any case of Gaucher disease. In type 2 disease, neuronophagia and neuronal cell death in the deeper layers of the cortex, thalamus, basal ganglia, brainstem nuclei, cerebellum, and spinal cord have been reported. Variable degrees of demyelination have been described in brains of type 2 patients. From the available information, one would have to conclude that the accumulation of acid beta-glucocerebrosidase in the brain produces dysfunction in surrounding cells long before discrete pathologic changes are seen (97). Extensive study of 14 brains from type 1 (including patients with parkinsonism), 2, and 3 Gaucher disease showed common neuropathologic findings in all forms of Gaucher disease (191). Unique patterns of gliosis and neuronal loss involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. Although these findings were common to all three Gaucher disease phenotypes, the extent of the changes varied depending on the severity of disease (191). Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all Gaucher disease patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as having type 1 Gaucher disease had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated acid beta-glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal 45Ca(2+) uptake autoradiography in rat brain was performed, demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium-release-sensitive (CICR-sensitive). These findings match biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity (136). In two patients with type 1 Gaucher disease and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found in hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant acid beta-glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in Gaucher disease (191). Progression of the neuropathology is very predictable in the mouse model including microglial activation and astrogliosis were spatially and temporally correlated with selective neuron loss (59). Glucocerebroside accumulates to a similar extent in most brain areas, and upon reaching a certain threshold of accumulation inflammation and neurodegeneration is initiated in susceptible brain areas (58). The same group found that receptor interacting protein (RIP) kinases-mediated necrosis plays a major role in inducing inflammation and neuronal death in neuronopathic Gaucher disease (178). Ripk3 deficiency (double knockout mice) dramatically improved the clinical course of Gaucher disease mice with increased survival and motor coordination. Therefore, Ripk3 is a new therapeutic target for neuronopathic Gaucher disease (178). Using the mouse model for the most severe form of neuronopathic Gaucher, it was shown that altered lysosomal localization and cytoskeleton disruption precede the neuroinflammatory pathways, axonal dystrophy, and neuronal loss previously characterized in neuronal forms of Gaucher disease (201).
Glucosylsphingosine has been implicated in toxic damage to neural cells. This molecule has been shown to accumulate in the cerebral and cerebellar cortex of patients with type 2 and 3 Gaucher disease (127; 127; 128) and in Gaucher mice. The highest levels of this metabolite were found in brain tissue from two fetuses with hydrops fetalis (133). Studies have found markedly elevated levels in type 1, type 2, and type 3 disease (49). Glycosphingolipids, including glucosylsphingosine, inhibit protein kinase C, mitochondrial cytochrome c oxidase, and CTP:phosphocholine cytidylyltransferase, which has been postulated to interfere with signal transduction and cellular differentiation (78).
Studies on the pathogenesis of neuropathic Gaucher disease suggest that defective calcium homeostasis is a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease (136). Agonist-induced calcium release via the ryanodine receptor was significantly enhanced in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) compared to the subacute (type 3) and the non-neuronopathic (type 1) forms and controls and correlated with levels of GlcCer accumulation (136). The precise mechanism by which glucocerebroside enhances calcium release via the ryanodine receptor is not known, but these findings suggest the use of certain calcium channel blockers in neuronopathic Gaucher disease. Altered expression and distribution of cathepsins in the brain of the neuronopathic Gaucher mouse suggests that inflammation plays a role in the disease and, therefore, may be a target for therapeutic intervention (177). Elevation of GBA2, a nonlysosomal glucocerebrosidase, may play a role in the disease (32).
Relationship between glucocerebrosidase and synucleinopathies. Normally, glucocerebrosidase interacts with its substrate glucosylceramide as well as monomers of α-synuclein in lysosomes, facilitating the breakdown of both at acidic pH (160).
Relationship between glucocerebrosidase (GCase) and neurologic diseases with Lewy bodies (1)
Normally, GCase interacts with its substrate glucosylceramiide (GlcCer) as well as monomers of alpha-synuclein in lysosomes, facilitating the breakdown of both at acidic pH. (Source: Stirnemann J, Belmatoug N, Camou F, et al. A...
A decrease in the activity of glucocerebrosidase (eg, due to mutations) causes a gradual buildup of glucosylceramide and also causes a slowdown of α-synuclein degradation with the resulting formation of α-synuclein oligomers and fibrils (42; 194; 125).
Relationship between glucocerebrosidase (GCase) and neurologic diseases with Lewy bodies (2)
Mutated GCase or decreased levels of GCase cause a slowdown of alpha-synuclein degradation with the resulting formation of alpha-synuclein oligomers and fibrils (Cullen et al 2011; Yap et al 2011; Murphy et al 2014). Glucosylce...
Glucosylceramide stabilizes the α-synuclein oligomers (116), which are able to bind to the mutated glucocerebrosidase molecules and inhibit the enzymatic activity of glucocerebrosidase, further decreasing enzyme activity (116; 197; 196). These impaired lysosomes show impaired chaperone-mediated autophagy and autophagosome fusion. This results in an increased accumulation of α-synuclein in the cytoplasm, forming insoluble aggregates that ultimately form Lewy bodies. These aggregates block trafficking of glucocerebrosidase from the endoplasmic reticulum (ER) to the Golgi (155). Mutant glucocerebrosidase is retained in the endoplasmic reticulum (ER), which causes ER stress and evokes the ER stress response ("unfolded protein response") (86). Saposin C can have a modulating effect on this by binding to glucocerebrosidase (195; 75).
Mouse models of Gaucher disease. The transgenic acid beta-glucocerebrosidase-deficient mouse model obtained by targeted knockout of the acid beta-glucocerebrosidase gene exhibits a severe phenotype with prenatal or perinatal death (174). A number of other mouse models were of limited use and did not represent a genuine model for the neuronopathic form of the disease (192). Two true models of the acute neuronopathic form of Gaucher disease were produced. One of the models had normal enzyme activity in hematopoietic cells but no enzyme activity in neuronal and astrocytic cells. There was no significant mitigation of the neuronal disease in this model, confirming the observation in patients that bone marrow transplantation is not effective in neuronopathic Gaucher disease (54).
Epidemiology
All types of Gaucher disease are inherited as an autosomal recessive trait. The collective subtypes of Gaucher disease constitute one of the most prevalent forms of the sphingolipidoses and the most common lysosomal storage disorder. Gaucher disease type 1, the non-neuronopathic form, occurs with an incidence of about 1 in 40,000 to 60,000 in the general population and 1 in 500 to 1000 among Ashkenazi Jews. Patients with Gaucher type 3 disease (chronic neuronopathic Gaucher disease) constitute about 5% of the population of Gaucher patients in the United States and in Europe, with an estimated incidence of about 1 out of 100,000. However, reports suggest the neuronopathic form of Gaucher disease predominates in countries like China, Japan, Korea, Taiwan, Egypt, and Syria (180; 38; 165; 93; 51; 05; 74). The reason is that the N370S mutation is common in European countries but almost absent in Northern Africa and Asia, whereas the L444P mutation is particularly common in the East (180; 38; 165; 93; 51; 05; 74).
Prevention
Although it is more frequent among Eastern European Jews, Gaucher disease type 1 is usually less severe in this group. It is more severe among blacks. This generalization is helpful in counseling, but there are exceptions. Therefore, it is important to know the types of complications of the disease that have occurred in a family. In general, the severity of the disorder tends to be similar among siblings. A single exceptional family has been reported in which one type 1 and one type 2 case occurred in full siblings.
Implications for genetic counseling. Testing and genetic counseling of immediate family members of affected patients are recommended. The differences in clinical subtypes and variability of some forms of the disease should be pointed out. Because of the high carrier frequency among the Ashkenazi, wide-scale carrier testing has been suggested. Because the disease among this group is not uniformly catastrophic (in fact, many cases do not come to medical attention until late in life), this kind of testing, if desired, should be done within a system providing careful counseling that includes adequate information about the disorder and an explanation of the limitations of carrier detection. More than 300 mutations have been described in the GBA1 gene, four account for the majority of the nucleotide alterations. In the Ashkenazi Jewish population, the p.Asn409Ser mutant allele accounts for about 75% of the abnormal genes (74). In this ethnic group, four alleles (p.Asn409Ser [formerly described as Asn370Ser], c.84insG [formerly described as 84GG], p.Leu483Pro [formerly described as Leu444Pro], and IVS2+1G> A) account for more than 95% of the chromosomes, thus, permitting population screening (12). In the general population, many "private" alleles or mutations confined to a single kindred are found. Testing for the four mutations listed above results in identification of fewer than 50% of the cases. Thus, except for the Eastern European Jewish group, population screening is not appropriate for this disease with currently available technology.
Prenatal diagnosis. Affected fetuses with any form of Gaucher disease can be diagnosed prenatally by enzymatic assay of cultured amniocytes or chorionic villi. This is particularly important in families in whom the neuronopathic subtypes have occurred. Because of the difficulty of the assay for carriers (45) and the lack of appropriate control data, prenatal carrier detection is unreliable by enzyme assay. However, molecular genetic methods permit this identification without difficulty in families where the mutations are known.
Differential diagnosis
Confusing conditions
Other childhood diseases with signs and symptoms overlapping with Gaucher disease include the following (187):
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• Cancers, particularly lymphoproliferative malignancies | |
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• Hematologic disorders (eg, idiopathic thrombocytopenia, von Willebrand disease) | |
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• Sarcoidosis | |
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• Legg-Calvé-Perthes disease | |
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• Metabolic bone disease (eg, rickets, vitamin C deficiency, copper deficiency sickle cell disease, Paget disease) | |
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• Bacterial osteomyelitis | |
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• Other lysosomal storage diseases (eg, GM1 gangliosidosis, lysosomal acid lipase deficiency, and Niemann-Pick disease types A and C). |
Painless splenomegaly is the most common initial presenting sign in Gaucher disease type 1. Lymphoproliferative malignancies are the chief concern in the diagnostic evaluation of patients presenting in this manner. The results of bone marrow biopsies may suggest the presence of Gaucher cells; however, the diagnosis should be made by enzymatic assay of acid beta-glucocerebrosidase in leukocytes or fibroblast cultures. If a patient is Jewish, Gaucher disease should be considered and an enzyme assay performed. Results can usually be obtained within several days. A disease virtually identical to Gaucher can rarely be caused by a deficiency in saposin c, the protein that activates glucocerebrosidase (175; 94). In this case, glucocerebrosidase activity is normal but the patient has clinical features resembling Gaucher disease. In infants with hepatosplenomegaly and a neurodegenerative course, Niemann-Pick disease type A and GM1 gangliosidosis are sometimes similar in presentation but usually can be distinguished by clinical presentation.
Diagnostic workup
The diagnosis of Gaucher disease should be considered in any case of unexplained splenomegaly with or without a bleeding diathesis or other manifestations of the disease in the skeleton or liver. The disorder should be considered likely in any infant with hepatosplenomegaly and a neurodegenerative course. Elevation of tartrate-resistant acid phosphatase in serum is suggestive of the disease. Demonstration of characteristic Gaucher cells in bone marrow biopsies narrows the diagnostic possibilities. The definitive diagnosis is made by assay of acid beta-glucocerebrosidase in leukocytes, fibroblasts, chorionic villi, or urine.
A diagnostic algorithm has been proposed for pediatric patients without a family history of Gaucher disease (99; 187).
Proposed diagnostic algorithm for pediatric patients without a family history of Gaucher disease
(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Adapted from: Kishnani PS, Al-Hertani W,...
In a cross-sectional study of 44 patients, dry blood spot samples were used to assess levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1) for Gaucher disease diagnosis (49). Of 444 screened subjects, 99 (22%) were diagnosed with Gaucher disease at a median age of 21 years (range 1 to 78). Lyso-Gb levels for genetically confirmed patients with Gaucher disease (median 252 ng/mL [range 9 to 1340]) were markedly higher than for patients without Gaucher disease (median 5.4 ng/mL [range 1.5 to 16]). Patients diagnosed with Gaucher disease type 1 and mild GBA1 variants had significantly lower lyso-Gb1 levels (median 194 ng/mL [range 9 to 1050]) compared to Gaucher disease type 1 and severe GBA1 variants (median 447 ng/mL [range 38 to 1340]), and neuronopathic Gaucher disease (median 325 ng/mL [range 116 to 1270]).
Subjects with heterozygous GBA1 variants (carrier) had significantly higher lyso-Gb1 levels (5.8 ng/mL [2.5 to 15.3]) compared to wild-type GBA1 (4.9 ng/mL [1.5 to 16]). Based on these results, the authors called for a change in the diagnostic approach to Gaucher disease, based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in dry blood spot samples (49).
After a diagnosis of Gaucher disease has been established, the burden of the disease should be assessed. Evaluation of the characteristic features of the disease should include hematological, visceral, skeletal, and quality of life parameters, as suggested by the Gaucher Disease Registry.
Minimum assessment recommendations in children with Gaucher disease type 1 have been proposed (95; 187).
Minimum recommendations for assessments in children with Gaucher disease type 1 (GD1)
(a) MRI should include sagittal T1-weighted scan of the spine and T1-weighted scan of the head of the femur. (b) DXA should include spine and total body Z-scores, which require comparison with age- and gender-specific norms. (c...
Additional recommended tests for children with Gaucher disease type 3 include neurologic examination, neuro-ophthalmological investigations, testing of hearing, brain imaging, electroencephalography, periodic pulmonary evaluation for interstitial lung disease, and neuropsychological evaluation. In addition, for those with Gaucher disease type 3c, characterized mainly by cardiovascular and neuro-ophthalmological findings (103), periodic chest x-ray, echocardiography, cardiac computed tomography, angiography, or coronary artery catheterization have been recommended (187), but with little detailed guidance of when and how such studies will be useful in impacting the course of the disease or quality of life.
Hematologic workup. Hemoglobin, platelet count, tartrate resistant acid phosphatase, angiotensin converting enzyme, and chitotriosidase should be measured when the diagnosis is established; follow up measurement is recommended every 3 months for patients on enzyme replacement therapy and at least every 12 months for patients who choose not to receive enzyme replacement therapy.
Visceral studies. Spleen and liver volume should also be assessed at the time of diagnosis. The recommended technique is volumetric CT scan or MRI. These tests are recommended every 12 months in patients receiving enzyme replacement therapy and every 24 months in those patients who achieve a stable state.
Enzymatic diagnosis. A variety of natural and artificial substrates provide accurate assays for homozygotes, but they all have the same limitations when used for heterozygote detection (189; 45). The best substrate employed for the assay is the 4-methylumbelliferyl-beta-D-glucopyranoside. Modifications and improvements in the original description of the assay involving the addition of taurocholate have made it useful as a diagnostic tool and equivalent to assays employing the natural substrate. The assay is easy to use, and the substrate is widely available, making it the method of choice for a diagnostic laboratory. Conduritol B-epoxide is a specific inhibitor of mammalian acid beta-glucocerebrosidase and permits confirmation of the enzyme deficiency in systems where nonspecific beta-glucosidase may be interfering. Leukocytes and fibroblasts may be prepared and shipped to laboratories for assay as whole cells or extracts. High throughput method for newborn screening has been developed (131).
From the time of the introduction of the assay of acid beta-glucocerebrosidase, it has been observed that the values of heterozygotes overlap those of control subjects for the activity of acid beta-glucocerebrosidase in leukocytes and leukocyte subpopulations. This subject has been reviewed extensively. A variety of methods have been developed, but all have the same problem in the detection of heterozygotes. In studies of known heterozygotes, approximately 20% of the carriers fall into the normal range. Fibroblasts have a higher specific activity of acid beta-glucocerebrosidase than leukocytes; however, a wide range of activity in control cells, which varies with time in culture and conditions, makes these cells no more useful in heterozygote detection. In those for whom the genotype is known, carrier detection by molecular methods is completely reliable.
Skeletal assessment. Computerized tomography, radionuclide scan, and magnetic resonance imaging have been useful in assessing the extent of bone abnormalities. The recommended method for routine assessment of bone disease is T1- and T2-weighted MRI of the entire femora (34).
Bone density should also be assessed in patients with Gaucher disease. DEXA studies are useful to determine and assess the risk of pathological fractures. Spine, femur, forearm, and whole-body densitometries can be performed in these patients. These studies should be performed at baseline and every 12 months in patients receiving enzyme replacement therapy.
Management
Gaucher disease type 1. Consensus management goals for Gaucher disease type 1 have been developed (171; 110)
Gaucher disease type 2. This severe form of Gaucher disease poses significant diagnostic, management and ethical challenges (188). None of the specific therapeutic approaches described above have been shown to be efficacious in patients with the most severe form of Gaucher disease. The overall management of patients with Gaucher disease type 2 is very difficult and has been reviewed (188).
Cell and organ transplantation. Splenic and renal transplantations have had little or no effect on the disease process in patients with Gaucher disease. Bone marrow transplantation has been reported in both Gaucher disease type 1 and type 3 patients. Rapid resolution of the enzyme deficiency in circulating white cells was achieved, indicating successful engraftment.
The indications for hematopoietic cell transplantation vary according to the subtype of Gaucher disease. In type 1 disease, allogeneic bone marrow transplantation leads to resolution of organomegaly within several months to 2 years. The bone disease is also ameliorated, with disappearance of Gaucher cells from the marrow, regression of bone lesions, improvement in linear growth, and disappearance of bone pain (164; 140; 82). Bone marrow transplantation may, therefore, be curative for type 1 disease, even though this therapeutic option is limited by donor availability and high short-term risks, which include a high percentage of procedure associated morbidity and mortality of about 15%. In type 2 and 3 disease, bone marrow transplantation has no effect on the neurologic disease and should be avoided (176).
Enzyme replacement. The ultimate development of enzyme replacement therapy was a fortunate intersection of scientific disciplines that provided key findings:
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• Discovery of receptors for glycoproteins (lectins) (09) |
The mannose moieties in the oligosaccharides are the key to successful enzyme replacement therapy. Mannose, rather than mannose-6-phosphate, binds to the mannose receptor on Kupffer cells. There are also mannose receptors on hepatocytes, although some of these are non-endocytic. Acid beta-glucocerebrosidase can, therefore, gain entry into both hepatocytes and Kupffer cells, but the delivery to Kupffer cells is much better for mannose-terminated (modified) acid beta-glucocerebrosidase.
Early studies of enzyme replacement produced great hope and excitement that Gaucher disease might be amenable to therapy by infusions of enzyme (29). The initial encouraging biochemical and clinical reports were not confirmed. Even though amounts of enzyme in subsequent trials were increased significantly, no changes could be measured in response to enzyme administration. These trials were unsuccessful because they failed to target the enzyme to the proper cells in sufficient quantity.
A method was devised to improve that aspect of the problem (64). Using enzymatic degradation of the oligosaccharide side chains of acid beta-glucocerebrosidase to expose mannose residues, the enzyme molecule was tailored to bind to the naturally occurring mannose receptors on macrophage plasma membranes. In animal model studies, this engineered acid beta-glucocerebrosidase was delivered to reticuloendothelial cells in quantities 10 times greater than the unmodified native enzyme (64). The function of the oligosaccharide side chains is not fully understood, but they are probably important in maintaining the tertiary structure of the protein during its synthesis and translocation to the lysosome. If addition of the sugar side chains is prevented completely, the protein is not properly folded and has no enzyme activity.
A clinical study in one patient demonstrated that this mannose-terminated acid beta-glucocerebrosidase was therapeutic (11). A formal clinical trial confirmed these results (14; 13). The commercial preparation is now widely used in patients and successfully reverses the visceral, hematologic, and skeletal manifestations of the disease.
After several clinical trials of placental derived acid beta-glucocerebrosidase (alglucerase) for the treatment of Gaucher disease, alglucerase was approved in 1991 (13). Production of the same protein using recombinant DNA technology was achieved, and the resultant drug, imiglucerase, received regulatory approval in 1994.
A review of the hepatic, splenic, and hematologic outcome from 175 patients was reported by Weinreb and colleagues (186). The authors concluded that the following four responses could be expected after 12 to 24 months of enzyme replacement therapy:
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(1) Patients with hepatomegaly will have approximately a 20% decrease in hepatic volume. |
The skeletal complications of Gaucher disease respond well within the same time frame as the other signs and symptoms of the disease. Bone pain is relieved, and the incidence of bone infarct is reduced dramatically to near zero in patients treated with 60 U/kg of recombinant human acid beta-glucocerebrosidase every 2 weeks prior to the development of a significant structural abnormality. The radiographic assessment of the skeletal complications, however, remains inadequate as a tool to measure the baseline and improvements in the bone in response to therapy.
Enzyme replacement has the same salutary effect on patients with type 3 Gaucher disease as it has in type 1 patients (148; 07). Treatment is indicated in these patients at a dose of 60 IU/kg of body weight every 2 weeks and should be closely monitored clinically and with laboratory studies to establish the response to the therapy (176). When initiated early in the course of the disease, enzyme replacement normalizes growth, corrects the hematologic abnormalities, and prevents the skeletal complications that occur in patients with type 3 Gaucher disease. This therapy has markedly ameliorated the course of the disease in this group of patients who used to die in their teens prior to the advent of enzyme replacement. However, in type 2 disease, enzyme replacement therapy may lengthen the course of the illness, but the neurologic deterioration progresses, and the poor prognosis of the disease is unaltered; therefore, enzyme replacement therapy should not be initiated in this group (139).
The adverse effects of enzyme replacement therapy are few and rarely a reason for discontinuing the therapy (123). Antibodies to enzyme replacement therapy have been reported in approximately 15% of patients. The incidence of serious complications is very low.
Effects of enzyme therapy cessation and withdrawal have been evaluated in patients who completely discontinued their therapies. These studies suggest that a complete cessation of therapy will inevitably endanger the patient by deteriorating hematological, biochemical, and skeletal parameters (179; 183). However, successful experiences of enzyme withdrawal for short periods of time have been reported (149).
Early initiation of enzyme replacement therapy is very important in children because it allows prevention of serious, irreversible skeletal complications. Children show an important increase in bone mineral density and growth rates (95; 08).
The COVID-19 pandemic ushered in a new era of next-generation mRNA vaccines. Studies have explored the use of mRNA as a potential tool for protein replacement therapy for a wide range of genetic disorders. Introduction of synthetic mRNA into a patient’s cells leads to production of therapeutic proteins that are otherwise missing or defective due to genetic mutations (60). The mRNA serves as a template to direct the synthesis of a therapeutic protein. Another type of RNA molecule, so-called self-amplifying RNA (saRNA), can replicate itself, allowing for sustained production of therapeutic proteins within cells. Both approaches have the potential to improve the delivery of protein replacement therapy in various genetic diseases, including Gaucher disease.
Application of saRNA and mRNA for Gaucher disease treatment as protein replacement therapy
(Left) When self-amplifying RNA (saRNA) is injected and delivered into cells, the translation of replicase takes place. The replicase uses the saRNA as a template and makes a negative saRNA strand, which in turn serves as a tem...
Other therapeutic approaches. The success of enzyme replacement therapy has lessened motivation to develop a gene therapy approach for the nonneurologic aspects of Gaucher disease. Because there is an unmet need to reverse or prevent the primary neurologic complications of Gaucher disease, research is ongoing to develop approaches that will enable delivery of acid beta-glucocerebrosidase or the normal copy of the GBA1 gene across the blood-brain barrier and into brain cells (159).
Substrate deprivation. N-butyldeoxynojirimycin (OGT-918), an inhibitor of the glucocerebroside synthase, initiates the glycosphingolipid pathway and catalyzes the formation of glucocerebroside (41). The rationale of this therapy is to decrease the formation of glucocerebroside to rates at which the residual acid beta-glucocerebrosidase activity of the patients would be sufficient to catabolize the substrate. Most patients experienced diarrhea, the most frequent side-effect, and two patients withdrew from the study because of this complaint. Some patients developed peripheral neuropathy. These results do not compare favorably to those obtained with enzyme replacement therapy, which normalizes or greatly impacts the clinical parameters with negligible side-effects (10; 120).
In a randomized controlled trial, miglustat was found not to be effective for the treatment of type 3 Gaucher disease (147).
A much more specific inhibitor of ceramide glycosyltransferase, the ceramide analogue eliglustat, has shown marked efficacy that is similar to enzyme replacement therapy at the 60 IU/kg/2 weeks dose (40). It does not have the side effect of miglustat but its metabolism is susceptible to the genotype of cytochrome P450 CYP2D6. Eliglustat was approved by the FDA in 2014 (138). Eliglustat tartrate is a P-glycoprotein substrate, possibly accounting for its poor distribution into the brain (151). Newer compounds with similar function but with good brain penetration are being developed and are being tested in human patients (115). Venglustat is currently being tested in adults with Gaucher disease type 3 (ClinicalTrials.gov Identifier: NCT02843035).
Pharmacological chaperones. A proposed approach for the treatment of Gaucher disease and other lysosomal storage diseases relies on the administration of active site competitive inhibitors that promote the correct folding and trafficking of the mutant protein (and even wild-type molecules). This process leads to increased levels of the mutant enzyme that can then function during the drug washout period (198; 181). The only pharmacological chaperone that is currently being clinically tested is ambroxol in high dose (112; 98).
Glucosylceramide metabolism in Gaucher diseases and effects of chaperone versus substrate reduction therapies
Ceramide, glucosylceramide shift between the Golgi apparatus and lysosomes. Ceramides (Cer), generated in the endoplasmic reticulum (ER), are transported to the Golgi apparatus, where UDP-glucosylceramide synthase (UGCG synthas...
It shows some promise in myoclonic forms of Gaucher disease type 3 (98). However, no controlled studies have been performed to confirm the clinical benefit of ambroxol.
Gene therapy. Gene therapy using an adeno-associated virus vector injected intrathecally is in the advanced planning stages.
Special considerations
Pregnancy
Patients with Gaucher disease can become pregnant and deliver normal healthy infants. Precautions should be taken for women who are anemic or thrombocytopenic during the pregnancy. Excessive bleeding is a frequent complication following delivery. The teratogenic potential of acid beta-glucocerebrosidase has not been evaluated, and patients contemplating pregnancy should be advised of this fact. Prudence suggests that pregnant women should not be treated with enzyme replacement during the first trimester. However, pregnant patients who were treated with at least two forms of enzyme replacement have delivered normal babies (52; 53).
Anesthesia
Patients with anemia, thrombocytopenia, or pulmonary involvement are at an increased risk for complications related to anesthesia and surgery. A particularly instructive case is a patient who was not diagnosed prior to cardiac surgery (119).
Media
References
- 01
- Abdelwahab M, Blankenship D, Schiffmann R. Long-term follow-up and sudden unexpected death in Gaucher disease type 3 in Egypt. Neurol Genet 2016;2(2):e55. PMID 27123474
- 02
- Abdelwahab M, Potegal M, Shapiro EG, Nestrasil I. Previously unrecognized behavioral phenotype in Gaucher disease type 3. Neurol Genet 2017;3(3):e158. PMID 28634598
- 03
- Aerts JMFG, Kuo CL, Lelieveld LT, et al. Glycosphingolipids and lysosomal storage disorders as illustrated by Gaucher disease. Curr Opin Chem Biol 2019;53:204-15. PMID 31783225
- 04
- Aghion A. La maladie de Gaucher dans l'enfance. Paris: Thèse, 1934.
- 05
- Alasmar D. Gaucher disease in Syrian children: common mutations identification, and clinical futures. Ann Saudi Med 2015;35(2):127-32. PMID 26336018
- 06
- Alcalay RN, Levy OA, Waters CC, et al. Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain 2015;138(Pt 9):2648-58. PMID 26117366
- 07
- Altarescu G, Hill S, Wiggs E, et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease. J Pediatr 2001;138(4):539-47. PMID 11295718
- 08
- Anderson LJ, Henley W, Wyatt KM, et al. Long-term effectiveness of enzyme replacement therapy in children with Gaucher disease: results from the NCS-LSD cohort study. J Inherit Metab Dis 2014;37(6):961-8. PMID 24638276
- 09
- Ashwell G, Morell AG. The role of surface carbohydrates in the hepatic recognition and transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol 1974;41(0):99-128. PMID 4609051
- 10
- Barranger JA. Risks of Gaucher's treatment. Lancet 2000;356:1353. PMID 11073045
- 11
- Barranger JA, Ohashi T, Hong CM, et al. Molecular pathology and therapy of Gaucher disease. Jpn J Inherit Metabol Dis 1989;51:45-71.
- 12
- Barranger JA, Rice E, Sakallah SA, Sansieri C, Mifflin TE, Cooper DL. Enzymatic and molecular diagnosis of Gaucher disease. Clin Lab Med 1995;15:899-913. PMID 8838229
- 13
- Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency: macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991b;324:1464-70. PMID 2023606
- 14
- Barton NW, Brady RO, Murray GJ, et al. Enzyme-replacement therapy for Gaucher's disease. N Engl J Med 1991a;325:1809-11. PMID 2023606
- 15
- Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife 2023;12:e87537. PMID 37249220
- 16
- Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol 2015;72(2):201-8. PMID 25506732
- 17
- Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15(1):59. PMID 33069254
- 18
- Benko W, Ries M, Wiggs EA, Brady RO, Schiffmann R, Fitzgibbon EJ. The saccadic and neurological deficits in type 3 Gaucher disease. PLoS One 2011;6:e22410. PMID 21799847
- 19
- Bloom W. Splenomegaly (type Gaucher) and lipid-histiocytosis (type Niemann). Am J Pathol 1925;1(6):595-626.9. PMID 19969674
- 20
- Bodamer OA, Church HJ, Cooper A, Wraith JE, Scott CR, Scaglia F. Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm and compound heterozygosity for a novel mutation (D409H/C16S). Am J Med Genet 2002;109(4):328-31. PMID 11992489
- 21
- Bohm P, Kunz W, Horny HP, Einsele H. Adult Gaucher disease in association with primary malignant bone tumors. Cancer 2001;91:457. PMID 11169926
- 22
- Boklan BF, Sawitsky A. Factor IX deficiency in Gaucher's disease. An in vitro phenomenon. Arch Intern Med 1976;136:489-92. PMID 1267559
- 23
- Boven LA, van Meurs M, Boot RG, et al. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am J Clin Pathol 2004;122(3):359-69. PMID 15362365
- 24
- Brady RO. Gaucher's disease: past, present and future. Baillieres Clin Haematol 1997;10(4):621-34. PMID 9497855
- 25
- Brady RO, Kanfer J, Shapiro D. The metabolism of glucocerebrosides. I. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue. J Biol Chem 1965a;240:39-43. PMID 14253443
- 26
- Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides. II. Evidence of enzymatic deficiency in Gaucher's disease. Biochem Biophys Res Commun 1965b;18:221-5. PMID 14282020
- 27
- Brady RO, Gal AE, Kanfer JN, Bradley RM. The metabolism of glucocerebrosides. 3. Purification and properties of a glucosyl- and galactosylceramide-cleaving enzyme from rat intestinal tissue. J Biol Chem 1965c;240(10):3766-70. PMID 5320641
- 28
- Brady RO, Kanfer JN, Bradley RM, Shapiro D. Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease. J Clin Invest 1966;45(7):1112-5. PMID 5338605
- 29
- Brady RO, Pentev PG, Gal AE, Hibbert SR, Dekeban AS. Replacement therapy for inherited enzyme deficiency: use of purified glucocerebrosidase in Gaucher's disease. N Engl J Med 1974;291:989-93. PMID 4415565
- 30
- Bremova-Ertl T, Schiffmann R, Patterson MC, et al. Oculomotor and vestibular findings in Gaucher disease type 3 and their correlation with neurological findings. Front Neurol 2017;8:711. PMID 29379464
- 31
- Bultron G, Kacena K, Pearson D, et al. The risk of Parkinson's disease in type 1 Gaucher disease. J Inherit Metab Dis 2010;33:167-73. PMID 20177787
- 32
- Burke DG, Rahim AA, Waddington SN, et al. Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes. J Inherit Metab Dis 2013;36(5):869-72. PMID 23151684
- 33
- Chan A, Holleran WM, Ferguson T, et al. Skin ultrastructural findings in type 2 Gaucher disease: Diagnostic implications. Mol Genet Metab 2011;104(4):631-6. PMID 21982627
- 34
- Charrow J, Esplin JA, Gribble TJ, et al. Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med 1998;158:1754-60. PMID 9738604
- 35
- Chester MA. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids--recommendations 1997. Eur J Biochem 1998;257(2):293-8. PMID 9826173
- 36
- Chiasserini D, Paciotti S, Eusebi P, et al. Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies. Mol Neurodegener 2015;10:15. PMID 25881142
- 37
- Cho L, Lytle BW, Moodie DS. Type IIIC Gaucher's disease. Circulation 2000;102:E69. PMID 10973854
- 38
- Choy FY, Zhang W, Shi HP, et al. Gaucher disease among Chinese patients: review on genotype/phenotype correlation from 29 patients and identification of novel and rare alleles. Blood Cells Mol Dis 2007;38(3):287-93. PMID 17196853
- 39
- Conradi NG, Sourander P, Nilsson O, Svennerholm L, Erikson A. Neuropathy of the Norrbottnian type of Gaucher disease. Acta Neuropathol 1984;65:99-109. PMID 6524300
- 40
- Cox TM, Drelichman G, Cravo R, et al. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood 2017;129(17):2375-83. PMID 28167660
- 41
- Cox T, Lachmann R, Hollak C, et al. Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 2000;355:1481. PMID 10801168
- 42
- Cullen V, Sardi SP, Ng J, et al. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol 2011;69(6):940-53. PMID 21472771
- 43
- D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16(1):431. PMID 34649574
- 44
- Dahl N, Lagerström M, Erikson A, Pettersson U. Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene. Am J Hum Genet 1990;47(2):275-8. PMID 2378352
- 45
- Daniels LB, Glew RH. Beta-glucosidase assays in the diagnosis of Gaucher's disease. Clin Chem 1982;28:569-77. PMID 6804115
- 46
- Debre R, Bertrand I, Grumbach R, Bargeton G. Maladie de Gaucher du Norrisson. Arch Fr Pediatr 1951;8:38. PMID 14820359
- 47
- de Duve C. Lysosomes revisited. Eur J Biochem 1983;137:391-7. PMID 6319122
- 48
- Dekker N, van Dussen L, Hollak CE, et al. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood 2011;118(16):e118-27. PMID 21868580
- 49
- Dinur T, Bauer P, Beetz C, et al. Gaucher disease diagnosis using Lyso-Gb1 on dry blood spot samples: time to change the paradigm? Int J Mol Sci 2022;23(3):1627. PMID 35163551
- 50
- Eghbali A, Hassan S, Seehra G, FitzGibbon E, Sidransky E. Ophthalmological findings in Gaucher disease. Mol Genet Metab 2019;127(1):23-7. PMID 31047801
- 51
- El-Morsy Z, Khashaba MT, Soliman Oel S, Yahia S, El-Hady DA. Glucosidase acid beta gene mutations in Egyptian children with Gaucher disease and relation to disease phenotypes. World J Pediatr 2011;7(4):326-30. PMID 21633851
- 52
- Elstein D, Granovsky-Grisaru S, Rabinowitz R, Kanai R, Abrahamov A, Zimran A. Use of enzyme replacement therapy for Gaucher disease during pregnancy. Am J Obstet Gynecol 1997;177(6):1509-12. PMID 9423759
- 53
- Elstein D, Hughes D, Goker-Alpan O, et al. Outcome of pregnancies in women receiving velaglucerase alfa for Gaucher disease. J Obstet Gynaecol Res 2014;40(4):968-75. PMID 24612151
- 54
- Enquist IB, Lo Bianco C, Ooka A, et al. Murine models of acute neuronopathic Gaucher disease. Proc Natl Acad Sci U S A 2007;104(44):17483-8. PMID 17954912
- 55
- Epstein E. Beitrag zur chemie der Gaucherschen krankheit. Hoppe-Seyler's Z Physiol Chem 1924;271:211.
- 56
- Erickson AH, Ginns EI, Barranger JA. Biosynthesis of the lysosomal enzyme glucocerebrosidase. J Biol Chem 1985;260:14319-24. PMID 3932353
- 57
- Erickson AH, Ginns EI, Barranger JA, Brady RO, Blobel G. Biosynthesis and processing of glucocerebrosidase, a lysosomal hydrolase. Fed Proc 1983;42:1912.
- 58
- Farfel-Becker T, Vitner EB, Kelly SL, et al. Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Hum Mol Genet 2014;23(4):843-54. PMID 24064337
- 59
- Farfel-Becker T, Vitner EB, Pressey SN, Eilam R, Cooper JD, Futerman AH. Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. Hum Mol Genet 2011;20(7):1375-86. PMID 21252206
- 60
- Feng S, Rcheulishvili N, Jiang X, et al. A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach. Int J Biol Sci 2024;20(6):2111-29. PMID 38617529
- 61
- Fredrickson DS, Sloan HR. In: Stanburg JB, Wyngaarden JB, Fredrickson DS, editors. The metabolic basis of inherited disease. 4th ed. New York: McGraw-Hill, 1978.
- 62
- Fujimoto A, Tayebi N, Sidransky E. Congenital ichthyosis preceding neurologic symptoms in two sibs with type 2 Gaucher disease. Am J Med Genet 1995;59(3):356-8. PMID 8599361
- 63
- Furbish FS, Blair HE, Shiloach J, Pentchev PG, Brady RO. Enzyme replacement therapy in Gaucher disease: large scale purification of glucocerebrosidase suitable for human administration. Proc Natl Acad Sci USA 1977;74(8):3560-3. PMID 269414
- 64
- Furbish FS, Steer CJ, Krett NL, Barranger JA. Uptake and distribution of placental glucocerebrosidase in rat hepatic cells and effects of sequential deglycosylation. Biochim Biophys Acta 1981;673:425-34. PMID 6784774
- 65
- Futerman AH, Platt FM. The metabolism of glucocerebrosides - From 1965 to the present. Mol Genet Metab 2017;120(1-2):22-6. PMID 27955980
- 66
- Gan-Or Z, Giladi N, Rozovski U, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 2008;70(24):2277-83. PMID 18434642
- 67
- Garvey MA, Toro C, Goldstein S, et al. Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease. Neurology 2001;56:391. PMID 11171908
- 68
- Gary SE, Ryan E, Steward AM, Sidransky E. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev Endocrinol Metab 2018;13(2):107-18. PMID 30058864
- 69
- Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.
- 70
- Gegg ME, Burke D, Heales SJ, et al. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann Neurol 2012;72:455-63. PMID 23034917
- 71
- Goker-Alpan O, Hruska KS, Orvisky E, et al. Divergent phenotypes in Gaucher disease implicate the role of modifiers. J Med Genet 2005;42(6):e37. PMID 15937077
- 72
- Goker-Alpan O, Schiffmann R, Park JK, Stubblefield BK, Tayebi N, Sidransky E. Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3. J Pediatr 2003;143(2):273-6. PMID 12970647
- 73
- Gonzalez A, Valeiras M, Sidransky E, Tayebi N. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 2014;111(2):84-91. PMID 24389070
- 74
- Grabowski GA, Zimran A, Ida H. Gaucher disease types 1 and 3: phenotypic characterization of large populations from the ICGG Gaucher Registry. Am J Hematol 2015;90 Suppl 1:S12-8. PMID 26096741
- 75
- Gruschus JM, Jiang Z, Yap TL, et al. Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C. Biochem Biophys Res Commun 2015;457(4):561-6. PMID 25600808
- 76
- Halter D, Neumann S, van Dijk SM, et al. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. J Cell Biol 2007;179(1):101-15. PMID 17923531
- 77
- Hanada K. Intracellular trafficking of ceramide by ceramide transfer protein. Proc Jpn Acad Ser B Phys Biol Sci 2010;86(4):426-37. PMID 20431265
- 78
- Hannun YA, Bell RM. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 1987;235:670-4. PMID 3101176
- 79
- Hers HG. Alpha-glucosidase deficiency in generalized glycogen storage disease (Pompe's disease). Biochem J 1963;86:1. PMID 13954110
- 80
- Hers HG. Inborn lysosomal diseases. Gastroenterology 1965;48:625. PMID 14280390
- 81
- Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12(4):e2427. PMID 38553911
- 82
- Hobbs JR, Jones KH, Shaw PJ, Lindsay J, Hancock M. Beneficial effect of pre-transplant splenectomy on displacement bone marrow transplantation for Gaucher’s syndrome. Lancet 1987;1:1111-5. PMID 2883444
- 83
- Hollak CE, Evers L, Aerts JM, van Oers MH. Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. Blood Cells Mol Dis 1997;23:201-12. PMID 9236158
- 84
- Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994;93(3):1288. PMID 8132768
- 85
- Holleran WM, Ziegler SG, Goker-Alpan O, et al. Skin abnormalities as an early predictor of neurologic outcome in Gaucher disease. Clin Genet 2006;69(4):355-7. PMID 16630170
- 86
- Horowitz M, Elstein D, Zimran A, Goker-Alpan O. New directions in Gaucher disease. Hum Mutat 2016;37(11):1121-36. PMID 27449603
- 87
- Hultberg B, Isaksson A, Sjoblod S, Ockerman PA. Acid hydrolases in serum from patients with lysosomal disorders. Clin Chem Acta 1980;100:33-8. PMID 6766092
- 88
- Inui K, Yanagihara K, Otani K, et al. A new variant neuropathic type of Gaucher's disease characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules. J Pediatr 2001;138:137. PMID 11148530
- 89
- Itzchaki M, Lebel E, Dweck A, et al. Orthopedic considerations in Gaucher disease since the advent of enzyme replacement therapy. Acta Orthop Scand 2004;75(6):641-53. PMID 15762253
- 90
- IUPAC-IUB joint commission on biochemical nomenclature (JCBN). Nomenclature of glycolipids recommendations 1997. J Mol Biol 1999;286(3):963-70. PMID 10024462
- 91
- Ivanova MM, Dao J, Kasaci N, et al. Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease. PLoS One 2021;16(10):e0247211. PMID 34695170
- 92
- James SP, Stromeyer FW, Chang CSC, Barranger JA. Liver abnormalities in Gaucher’s disease. Gastroenterology 1981;80:126-33. PMID 7450398
- 93
- Jeong SY, Park SJ, Kim HJ. Clinical and genetic characteristics of Korean patients with Gaucher disease. Blood Cells Mol Dis 2011;46(1):11-4. PMID 20729108
- 94
- Kang L, Zhan X, Ye J, et al. A rare form of Gaucher disease resulting from saposin C deficiency. Blood Cells Mol Dis 2018;68:60-5. PMID 28457694
- 95
- Kaplan P, Baris H, De Meirleir L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr 2013;172(4):447-58. PMID 22772880
- 96
- Kattlove HE, Williams JC, Gaynor E, Spivak M, Bradley RM, Brady RO. Gaucher cells in chronic myelocytic leukemia: an acquired abnormality. Blood 1969;33:379-90. PMID 5250471
- 97
- Kaye EM, Ullman MD, Wilson ER, Barranger JA. Type 2 and type 3 Gaucher disease: a morphological and biochemical study. Ann Neurol 1986;20:223-30. PMID 3752966
- 98
- Kim YM, Yum MS, Heo SH, et al. Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy. J Med Genet 2020;57(2):124-31. PMID 31649052
- 99
- Kishnani PS, Al-Hertani W, Balwani M, et al. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab 2022;135(2):154-62. PMID 34972655
- 100
- Klein AD, Ferreira NS, Ben-Dor S, et al. Identification of modifier genes in a mouse model of Gaucher disease. Cell Rep 2016;16(10):2546-53. PMID 27568557
- 101
- Knudson AG, Kaplan WD. Genetics of the sphingolipidoses. In: Aronson SM, Volk BW, editors. Cerebral sphingolipidoses. New York: Academic Pr, 1962:395.
- 102
- Kowarz L, Goker-Alpan O, Banerjee-Basu S, et al. Gaucher mutation N188S is associated with myoclonic epilepsy. Hum Mutat 2005;26(3):271-3. PMID 16086325
- 103
- Kurolap A, Del Toro M, Spiegel R, et al. Gaucher disease type 3c: new patients with unique presentations and review of the literature. Mol Genet Metab 2019;127(2):138-46. PMID 31130326
- 104
- Landgren O, Turesson I, Gridley G, Caporaso NE. Risk of malignant disease among 1525 adult male US Veterans with Gaucher disease. Arch Intern Med 2007;167(11):1189-94. PMID 17563029
- 105
- Lee SY, Mak AW, Huen KF, Lam ST, Chow CB. Gaucher disease with pulmonary involvement in a 6-year-old girl: report of resolution of radiographic abnormalities on increasing dose of imiglucerase. J Pediatr 2001;139(6):862-4. PMID 11743514
- 106
- Liaqat K, Hussain S, Acharya A, et al. Phenotype expansion for atypical Gaucher disease due to homozygous missense PSAP variant in a large consanguineous Pakistani family. Genes (Basel) 2022;13(4):662. PMID 35456468
- 107
- Lieb H. Der zucker im cerebrosid der milz bei der Gaucher krankheit. Hoppe-Seyler's Z Physiol Chem 1924;271:211.
- 108
- Lieberman RL. A guided tour of the structural biology of Gaucher disease: Acid-β-glucosidase and saposin C. Enzyme Res 2011;2011:973231. PMID 22145077
- 109
- Lieberman J, Beutler E. Elevation of serum angiotensin-converting enzyme in Gaucher's disease. N Engl J Med 1976;294:1442-4. PMID 179000
- 110
- Louw VJ, Fraser I, Giraldo P. Management goals of type 1 Gaucher disease in South Africa: an expert Delphi consensus document on good clinical practice. PLoS One 2023;18(8):e0290401. PMID 37607165
- 111
- Low ZX, Hariharan G. Gaucher disease - a rare cause of collodion. Indian J Pediatr 2020;87(1):82. PMID 31529381
- 112
- Maegawa GH, Tropak MB, Buttner JD, et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem 2009;284(35):23502-16. PMID 19578116
- 113
- Maor G, Rencus-Lazar S, Filocamo M, Steller H, Segal D, Horowitz M. Unfolded protein response in Gaucher disease: from human to drosophila. Orphanet J Rare Dis 2013;8:140. PMID 24020503
- 114
- Marchand F. Uber soq. Idiopathische splenomegalie-typus Gaucher. Meunch Med Wochenschr 1907;54:1102.
- 115
- Marshall J, Sun Y, Bangari DS, et al. CNS-accessible inhibitor of glucosylceramide synthase for substrate reduction therapy of neuronopathic Gaucher disease. Mol Ther 2016;24(6):1019-29. PMID 26948439
- 116
- Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37-52. PMID 21700325
- 117
- Mengel E, Gaedeke J, Gothe H, et al. The patient journey of patients with Fabry disease, Gaucher disease and Mucopolysaccharidosis type II: A German-wide telephone survey. PLoS One 2020;15(12):e0244279. PMID 33382737
- 118
- Mignot C, Gelot A, Bessieres B, et al. Perinatal-lethal Gaucher disease. Am J Med Genet 2003;120A(3):338-44. PMID 12838552
- 119
- Mireles SA, Seybold J, Williams G. Undiagnosed type IIIc Gaucher disease in a child with aortic and mitral valve calcification: perioperative complications after cardiac surgery. J Cardiothorac Vasc Anesth 2010;24(3):471-4. PMID 19632857
- 120
- Mistry PK. Treatment of Gaucher's disease with OGT 918. Lancet 2000;356:676. PMID 10968454
- 121
- Mistry PK, Liu J, Sun L, et al. Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci U S A 2014;111(13):4934-9. PMID 24639522
- 122
- Moffitt KD, Chambers JP, Diven WF, Glew RH, Wenger DA, Farrell DF. Characterization of lysosomal hydrolases that are elevated in Gaucher's disease. Arch Biochem Biophys 1978;190:247-60. PMID 101149
- 123
- Morales LE. Gaucher's disease: a review. Ann Pharmacother 1996;30(4):381-8. PMID 8729893
- 124
- Moran MT, Schofield JP, Hayman AR, Shi GP, Young E, Cox TM. Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K. Blood 2000;96:1969. PMID 10961902
- 125
- Murphy KE, Gysbers AM, Abbott SK, et al. Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson's disease. Brain 2014;137(Pt 3):834-48. PMID 24477431
- 126
- Narita A, Shirai K, Itamura S, et al. Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study. Ann Clin Transl Neurol 2016;3(3):200-15. PMID 27042680
- 127
- Nilsson O. Glycolipid changes in Gaucher disease [thesis]. Goteborg, 1982.
- 128
- Nilsson O, Grabowski GA, Ludman MD, Desnick RJ, Svennerholm L. Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants. Clin Genet 1985;27:443-50. PMID 3924448
- 129
- Nilsson O, Svennerholm L. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J Neurochem 1982;39:709-18. PMID 7097276
- 130
- Ockerman PA, Kohlin P. Acid hydrolases in plasma in Gaucher's disease. Clin Chem 1969;15:61-4. PMID 4884797
- 131
- Olivova P, Cullen E, Titlow M, et al. An improved high-throughput dried blood spot screening method for Gaucher disease. Clin Chim Acta 2008;398(1-2):163-4. PMID 18812173
- 132
- Oka S, Kawasaki T, Yamashina I. Isolation and characterization of mannan-binding proteins from chicken liver. Arch Biochim Biophys 1985;241:95-105. PMID 4026327
- 133
- Orvisky E, Park JK, LaMarca ME, et al. Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. Mol Genet Metab 2002;76(4):262. PMID 12208131
- 134
- Park JK, Orvisky E, Tayebi N, et al. Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup. Pediatr Res 2003;53(3):387-95. PMID 12595585
- 135
- Patrick AD. A deficiency of glucocerebrosidase in Gaucher's disease. Biochem J 1965;97:17C.
- 136
- Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH. Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiol Dis 2005;18(1):83-8. PMID 15649698
- 137
- Poll LW, Koch JA, vom Dahl S, et al. Type I Gaucher disease: extraosseous extension of skeletal disease. Skeletal Radiol 2000;29:15-21. PMID 10663584
- 138
- Poole RM. Eliglustat: first global approval. Drugs 2014;74(15):1829-36. PMID 25239269
- 139
- Prows CA, Sanchez N, Daugherty C, Grabowski GA. Gaucher disease: enzyme therapy in the acute neuronopathic variant. Am J Med Genet 1997;71(1):16-21. PMID 9215762
- 140
- Rappeport JM, Barranger JA, Ginns EI. Bone marrow transplantation in Gaucher disease. Birth Defects 1986;22:101-9. PMID 3516238
- 141
- Revel-Vilk S, Fuller M, Zimran A. Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in Gaucher disease: A systematic literature review. Int J Mol Sci 2020;21(19):7159. PMID 32998334
- 142
- Robak LA, Jansen IE, van Rooij J, et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain 2017;140(12):3191-203. PMID 29140481
- 143
- Robinson DB, Glew RH. Acid phosphatase in Gaucher's disease. Clin Chem 1980;26:371-82. PMID 6988111
- 144
- Rogaeva E, Hardy J. Gaucher and Parkinson diseases: unexpectedly related. Neurology 2008;70(24):2272-3. PMID 18541881
- 145
- Ron I, Horowitz M. ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum Mol Genet 2005;14(16):2387-98. PMID 16000318
- 146
- Sawicka-Gutaj N, Machaczka M, Kulinska-Niedziela I, et al. The appearance of newly identified intraocular lesions in Gaucher disease type 3 despite long-term glucocerebrosidase replacement therapy. Ups J Med Sci 2016;121(3):192-5. PMID 27064303
- 147
- Schiffmann R, Fitzgibbon EJ, Harris C, et al. Randomized, controlled trial of miglustat in Gaucher's disease type 3. Ann Neurol 2008;64(5):514-22. PMID 19067373
- 148
- Schiffmann R, Heyes MP, Aerts JM, et al. Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease. Ann Neurol 1997;42:613-21. PMID 9382473
- 149
- Schwartz IV, Karam S, Ashton-Prolla P, et al. Effects of imiglucerase withdrawal on an adult with Gaucher disease. Br J Haematol 2001:113(4):1089. PMID 11442517
- 150
- Sestito S, Filocamo M, Ceravolo F, et al. Norrbottnian clinical variant of Gaucher disease in Southern Italy. J Hum Genet 2017;62(4):507-11. PMID 28003644
- 151
- Shayman JA. Eliglustat tartrate: Glucosylceramide synthase inhibitor treatment of type 1 Gaucher disease. Drugs Future 2010;35(8):613-20. PMID 22563139
- 152
- Shiran A, Brenner B, Laor A, Tatarsky I. Increased risk of cancer in patients with Gaucher disease. Cancer 1993;72:219-24. PMID 8508410
- 153
- Sidransky E, Fartasch M, Lee RE, et al. Epidermal abnormalities may distinguish type 2 from type 1 and type 3 of Gaucher disease. Pediatr Res 1996;39(1):134-41. PMID 8825398
- 154
- Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009;361:1651-61. PMID 19846850
- 155
- Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014;137(Pt 5):1304-22. PMID 24531622
- 156
- Silverstein E, Friedland J. Elevated serum and spleen angiotensin converting enzyme and serum lysozyme in Gaucher's disease. Clin Chim Acta 1977;74:21-5. PMID 188566
- 157
- Singer R. William Bloom. National Academy of Sciences 1993. Biographical memoirs: Volume 62. Washington, DC: The National Academies Press, 1993:17-29.
- 158
- Snyder RA, Brady RO. The use of white cells as a source of diagnostic material for lipid storage disease. Clin Chim Acta 1969;25:331-8. PMID 4895581
- 159
- Spencer BJ, Verma IM. Targeted delivery of proteins across the blood-brain barrier. Proc Natl Acad Sci U S A 2007;104(18):7594-9. PMID 17463083
- 160
- Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18(2):441. PMID 28218669
- 161
- Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E. Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. Hum Mutat 2000;15:181-8. PMID 10649495
- 162
- Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a case report. J Med Case Rep 2022;16(1):203. PMID 35562809
- 163
- Svennerholm L. The metabolism of gangliosides in cerebral lipidoses. In: Aronson SM, Volk BW, editors. Inborn disorders of sphingolipid metabolism. New York: Pergamon Pr, 1967:169.
- 164
- Svennerholm L, Mansson JE, Nilsson O, et al. Bone marrow transplantation in the Norrbottnian form of Gaucher's. In: Barranger JA, Brady RO, editors. Molecular basis of lysosomal storage disorders. New York: Academic Pr, 1984:441.
- 165
- Tajima A, Yokoi T, Ariga M, et al. Clinical and genetic study of Japanese patients with type 3 Gaucher disease. Mol Genet Metab 2009;97(4):272-7. PMID 19481486
- 166
- Takasaki S, Murray GJ, Furbish FS, Brady RO, Barranger JA, Kobata A. Structure of the N-asparagine-linked oligosaccharide units of human placental glucocerebrosidase. J Biol Chem 1984;259:10112-7. PMID 6469957
- 167
- Tamargo RJ, Velayati A, Goldin E, Sidransky E. The role of saposin C in Gaucher disease. Mol Genet Metab 2012;106(3):257-63. PMID 22652185
- 168
- Tayebi N, Stone DL, Sidransky E. Type 2 Gaucher disease: an expanding phenotype. Mol Genet Metab 1999;68:209-19. PMID 10527671
- 169
- Thudichum JL. A Treatise on the chemical constitution of the brain: based throughout upon original researches. London: Bailliere, Tindall, and Cox, 1884.
- 170
- Thudichum JL. Die chemische konstitution des gehirns des Menschen und der tiere. Tübingen: Franz Pietzcker, 1901.
- 171
- Torralba-Cabeza MA, Olivera-González S, Sierra-Monzón JL. The importance of a multidisciplinary approach in the management of a patient with type I Gaucher disease. Diseases 2018;6(3):69. PMID 30049986
- 172
- Tsitsi P, Markaki I, Waldthaler J, Machaczka M, Svenningsson P. Neurocognitive profile of adults with the Norrbottnian type of Gaucher disease. JIMD Rep 2021;63(1):93-100. PMID 35028274
- 173
- Tuchman LR, Suna H, Carr JJ. Elevation of serum acid phosphatase in Gaucher's disease. J Mt Sinai Hosp 1956;23:277. PMID 13307230
- 174
- Tybulewicz VL, Tremblay ML, LaMarca ME, et al. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 1992;357(6377):407-10. PMID 1594045
- 175
- Tylki-Szymanska A, Groener JE, Kaminski ML, Lugowska A, Jurkiewicz E, Czartoryska B. Gaucher disease due to saposin C deficiency, previously described as non-neuronopathic form--no positive effects after 2-years of miglustat therapy. Mol Genet Metab 2011;104:627-30. PMID 21978771
- 176
- Vellodi A, Tylki-Szymanska A, Davies EH, et al. Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis 2009;32:660-4. PMID 19655269
- 177
- Vitner EB, Dekel H, Zigdon H, et al. Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum Mol Genet 2010;19:3583-90. PMID 20616152
- 178
- Vitner EB, Salomon R, Farfel-Becker T, et al. RIPK3 as a novel potential therapeutic target for Gaucher disease. Nat Med 2014;20(2):204-8. PMID 24441827
- 179
- vom Dahl S, Poll LW, Hausinger D. Clinical monitoring after cessation of enzyme replacement therapy in M Gaucher. Br J Haematol 2001;113(4):1084-7. PMID 11442513
- 180
- Wan L, Hsu CM, Tsai CH, Lee CC, Hwu WL, Tsai FJ. Mutation analysis of Gaucher disease patients in Taiwan: high prevalence of the RecNciI and L444P mutations. Blood Cells Mol Dis 2006;36(3):422-5. PMID 16546416
- 181
- Wang GN, Reinkensmeier G, Zhang SW, et al. Rational design and synthesis of highly potent pharmacological chaperones for treatment of N370S mutant Gaucher disease. J Med Chem 2009;52(10):3146-9. PMID 19397268
- 182
- Weinreb NJ. Serum and splenic lysozyme in Gaucher's disease. Clin Res 1976;24:295A.
- 183
- Weinreb NJ. Interruption in enzyme replacement therapy for Gaucher disease. Br J Haematol 2001;113(4):1087-9. PMID 11442515
- 184
- Weinreb NJ. The international cooperative Gaucher group (ICCG) Gaucher registry. Best Pract Res Clin Haematol 2023;36(4):101522. PMID 38092479
- 185
- Weinreb NJ, Barbouth DS, Lee RE. Causes of death in 184 patients with type 1 Gaucher disease from the United States who were never treated with enzyme replacement therapy. Blood Cells Mol Dis 2018;68:211-7. PMID 27816427
- 186
- Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med 2002;113(2):112-9. PMID 12133749
- 187
- Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136(1):4-21. PMID 35367141
- 188
- Weiss K, Gonzalez AN, Lopez G, Pedoeim L, Groden C, Sidransky E. The clinical management of type 2 Gaucher disease. Mol Genet Metab 2015;114(2):110-22. PMID 25435509
- 189
- Wenger DA, Olson GC. Heterogeneity in Gaucher's disease. In: Callahan JW, Lowden JA, editors. Lysosomes and lysosomal storage disorders. New York: Raven, 1981:157.
- 190
- Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: a review. Cell Mol Life Sci 2002;59(4):694-707. PMID 12036828
- 191
- Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82(3):192-207. PMID 15234332
- 192
- Xu YH, Quinn B, Witte D, Grabowski GA. Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. Am J Pathol 2003;163(5):2093-101. PMID 14578207
- 193
- Yang C, Wang H, Zhu D, et al. Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation. Proc Natl Acad Sci U S A 2015;112(4):1137-42. PMID 25583479
- 194
- Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with Glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 2011;286(32):28080-8. PMID 21653695
- 195
- Yap TL, Gruschus JM, Velayati A, Sidransky E, Lee JC. Saposin C protects glucocerebrosidase against α-synuclein inhibition. Biochemistry 2013b;52(41):7161-3. PMID 24070323
- 196
- Yap TL, Jiang Z, Heinrich F, et al. Structural features of membrane-bound glucocerebrosidase and α-synuclein probed by neutron reflectometry and fluorescence spectroscopy. J Biol Chem 2015;290(2):744-54. PMID 25429104
- 197
- Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound α-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol Genet Metab 2013a;108(1):56-64. PMID 23266198
- 198
- Yu Z, Sawkar AR, Kelly JW. Pharmacologic chaperoning as a strategy to treat Gaucher disease. FEBS J 2007;274(19):4944-50. PMID 17894779
- 199
- Zancan I, Bellesso S, Costa R, et al. Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/beta-catenin signaling. Hum Mol Genet 2015;24(5):1280-94. PMID 25326392
- 200
- Zigdon H, Savidor A, Levin Y, Meshcheriakova A, Schiffmann R, Futerman AH. Identification of a biomarker in cerebrospinal fluid for neuronopathic forms of Gaucher disease. PLoS One 2015;10(3):e0120194. PMID 25775479
- 201
- Zigdon H, Meshcheriakova A, Farfel-Becker T, Volpert G, Sabanay H, Futerman AH. Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease. FEBS Lett 2017;591(5):774-83. PMID 28186340
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile
Former Authors
- John A Barranger MD PhD
- Tiffany W Chow MD
- Erin O'Rourke MS CGC
- Mario A Cabrera-Salazar MD
- Raphael Schiffmann MD
Patient Profile
- Age range of presentation
-
- 0 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- heredity typical
- autosomal recessive
- Population groups selectively affected
-
- Ashkenazi Jews
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Gaucher disease: E75.2
- ICD-11
-
- Other specified sphingolipidosis: 5C56.0Y
- OMIM
-
- Non-neuronopathic Gaucher disease: #230800
- Acute neuronopathic Gaucher disease: #230900
- Subacute neuronopathic Gaucher disease: #231000
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