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Nondominant hereditary ataxias …
- Updated 05.20.2024
- Released 10.21.2003
- Expires For CME 05.20.2027
Nondominant hereditary ataxias
Introduction
Overview
The autosomal recessive cerebellar ataxias comprise a large group of rare diseases, the most common forms being Friedreich ataxia, ataxia-telangiectasia, and early-onset cerebellar ataxia with retained tendon reflexes. This is a large and expanding group of disorders characterized by degeneration or developmental anomalies of the cerebellum and spinal cord, age of onset prior to 20 years, and autosomal recessive inheritance. The author provides an updated comprehensive review of this disorder and its classifications. The disorders of X-linked inheritance are also described here. The “Differential diagnosis” section describes the utility of using associated symptoms as a clinical tool to investigate etiologies. Methods such as in proteomics, molecular and genetic studies, and high-throughput drug screening are allowing researchers to better understand the mechanisms of this group of disorders and arrive at targeted therapy.
Key points
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• Nondominant hereditary ataxias are a group of heterogeneous, rare neurologic disorders characterized by degeneration or developmental abnormality of the cerebellum and spinal cord. | |
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• The most common of these is Friedreich ataxia, mapped to genetic locus 9q13-q21 and caused by GAA triplet repeat expansion. | |
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• The list of diseases comprising this group is extensive and continues to grow as genome analysis has become more widespread and accessible. | |
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• Because of an increased knowledge of underlying molecular mechanisms, management and targeted therapy has advanced to trial phases in certain disorders, including Friedreich ataxia. |
Historical note and terminology
Autosomal recessive cerebellar ataxias are a group of heterogeneous rare neurologic disorders characterized by degeneration or developmental abnormality of the cerebellum and spinal cord, with onset prior to 20 years of age. Among the hereditary cerebellar ataxias, there are at least 36 different forms of autosomal dominant cerebellar ataxia, 20 autosomal recessive cerebellar ataxias, two X-linked ataxias, and several forms of ataxia associated with mitochondrial defects (96). They are characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements (06).
In 1893 Pierre Marie described a clinical condition that he termed “hereditary cerebellar ataxia,” in which cerebellar signs and spasticity prevailed. This disorder was later referred to as “Marie’s cerebellar ataxia.” Subsequently, the term was used broadly to describe a variety of hereditary conditions with spinocerebellar manifestations, including the spastic ataxia of Sanger-Brown, Menzel spinocerebellar ataxia with olivopontocerebellar degeneration, the cerebello-olivary degeneration of Holmes, and the olivopontocerebellar degeneration reported by Dejerine and Thomas (24). In 1974, Skre of Norway studied the hereditary ataxias such as Friedreich ataxia and pioneered the term “spinocerebellar ataxias” (140; 141).
The most well-known and the most common hereditary ataxia is Friedreich ataxia. Nikolaus Friedreich (1825-1882) first described the disorder in a series of five articles, starting in 1863. Although nystagmus was not a consistent finding, he initially used the term “ataxic nystagmus” (40). After ataxic nystagmus was found to be a distinct entity and not just a part of the natural history of progressive locomotor ataxia and disseminated sclerosis, Brousse coined the term “maladie de Friedreich” in 1882. He was the first to describe the diagnostic criteria for Friedreich ataxia, which remain applicable today. In 1988, Chamberlain and colleagues mapped the genetic locus for Friedrich ataxia to chromosome 9q13-q21 (15). The causative GAA triplet repeat expansion was discovered in 1996 (13).
The first description of patients with ataxia-telangiectasia was published in 1926 by French investigators Syllaba and Henner (145). They reported three adolescent siblings with progressive choreoathetosis and ocular telangiectasia. In 1957, the clinical and pathological description became clearer, and the disorder was given the name “ataxia-telangiectasia” by Boder and Sedgwick (07).
Dejerine and Thomas introduced the term “olivopontocerebellar atrophy” in 1900. They described two patients with a chronic progressive cerebellar degeneration appearing in middle-age (24). The characteristic presentation of olivopontocerebellar atrophy is progressive, symmetric cerebellar dysfunction in childhood, followed by dysarthria, spasticity, and hyperreflexia. However, in 1970 Konigsmark and Weiner published a paper in which they recognized the heterogeneity of olivopontocerebellar atrophy and proposed a classification based on clinical, genetic, and anatomic features (77). Familial cases of olivopontocerebellar atrophy are now included within the spinocerebellar ataxia rubric (119).
Multiple attempts to classify inherited ataxias have been proposed. In 1907, Holmes suggested a classification based on pathologic findings, but this did not take into account genetic or clinical features of the disorders. In 1954, Greenfield classified the inherited ataxias into three categories: (1) predominantly spinal, (2) predominantly cerebellar, and (3) combined spinocerebellar (45). In 1983, Harding proposed a classification based primarily on the biochemical pathogenesis and age of onset of the ataxia (53). She divided those with a known etiology (eg, abetalipoproteinemia, ataxia-telangiectasia) from those whose etiology was unknown (eg, Friedreich ataxia). In the latter category, she further subdivided the disorders based on whether the onset was before the age of 20 years or later. As genetic mutations were identified in a number of disorders, newer classification schemes were suggested (26). The correlation of clinical disease with the underlying genetic defect has enabled more complete classification of these ataxias (61).
The autosomal recessive ataxias are now subdivided as shown in Table 1.
Table 1. Current Categorization of Autosomal Recessive Ataxias
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Degenerative ataxias | |
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• Friedreich ataxia | |
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DNA repair defects | |
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• Ataxia-telangiectasia | |
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Congenital ataxias | |
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• Joubert syndrome (JBTS 1-5) | |
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Metabolic ataxias | |
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• Ataxia with isolated vitamin E deficiency (AVED) | |
Clinical manifestations
Presentation and course
Friedreich ataxia. Friedreich ataxia is the most common form of progressive autosomal recessive ataxias among Caucasian individuals. Symptoms develop insidiously, and in the majority of patients symptoms are noted between the ages of 2 and 16 years (52). The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedrich ataxia (130). Stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich ataxia.
The most common presenting complaint is unsteady gait that begins before puberty. If the ataxia occurs early, it can be reported as a delay in the acquisition of motor milestones. Progressive ataxia of the limbs and the trunk is typically present in all patients. Truncal ataxia is at times so severe that patients cannot sit without support. The patients may develop dysarthria, lower limb areflexia, and axonal proprioceptive sensory loss (32). In addition, patients may have pyramidal-type weakness and distal muscle atrophy that is more severe in the legs than in the arms (05). The Babinski response is present in about two thirds of patients. Harding analyzed a large number of patients and published diagnostic criteria for Friedreich ataxia (52). Lower extremity reflexes are almost always absent, and in about one third of cases areflexia of the upper extremities is also noted. Rarely, reflexes are exaggerated, or deep sensation is impaired or abolished (107; 20).
Table 2. Harding’s Essential Diagnostic Criteria for Friedreich Ataxia
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When symptoms have been present for less than 5 years: | |
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(1) Onset of symptoms before 25 years of age | |
Loss of joint position sense, 2-point discrimination, and vibration sense is noted in majority of the patients. Dysarthria usually develops later in the course of the disorder. Harding reported that dysarthria is seen in 60% of patients within 5 years of disease onset and in all patients after 10 years (52). Fifty percent or more develop pes cavus, scoliosis, distal wasting, hypertrophic cardiomyopathy, a positive Romberg sign, impaired speech discrimination, and abnormal extraocular movements. The abnormal extraocular movements include fixation instability with square wave jerks and reduced gain of vestibulo-ocular reflex (75). Saccadic latency was observed to be prolonged in genetically confirmed individuals (35). In a study, three of 28 childhood-onset patients presented with cardiomyopathy (02). Troponin I values provide a marker of cardiac hypertrophy and serve as a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia (93). A minority of affected individuals develops optic atrophy, nystagmus, sensorineural hearing loss, sphincter dysfunction, diabetes mellitus, or impaired glucose tolerance (27).
Although Harding’s criteria remain important, studies that classify patients by genotype have expanded the clinical phenotype to include variant (atypical) forms. The most commonly altered criteria are 1 and 3, which would account for a later onset and retention of tendon reflexes. As many as 25% of affected individuals are atypical (136). One of these clinical variants, late-onset Friedreich ataxia, is characterized by less severe skeletal deformities and onset after the age of 25 years. This milder form of Friedreich ataxia occurs in 14% of affected individuals. There is also a variant called "very-late-onset Friedreich ataxia," in which ataxia begins after the age of 40 years. A less common variant, Friedreich ataxia with retained reflexes, causes early-onset ataxia with preservation of tendon reflexes (12% of patients). Acadian Friedreich ataxia is ethnically limited (32; 107). As genetic testing has become more available, the phenotypic variability has broadened. Remarkably, two patients have been reported to have chorea without cerebellar signs (51). Also, there has been a report of Friedreich ataxia presenting in a 51-year-old man with slowly progressive spastic quadriparesis, pseudobulbar palsy, no cerebellar signs, and a normal brain MRI (85).
Early-onset cerebellar ataxia with retained reflexes. Early-onset cerebellar ataxia with retained reflexes causes progressive ataxia, oculomotor dysfunction, and impaired vibratory and position sense (75). Tendon reflexes are retained. It is diagnosed only after Friedreich ataxia and other causes of progressive ataxia have been excluded (119).
Other. There are many other rare syndromes that cause early-onset cerebellar ataxia. Behr syndrome causes ataxia, optic atrophy, spasticity, and mental retardation. Peripheral neuropathy may also be present (149). Holmes syndrome causes cerebellar ataxia and hypogonadism (75). Marinesco-Sjogren syndrome is early-onset ataxia with cataracts and mental retardation. Hallgren syndrome causes cerebellar ataxia, retinal degeneration, and deafness. Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a cerebellar ataxia associated with spasticity, amyotrophy, and bladder dysfunction.
Ataxia-telangiectasia and other disorders of DNA repair. In ataxia-telangiectasia, slowly progressive cerebellar ataxia is associated with choreoathetosis, telangiectasia of the skin and conjunctiva, susceptibility to sinopulmonary infections, and an increased incidence of lymphoreticular and other malignancies (134; 152). Symptoms usually begin as truncal ataxia in infancy (119). With progression, there is a diminution of deep tendon reflexes and atrophy of the hands and feet (80). Children are usually wheelchair-dependent by 12 years of age.
The characteristic telangiectasias usually appear in the eyes and skin at 3 to 5 years of age. Occasionally, they can be the presenting feature, but they usually develop after ataxia. As in Friedreich ataxia, a patient with ataxia-telangiectasia can develop dysarthria and nystagmus. Patients with ataxia-telangiectasia can have a variety of movement disorders, including dystonic posturing, choreoathetosis, and myoclonus. Unlike Friedreich ataxia, areflexia is less prominent. Patients may have cognitive decline or a plateau in their cognitive development. Patients have ocular-motor apraxia, manifested as difficulty initiating saccadic eye movements.
There are multiple non-neurologic abnormalities that occur in children with ataxia-telangiectasia. They have frequent sinopulmonary infections due to immunodeficiency. This can lead to bronchiectasis and pulmonary insufficiency (119). However, despite multiple laboratory immunologic abnormalities, it is rare for individuals with ataxia-telangiectasia to have systemic bacterial, severe viral, and opportunistic infections (113). Affected individuals may have delayed sexual development and signs of premature aging. Many patients develop cancer, especially leukemias and lymphomas.
The underlying molecular defect in ataxia-telangiectasia is abnormal DNA repair. Two other disorders of DNA repair, xeroderma pigmentosa and Cockayne syndrome, also cause ataxia. Like ataxia-telangiectasia, patients with xeroderma pigmentosa have choreoathetosis, but additional associated features include skin cancer due to photosensitivity, intellectual disability, dementia, seizures, spasticity, deafness, and large-fiber sensory neuropathy. Cockayne syndrome causes ataxia, intellectual disability, photosensitivity that predisposes to skin cancers, and neuropathy. Cockayne syndrome is characterized by a unique bird-like face, short stature, progeria, cataracts, and basal ganglia calcifications (111).
Ataxia with oculomotor apraxia type 1 (AOA1). After Friedreich ataxia, this inherited ataxia is the second most common cause of recessively inherited ataxia in some regions of the world. It is characterized by cerebellar ataxia, axonal sensorimotor neuropathy, and cognitive impairment. Other common features include oculomotor apraxia, hypometric saccades, hypoalbuminemia, and hypercholesterolemia (83). Choreoathetosis is a common feature at presentation, but this usually improves.
Ataxia with oculomotor apraxia type 2 (AOA2). Although similar to AOA1, AOA2 is a distinct clinical entity that shows linkage to 9q34. Characteristic features include ataxia (100%), oculomotor apraxia (56%), sensorimotor neuropathy (92%), and choreic or dystonic movements (44%) (82). Alpha-fetoprotein levels were elevated in all individuals. Individuals with AOA2 may also have hypoalbuminemia and hypercholesterolemia. Unlike ataxia-telangiectasia, AOA2 may cause elevations in immunoglobulin levels.
Congenital ataxias. Cerebellar malformations are the common neuroanatomic feature of the congenital ataxia syndromes. Malformations include cerebellar aplasia, vermian aplasia, Joubert syndrome, cerebellar hypoplasia, Dandy-Walker malformation, and Chiari malformation. They present with ataxia but are associated with hydrocephalus, hyperpnea, spasticity, intellectual disability, or seizures. Unlike other forms of inherited ataxia, the symptoms are not progressive.
The progressive myoclonic ataxia, formerly Ramsay Hunt syndrome, cause progressive ataxia and intention myoclonus in children (142). Progressive myoclonic ataxias have multiple etiologies, including mitochondrial disorders such as myoclonic epilepsy with ragged-red fibers and Kearns-Sayre syndrome. Clinically, Kearns-Sayre syndrome presents with ophthalmoplegia, cardiomyopathy, hearing loss, and retinopathy. Neuropathy, ataxia, and retinitis pigmentosa is another mitochondrial disorder associated with ataxia. However, unlike myoclonic epilepsy with ragged-red fibers and Kearns-Sayre syndrome, it does not cause myoclonus. Other causes of progressive myoclonic ataxia include celiac disease and dentatorubral-pallidoluysian atrophy.
Progressive myoclonic epilepsies can also cause early-onset progressive ataxia. Progressive myoclonic epilepsies are characterized by myoclonic epilepsy and cognitive impairment. Etiologies include neuronal ceroid lipofuscinosis, Lafora disease, the sialidoses, Unverricht-Lundborg disease, and myoclonic epilepsy with ragged-red fibers. The progressive myoclonic ataxias are similar to the progressive myoclonic epilepsies, but individuals with progressive myoclonic ataxia usually have fewer seizures and no cognitive decline. Nevertheless, progressive myoclonic epilepsy can cause ataxia, and differentiating these two categories of disease requires thorough evaluation.
Ataxia with isolated vitamin E deficiency. Ataxia with primary vitamin E deficiency is clinically identical to Friedreich ataxia (56). The only distinguishing feature is the low vitamin E level in the former (14).
Abetalipoproteinemia. Abetalipoproteinemia or Bassen-Kornzweig disease is a disorder of lipoprotein metabolism associated with malabsorption of the fat-soluble vitamins, A, D, E, and K. Patients usually present in the first decade of life with steatorrhea, sensorimotor neuropathy, and retinitis pigmentosa. They may also develop ataxia, dysarthria, areflexia, and ophthalmoparesis. Most of these symptoms are due to vitamin E deficiency. Friedreich ataxia and abetalipoproteinemia can both cause a cardiomyopathy. However, in Friedreich ataxia, there is usually evidence of cardiac involvement early in the course of the disease. If cardiomyopathy develops in abetalipoproteinemia, it is usually a late finding.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Autosomal recessive spastic ataxia of Charlevoix-Saguenay or Charlevoix-Saguenay spastic ataxia is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean region in Quebec (146). Spasticity, muscle wasting (atrophy), ataxia, retinal optic nerve hypermyelination, pes cavus, intellectual disability, epilepsy, hearing loss, dysphagia, nystagmus, scoliosis, and limb deformities are frequently observed in affected individuals. Mutations in the SACS gene cause unstable sacsin protein, which may impair normal organization of intermediate filaments such as neurofilaments, leading to disruption in neuron function (04).
Inborn errors of metabolism. Table 3 lists inborn errors of metabolism that can cause ataxia. Each disease is listed with its mode of inheritance, temporal course of the ataxia, and distinguishing features (16).
Table 3. Inborn Errors of Metabolism Resulting in Ataxia
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Amino acid and organic acid metabolism | |
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Biotinidase deficiency | |
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• Inheritance: autosomal recessive | |
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Gamma-glutamylcysteine synthetase | |
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• Inheritance: autosomal recessive | |
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Hartnup disease | |
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• Inheritance: autosomal recessive | |
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L-2 hydroxyglutaric aciduria | |
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• Inheritance: autosomal recessive | |
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Isovaleric acidemia | |
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• Inheritance: autosomal recessive | |
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Maple syrup urine disease | |
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• Inheritance: autosomal recessive | |
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Methylmalonic acidemia | |
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• Inheritance: autosomal recessive | |
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Propionic acidemia | |
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• Inheritance: autosomal recessive | |
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Dyslipoproteinemias | |
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Abetalipoproteinemia | |
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• Inheritance: autosomal recessive | |
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Cerebrotendinous xanthomatosis | |
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• Inheritance: autosomal recessive | |
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Leukodystrophies | |
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Adrenoleukodystrophy | |
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• Inheritance: X-linked | |
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Krabbe (globoid cell) | |
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• Inheritance: autosomal recessive | |
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Metachromatic leukodystrophy | |
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• Inheritance: autosomal recessive | |
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Lysosomal storage diseases | |
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Fabry (105) | |
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• Inheritance: X-linked | |
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GM2 gangliosidoses | |
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• Inheritance: autosomal recessive | |
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Galactosialidosis | |
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• Inheritance: autosomal recessive | |
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Gaucher type 3 | |
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• Inheritance: autosomal recessive | |
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Multiple sulfatase deficiency | |
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• Inheritance: autosomal recessive | |
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Niemann-Pick type C | |
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• Inheritance: autosomal recessive | |
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Mitochondrial | |
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Kearns-Sayre syndrome (KSS) | |
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• Inheritance: sporadic | |
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Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) | |
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• Inheritance: mitochondrial or autosomal recessive | |
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Myoclonic epilepsy with ragged-red fibers (MERRF) | |
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• Inheritance: mitochondrial | |
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Neuropathy, ataxia, retinitis, and pigmentosa (NARP) | |
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• Inheritance: mitochondrial | |
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Other | |
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Aceruloplasminemia (103; 104) | |
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• Inheritance: autosomal recessive | |
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Cobalamin (vitamin B12 deficiency) | |
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• Inheritance: autosomal recessive | |
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Congenital disorders of glycosylation (31; 74) | |
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• Inheritance: autosomal recessive | |
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Giant axonal neuropathy | |
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• Inheritance: autosomal recessive | |
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Neuronal ceroid lipofuscinosis | |
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• Inheritance: autosomal recessive | |
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Pyruvate dehydrogenase | |
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• Inheritance: X-linked or autosomal recessive | |
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Refsum disease | |
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• Inheritance: autosomal recessive | |
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Urea cycle defects | |
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• Inheritance: X-linked (OTC deficiency) or autosomal recessive | |
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Wilson disease | |
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• Inheritance: autosomal recessive | |
X-linked spinocerebellar ataxia syndromes. X-linked sideroblastic anemia with ataxia causes a nonprogressive early-onset ataxia with dysmetria, tremor, and dysarthria (115). Male carriers of the fragile X premutation can develop progressive ataxia and intention tremor (50). All of the men diagnosed with this syndrome have been older than 50 when they began to show symptoms. They also have progressive cognitive difficulties and behavioral problems. Other less common features include parkinsonism, peripheral neuropathy, proximal leg weakness, lower leg spasticity, and autonomic dysfunction.
There are many other X-linked inherited ataxias reported in the literature. However, these syndromes are not yet well characterized. They each manifest significant phenotypic variability, and the genetic abnormalities are largely unknown.
Application of state-of-the-art MRI technology, particularly involving the cerebellum, has gained interest for diagnosing and understanding hereditary ataxias (124; 23).
Prognosis and complications
Friedreich ataxia. The disease is slowly progressive, and most patients are unable to walk 10 years to 15 years after the onset of neurologic symptoms. They usually require the use of a wheelchair at about 20 years of age (107). Patients with earlier onset often have a more rapidly progressive deterioration. Earlier age of onset in Friedreich ataxia correlates with earlier need for wheelchair use (76). Although variable, the average duration of the disease from presentation to death is usually 37 years. Survival into the sixth and seventh decades is rare, but it has been reported (52). Progressive skeletal deformities like kyphoscoliosis can occur. With a longer duration of disease, the following problems occur or worsen: amyotrophy and muscle weakness in the legs, hypotonia, dysarthria, impairment of vibration sense, decreased visual acuity, hearing loss, sphincter disturbances, and swallowing difficulties (32). Diabetes mellitus develops in about 10% of patients overall but in about 25% who have onset before 10 years of age (27). It is due to insulin resistance, which can also be detected in the first-degree relatives of individuals with Friedreich ataxia (36). Death most commonly results from hypertrophic cardiomyopathy, dysrhythmia, or intercurrent infections.
Ataxia-telangiectasia. Patients have frequent sinopulmonary infections. They usually die in early adulthood from an infection or neoplasm.
Congenital ataxias. Prognosis depends on the underlying defect and the severity of the associated symptoms.
Sleep disorders are common in hereditary ataxias. The main sleep disorders related to hereditary ataxias include REM sleep behavior disorder, insomnia, excessive daytime sleepiness, obstructive and central sleep apnea, periodic leg movement in sleep, and restless legs syndrome (60).
Clinical vignette
A 6-year-old girl with a 4-year history of progressive ataxia presented to genetics clinic. She was healthy and developmentally normal until 2 years of age. At that time, she began to fall when running. Falling became more frequent, especially going up stairs. The patient was evaluated by a neurologist for a possible myopathy. Her C12 to C26 fatty acids were elevated on the acylcarnitine profile. A muscle biopsy revealed predominant type 2 fiber loss, and the electron microscopy showed abnormal mitochondria. However, the activity levels of pyruvate dehydrogenase and the electron transport chain complexes were normal.
As time went on, the patient continued to fall frequently. At 5 years of age, she developed truncal titubation and an intention tremor. These symptoms continued to worsen until the intention tremor and dysmetria impaired her ability to feed herself.
Her school teachers reported that she had decreased mental processing skills and slow responses to questions. She interacted less with peers. She developed speech problems and echolalia.
The patient’s family history was noncontributory. There was no history of ataxia or other neurologic disorders. Her parents were nonconsanguineous. On review of symptoms, her parents reported that she developed urinary incontinence. She also had a low pain threshold.
On physical examination, the patient had normal vital signs. Her height was at the 10th percentile for age, but her weight was only 14.7 kg, significantly less than the 5th percentile for age. Head circumference was at the 50th percentile for age. General physical examination was unremarkable. She had no dysmorphic features. There was no hepatosplenomegaly. On neurologic examination, she occasionally had echolalia. She had hypometric saccades. Bulk was decreased. There was diffuse hypotonia. She had distal arm and proximal leg weakness. No fasciculations were observed. No sensory deficits were noted. She was hyperreflexic. Babinski sign was present on the left and equivocal on the right. She had prominent dysmetria on finger-to-nose testing. She had severe dysdiadochokinesia. Her gait was wide-based. There was dystonic posturing of her arms during ambulation. She could not stand unassisted with her feet together and her arms outstretched.
Multiple laboratory studies were completed, but no specific diagnosis was made. High-resolution karyotype was normal 46, XX. Plasma amino acids revealed an elevated alanine of 40.9 (11.7-35.3). The patient’s cerebrospinal fluid alanine level was elevated at 678 (143-439). Serum and cerebrospinal fluid lactate levels were normal. The remainder of the cerebrospinal fluid indices were normal. Urine organic acid analysis, ammonium, CK, and serum copper were normal. Ceruloplasmin was not studied. Isoelectric focusing for congenital disorders of glycosylation was normal. Mevalonic acid level was normal. Electromyography and nerve conduction studies were normal. Echocardiogram revealed a small patent foramen ovale. Electroencephalography was normal.
There were trace amounts of mucopolysaccharides in the patient’s urine. Also, a repeat brain MRI revealed progressive cerebellar atrophy.
Laboratory studies were performed to determine the etiology of the progressive cerebellar atrophy. Vitamin E level, alpha-fetoprotein level, quantitative carnitine, and a repeat acylcarnitine profile were all normal. However, hexosaminidase activity was markedly reduced. Total activity was 87.8 nanomoles of substrate cleaved per mg protein per hour (normal is 1100). Hexosaminidase A activity was within normal limits. The results were confirmed in a fibroblast culture. Based on these results, the patient was diagnosed with the juvenile form of Sandoff disease (GM2 gangliosidosis). The diagnosis, natural history of the disease, and mode of inheritance were discussed at length with the family during a follow-up clinic appointment. The patient was referred to a local neurologist and geneticist for ongoing management.
Biological basis
Etiology and pathogenesis
When known, the etiology of nonautosomal dominant inherited ataxias is always a pathogenic mutation of a gene. For this reason, please see the "Pathogenesis and pathophysiology" section for etiology.
For each of the nonmetabolic causes of inherited ataxia, the following table lists each disease with its gene locus, gene product, and causative mutation.
Table 4. Pathogenesis, Pathophysiology, and Etiology of Nonautosomal Dominant Inherited Ataxias
|
Name |
Chromosome |
Gene product |
Mutation or defect |
|
Friedreich ataxia |
9q13-21 |
Frataxin (FXN) |
GAA repeat expansion |
|
Ataxia with isolated vitamin E deficiency |
8q13 |
Alpha-tocopherol transfer protein |
Frame shift mutations |
|
Ataxia-telangiectasia |
11q22-23 |
Ataxia-telangiectasia mutated (ATM) |
Impaired DNA repair |
|
Ataxia with oculomotor apraxia type 1 |
9p13 |
Aprataxin (APTX) | |
|
Ataxia with oculomotor apraxia, type 2 |
9q34 |
Senataxin (SETX) | |
|
Autosomal recessive spastic ataxia |
13q11 |
Sacsin |
Truncation mutations |
|
X-linked sideroblastic anemia |
Erythroid-specific 5-Aminolevulinate synthetase |
Variable |
Friedreich ataxia. Friedreich ataxia is due to mutations in the frataxin gene on chromosome 9q13. It is the only autosomal recessive trinucleotide repeat disease. Most repeat expansions are common, benign polymorphisms. For example, the frataxin gene has a GAA-repeat expansion in the first intron that usually has 8 to 22 repeats (13). But in Friedreich ataxia the GAA-repeat expansion is enlarged to 66 to 1700 repeats (32; 100). Repeat expansions are “dynamic” mutations because they are unstable and can undergo enlargement or contraction during meiosis. The intergenerational instability of the GAA trinucleotide repeat is greater in maternal transmission than in paternal transmission (122). During maternal transmission of the GAA allele, expansions or contractions can occur. But in paternal transmission, only contractions occur.
In about 95% to 98% of the causative mutations, there are homozygous unstable GAA-repeat expansions in the first intron of the frataxin gene. The size of the expansion in the smaller of the two enlarged trinucleotide repeat sequences correlates with disease severity. Thus, larger expansions cause (1) an earlier age of onset, (2) a shorter amount of time until a patient loses ambulation, and (3) additional manifestations including dysarthria, cardiomyopathy, pes cavus, scoliosis, and extensor plantar responses (32; 107; 136; 76; 100). The mechanisms and types of GAA repeat instability differ dramatically between dividing and nondividing cells, suggesting that distinct repeat-mediated mutations in terminally differentiated somatic cells might influence Friedreich ataxia pathogenesis (112). In some studies, smaller expansion size correlated with variant forms such as Friedreich ataxia with retained reflexes (32), but in other studies, smaller expansion size did not correlate with Friedreich ataxia with retained reflexes or with Acadian Friedreich ataxia (107). A longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7 to 9 years demonstrated progressive expansions of the GAAs with maximum gain of approximately nine repeats per year (89). The group suggests continuous GAA expansions throughout the patient's lifespan, as observed in Friedreich ataxia lymphocytes, which should be considered in clinical trial designs and data interpretation.
The remaining patients with Friedreich ataxia have compound heterozygous mutations. These individuals have a GAA-repeat expansion in one allele of the frataxin gene and a point mutation (missense or frameshift) in the other allele (20; 03; 123). These patients have a milder course and later onset than homozygous patients. They have a higher prevalence of optic disc pallor (33%). In 25% of the compound heterozygotes, the patients have spastic gait with mild or no ataxia and no dysarthria (20). If an expansion is not detected on either allele, Friedreich ataxia is ruled out.
Frataxin, a 210-amino acid nuclear-encoded protein, is an iron-binding protein that is involved in iron metabolism in the mitochondria (125). Frataxin is expressed in the brain, heart, pancreas, liver, muscle, thymus, and brown fat. The expansion mutation causes reduced expression of frataxin, leading to a deficiency of an iron-sulfur protein involved in iron homeostasis (aconitase) and accumulation of iron in cardiac muscle and the dentate nucleus (153). Yeast with the homologous mutation accumulates iron in the mitochondria and are sensitive to oxidative stress. Similarly, there is impaired oxidative phosphorylation function; severe deficiencies in the mitochondrial respiratory chain complex 1, complex 2, and complex 3; and diminished aconitase activity in the cardiac muscle of patients with Friedreich ataxia (09). Finally, there is evidence that mitochondrial respiration is impaired in skeletal muscle of patients with Friedreich ataxia. Therefore, the disorder can be considered a mitochondrial disease, in which iron accumulation causes oxidative damage (87). Frataxin is documented to have a main role in the biogenesis of mitochondrial iron sulfur clusters (128). Proteomic, metabolic, and functional studies performed by Selak and colleagues found that frataxin protein levels were significantly decreased in platelets and peripheral blood mononuclear cells from Friedreich ataxia patients (139). The most significant differences associated with frataxin deficiency in Friedreich ataxia blood cell mitochondria were the decrease of two mitochondrial heat shock proteins.
Quantitative PCR and microarrays were applied to Friedreich ataxia patient lymphocytes, and a subset of genes was found to be changed in cells from patients with pathological frataxin deficiency (19). These changes in gene expression were related to mitochondria, lipid metabolism, cell cycle, and DNA repair, consistent with known pathophysiology. Therefore, this study shows that Frataxin downregulation is associated with changes in gene expression in vitro, and if verified in vivo, these peripheral biomarkers could be used to study therapeutic and other outcomes. Coppola and colleagues further evaluated the effect of multiple compounds such as histone deacetylase inhibitors on this set of genes and found that the biochemical phenotype was ameliorated in accordance with drug efficacy (19).
Another area of expanding interest is identification of mitochondrial DNA polymerase gamma (POLG) mutations in patients with ataxia. These disorders have become recognized as one of the most common inherited mitochondrial diseases, and novel recessive mutations found by genomic array studies describe a broad spectrum of disorders (147; 58).
R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA (46). They play crucial biological functions and are implicated in neurologic diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia, fragile X syndrome), and cancer.
Pathology. On gross inspection, the cerebellum and spinal cord may look normal. The posterior portions of the spinal cord are more severely involved. Microscopically, the characteristic findings include loss of large sensory neurons in the dorsal root ganglia and degeneration of the dorsal and ventral spinocerebellar tracts, the posterior columns, and the corticospinal tracts. A distinct pattern of fiber degeneration in the lateral corticospinal tract has been reported (110). This abnormality rarely extends above the medulla. Motor evoked potentials by magnetic stimulation are predictably abnormal (106). Less commonly, degeneration of the dorsal roots, dorsal root ganglia, and peripheral nerves as well as loss of cells in Clarke column and substantia gelatinosa are observed. A distal axonopathy occurs (67). The anterior horn cells are usually normal. The cerebrum, cerebellum, and brainstem are usually normal, but Purkinje cell loss in the cerebellum and diminution of Betz cells in the motor cortex has been reported. Cardiac histology evaluation reveals chronic interstitial fibrosis and hypertrophic obstructive cardiomyopathy. The areas of greatest pathology parallel the areas in which normal frataxin RNA expression is highest; frataxin expression is high in the heart and spinal cord, not as high in the cerebellum, and low in the cortex (63; 125). Two novel FXN isoforms (II and III), specifically expressed in cerebellum and heart tissues, respectively, have been identified (159). These findings improve our understanding of the mechanism of tissue-specific pathology in Friedreich ataxia.
Early-onset cerebellar ataxia. Early-onset cerebellar ataxia with retained reflexes may have multiple modes of inheritance, including autosomal recessive, X-linked, and sporadic (75). There is diffuse cerebellar atrophy. Nerve conduction studies reveal an axonal neuropathy. The pathogenesis of this disorder is unknown.
Progressive myoclonic ataxia can be caused by mitochondrial DNA abnormalities. Myoclonic epilepsy with ragged-red fibers is due to a lysine-tRNA missense mutation of mitochondrial DNA. Kearns-Sayre syndrome is usually due to large deletions in mitochondrial DNA. Neuropathy, ataxia, retinitis, and pigmentosa is due to a point mutation in the mitochondrial ATPase 6 gene.
Unverricht-Lundborg, a cause of progressive myoclonic epilepsy, is due to a dodecanucleotide repeat expansion. The other causes of progressive myoclonic epilepsy are inborn errors of metabolism due to single-gene mutations.
Other. Autosomal recessive spastic ataxia of Charlevoix-Saguenay is due to truncating mutations on chromosome 13q11. The gene, named SACS, encodes for a protein named sacsin (34). The structure of sacsin has similarities with proteins that chaperone protein folding (29).
Ataxia-telangiectasia. This is an autosomal recessive disease caused by mutations of the ataxia-telangiectasia mutated gene on chromosome 11 (134). The ataxia-telangiectasia mutated gene encodes a large protein that is believed to regulate the cell cycle when DNA has been damaged (101). The ataxia-telangiectasia mutated protein has a structure similar to phosphoinositol-3-kinases. These kinases appear to participate in insulin-dependent glucose transport and growth factor responses. This may explain why some individuals with ataxia-telangiectasia develop diabetes (71). The ataxia-telangiectasia mutated protein also has similarities with yeast proteins that are involved in DNA repair. Defects in the ability to repair damaged DNA could account for the increased susceptibility of cancer in ataxia-telangiectasia patients (71). New mutations have been reported for ataxia-telangiectasia as mutational screening has become increasingly available (28).
Ataxia-telangiectasia is associated with atrophy of the cerebellum that begins in the lateral portions of the hemispheres. As the disease progresses or in severe cases, there is diffuse atrophy of the cerebellum involving both the hemispheres and the superior vermis more than the inferior vermis (148). A study showed, for the first time, in vivo evidence of depleted neural stem cells in the subventricular zone of Atm(-/-) mice and also demonstrated that pharmacologic inhibition of p38MAPK signaling has the potential to treat neurologic defects of ataxia-telangiectasia (73). This study and other current research show promise for targeting the oxidative stress-dependent p38 signaling pathway for ataxia-telangiectasia and other neurodegenerative disorders.
Residual kinase activity confers a milder phenotype, but there is no difference between kinase-dead and protein-null genotypes (65).
Ataxia with oculomotor apraxia type 1. Mutations in APTX, the gene that encodes aprataxin, lead to ataxia with oculomotor apraxia. Aprataxin has domains that are homologous to proteins that are essential for signalling DNA damage and repairing DNA (47). Cells from individuals with this syndrome show genome instability that is corrected with transfection with full-length aprataxin cDNA. Finally, aprataxin interacts with a variety of proteins involved in DNA repair. Cerebellar atrophy is a universal finding. Predominant vermian atrophy is present in two thirds of cases (83).
Ataxia with oculomotor apraxia type 2. Similar to ataxia with oculomotor apraxia type 1, ataxia with oculomotor apraxia type 2 causes severe cerebellar atrophy with predominant vermian hypoplasia (82).
Congenital ataxias. Joubert syndrome secondary to two frameshift mutations and one missense mutation in the AHI1 gene was identified in three consanguineous families (30). AHI1 encodes the Jouberin protein. Its expression in embryonic hindbrain and forebrain suggests that the protein is important for cerebellar and cortical development.
Ataxia with primary vitamin E deficiency. Like Friedreich ataxia, ataxia with primary vitamin E deficiency is autosomal recessive. It is caused by a frameshift mutation in the gene for the alpha-tocopherol transfer protein on chromosome 8 (44). In this disease, alpha-tocopherol cannot be incorporated into lipoproteins (114).
Abetalipoproteinemia. Abetalipoproteinemia is an autosomal recessive disorder due to a mutation in the microsomal triglyceride transfer protein that causes abnormalities in lipoprotein metabolism. Betalipoproteins, the primary protein of chylomicrons and low density lipoproteins, cannot be synthesized (33). Chylomicrons are essential for absorption of the fat-soluble vitamin A, vitamin D, vitamin E, and vitamin K. Most of the clinical symptoms are due to vitamin E deficiency.
X-linked spinocerebellar ataxia syndromes. X-linked sideroblastic anemia with ataxia is due to mutations on X13q. The pathogenesis of this disorder is unclear, but it may relate to mitochondrial iron accumulation (70).
Fragile X syndrome, the most common cause of inherited mental retardation, is caused by deficiency in FMRP, a protein important for early brain development. The disorder is caused by an expansion of more than 200 CGG trinucleotide repeats in the FMR1 gene. Premutation carriers have 55 to 200 CGG repeats. It is widely known that women with premutations can have premature ovarian failure. Men older than 50 who have premutations have been shown to be at risk for developing a progressive cerebellar syndrome. Neuroimaging studies in these men have revealed the presence of symmetric white mater lesions of the middle cerebral peduncle, mild to moderate cerebellar hemisphere atrophy, and periventricular and deep white matter cerebral hyperintensities (11; 66).
Other genetics. Genetic studies in nondominant hereditary ataxias are revealing an expanding number of mutations across the clinical spectrum of these disorders. In addition, attention toward mitochondrial and epigenetic phenomena is increasingly popular. Multigenic inheritance applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered (59). The list of mutations is too extensive to discuss in this clinical review. Examples of a few findings include CABC1/ADCK3 (42), PEX10 (131), and ANO10 (151). These promising findings are helping to unravel the molecular mechanisms underlying these groups of disorders. Next-generation genetic sequencing is contributing to understanding the clinically and genetically heterogeneous neurodegenerative disorders that comprise the hereditary ataxias (22; 127).
Epidemiology
Friedreich ataxia. Harding reported that the incidence of Friedreich ataxia in the general population is one to two per 100,000 (54). Friedreich ataxia is the most common hereditary ataxia. In a study that used consanguinity data from Spain, the gene frequency was estimated to be one in 127 and the incidence was 6.18 in 100,000 live births. The prevalence, similar to Harding’s estimate, was 3.83 in 100,000 (90). In North America, Acadian Friedreich ataxia is an ethnic variant characterized by milder course and rarity of cardiac involvement (107).
Early-onset cerebellar ataxia. The prevalence of early-onset cerebellar ataxia with retained reflexes has been reported to be 0.5 to 2.3 per 100,000 individuals. Autosomal recessive spastic ataxia of Charlevoix-Saguenay has a high prevalence in Quebec, Canada (29).
Ataxia with primary vitamin E deficiency. This is seen in families from the southern Mediterranean area (29).
Ataxia-telangiectasia. This has an estimated incidence of about one in 80,000 to 100,000 live births (144).
Ataxia with oculomotor apraxia. This is most common in Japan and Portugal.
Congenital ataxias. These disorders are too rare to establish epidemiologic data.
Prevention
Friedreich ataxia. Prenatal diagnosis is available (118). Direct testing of fetal blood that shows the GAA-repeat expansion on both alleles is diagnostic for Friedreich ataxia. If only one allele is expanded, the fetus may be a normal carrier or an affected compound heterozygote (expansion on one allele and a point mutation on the other). When both alleles have GAA repeats in the normal size range, Friedreich ataxia is excluded (32). If one child is affected, each sibling has a 25% risk of developing Friedreich ataxia. As with other autosomal recessive diseases, consanguinity between parents increases the risk of having a child with Friedreich ataxia.
Differential diagnosis
This section will discuss the differential diagnosis of all forms of inherited ataxia, including those that are inherited in an autosomal dominant, autosomal recessive, X-linked, or mitochondrial pattern.
The unifying factor among these diseases is ataxia, most often progressively worsening in nature. The differential diagnosis for ataxia is extensive. Grouping the various ataxic disorders by their associated features can help differentiate them. The associated features include the inheritance pattern, temporal course, signs of pyramidal tract involvement, ophthalmologic abnormalities, eye movement abnormalities, peripheral nervous system involvement, the occurrence of seizures, and various idiosyncratic features (eg, acanthocytes).
Inheritance pattern. If the patient with ataxia does not have a family history of ataxia, genetic, nongenetic, and sporadic causes should be considered. The sporadic causes of spinocerebellar syndromes include multiple system atrophy (olivopontocerebellar atrophy, striatonigral degeneration, Shy-Drager syndrome), immune dysfunction (multiple sclerosis, glutamic acid decarboxylase antibody, paraneoplastic syndromes), or systemic diseases (celiac disease, vitamin E deficiency, hypothyroidism) (97). Other acquired causes of ataxia include stroke, CNS infection, hydrocephalus, and structural lesions such as posterior fossa tumors (119).
If a child with progressive ataxia, pes cavus, kyphoscoliosis, and signs of spinocerebellar dysfunction has a sibling with ataxia, Friedreich ataxia is a likely diagnosis. Because Friedreich ataxia is autosomal recessive, the parents are usually asymptomatic.
If either parent is affected with ataxia, the disorder is more likely to be one of the autosomal dominant spinocerebellar ataxias. However, ataxia in a parent does not necessarily exclude Friedreich ataxia (81). In Friedreich ataxia, the patient is usually areflexic. The spinocerebellar ataxias (SCAs) usually cause hyperreflexia. Autosomal dominant inheritance and anticipation patterns in SCAs of unknown cause should be evaluated for a homozygous recessive mitochondrial disorder such as mitochondrial recessive ataxia syndrome (MIRAS) (116). Such cases represent a high carrier frequency resulting in two independent introductions of the mutant allele, mimicking dominant inheritance.
Features that cast doubt on the diagnosis of Friedreich ataxia include the following (107):
|
• intellectual disability |
Temporal course. Periodic episodes of ataxia associated with vomiting are observed in urea cycle defects. Other causes of episodic ataxia include pyruvate dehydrogenase deficiency; propionic acidemia; methylmalonic acidemia; isovaleric acidemia; maple syrup urine disease; myoclonic epilepsy with ragged-red fibers; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome; and Hartnup disease. The remainder of the inherited ataxias usually causes progressive ataxia.
Spasticity. Hereditary spastic paraplegia causes slowly progressive spastic weakness of both lower extremities. If it occurs in the “pure” or “uncomplicated” form, the patient has lower extremity stiffness and weakness, urinary dysfunction, paresthesias, diminished vibratory sensation, and hyperreflexia of the lower extremities. This symptom complex is rarely confused with spinocerebellar degeneration. However, there are “complicated” forms that cause other neurologic problems such as ataxia, pes cavus, optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ichthyosis, intellectual disability, and deafness (38). The complicated forms may cause confusion with Friedreich ataxia.
The ataxia of juvenile GM2 gangliosidosis, unlike Friedreich ataxia, is associated with spasticity and progressive mental deterioration in the absence of neuropathy. A deficiency of hexosaminidase A confirms the diagnosis. Areflexia with amyotrophy and spasticity of the lower limbs also occurs in xeroderma pigmentosum and Chediak-Higashi syndrome.
Ophthalmologic abnormalities. Ophthalmologic findings have been associated with several ataxic disorders. Corneal clouding is characteristic of adult beta-galactosidase deficiency and multiple sulfatase deficiency. Cataracts have been seen in Marinesco-Sjogren disease, Usher syndrome, and cerebrotendinous xanthomatosis (cholestanolosis) as well as in some patients with Friedreich ataxia and spinocerebellar ataxia. Retinal disease, in particular retinitis pigmentosa, has been recognized in abetalipoproteinemia, hypobetalipoproteinemia, Refsum disease, the spinocerebellar ataxias, and Kearns-Sayre syndrome. Spinocerebellar atrophy type 7 is particularly likely to cause impaired vision and retinal disease (68). Disordered macular pigmentation or cherry-red spots of the macula occur in neuronal ceroid lipofuscinosis, Niemann-Pick disease, multiple sulfatase deficiency, adult-onset beta-galactosidase deficiency, and hexosaminidase B deficiency. The myoclonus of the cherry red spot-myoclonus syndrome is occasionally confused with ataxia. Optic atrophy occurs in Marinesco-Sjogren syndrome, Friedreich ataxia, ataxia-telangiectasia, Leigh disease, and some forms of spinocerebellar ataxia.
Eye movement abnormalities. Eye movement disorders may occur in syndromes that cause ataxia. Vertical nystagmus has been observed in multiple sulfatase deficiency. Primary-position upbeat nystagmus has been seen in episodic ataxia and in syndromes that cause cerebellar vermian atrophy. Spontaneous downbeat nystagmus has been noted in late-onset cerebellar ataxia and other lesions of the craniocervical junction, including Chiari malformations, multiple sclerosis, and neoplasms. Anticonvulsant toxicity may also present with downbeat nystagmus. Ocular motor apraxia is seen in ataxia-telangiectasia. When saccades are slow or when there is a combined loss of pursuit and vestibular function, one should consider an autosomal dominant spinocerebellar ataxia (154).
Peripheral nervous system abnormalities. A neuropathy has been associated with several disorders that cause ataxia, including Friedreich ataxia, the spinocerebellar ataxias, xeroderma pigmentosum, Behr syndrome, Refsum disease, adrenomyeloneuropathy, cerebrotendinous xanthomatosis (cholestanolosis), and Dejerine-Thomas ataxia. Diagnosis of ataxia may be particularly difficult early in the course of the disease when only impaired vibratory sensation, ataxia, and areflexia in the legs are present. In these cases, hereditary motor and sensory neuropathy should be considered. Motor nerve conduction velocity is decreased in HMSN type 1 but is usually normal in Friedreich ataxia and HMSN type 2. DNA testing may be necessary to differentiate Friedreich ataxia from hereditary motor and sensory neuropathy type 2. Weakness and distal amyotrophy are seen in Friedreich ataxia, ataxia-telangiectasia, the spinocerebellar ataxias, and Joseph syndrome.
The differential diagnosis of childhood-onset areflexia combined with extensor plantar responses includes Friedreich ataxia and neurodegenerative disorders such as metachromatic leukodystrophy, globoid cell leukodystrophy, neuroaxonal dystrophy, and the rare syndrome of congenital absence of intrinsic factor with B12 deficiency. Areflexia may be seen late in the course of ataxia-telangiectasia, cerebellar ataxia with hypogonadism, some forms of spinocerebellar ataxia, and juvenile metachromatic leukodystrophy. Cockayne syndrome, which may cause areflexia and ataxia, is typically associated with a wizened appearance and cerebral leukodystrophy.
Seizures. Seizures can be a prominent feature in xeroderma pigmentosa, some congenital ataxias, the progressive myoclonic ataxias, and the progressive myoclonic epilepsies. For example, Baltic myoclonus (Unverricht-Lundborg disease) reported predominantly from Scandinavia presents with myoclonus or generalized seizures followed by ataxia, dysarthria, and pyramidal signs in the limbs (78). Many inborn errors of metabolism can cause ataxia and seizure disorders, including pyruvate dehydrogenase deficiency, L-2-hydroxyglutaric aciduria, biotinidase deficiency, urea cycle defects, Gaucher disease type 2, galactosialidosis, and neuronal ceroid lipofuscinosis. Dentatorubral-pallidoluysian atrophy can cause epilepsy, but epilepsy rarely occurs in the autosomal dominant spinocerebellar ataxias (except SCA10).
Idiosyncratic abnormalities. Neuronal intranuclear hyaline inclusion disease is similar to Friedreich ataxia with seizures but without cardiac abnormalities (143).
Acquired vitamin E deficiency can cause symptoms that mimic Friedreich ataxia. There are multiple etiologies for acquired vitamin E deficiency, including inflammatory diseases (celiac disease, inflammatory bowel disease, chronic pancreatitis, chronic cholestatic liver disease), infections (Whipple disease, tropical sprue) malnutrition, postgastrectomy, short bowel syndrome, and cystic fibrosis (64).
The association of tendon xanthomas with mental deterioration differentiates cerebrotendinous xanthomatosis from the spinocerebellar ataxias.
In sporadic cases where no skeletal deformities are found, the neurologic signs of Friedreich ataxia may be similar to multiple sclerosis. The younger age distribution and absence of deep tendon reflexes in Friedreich ataxia differentiate it from multiple sclerosis. In addition, the history of optic neuritis helps to establish the diagnosis of multiple sclerosis.
Adrenomyeloneuropathy, a phenotypic variant of X-linked adrenoleukodystrophy, may present with a spinocerebellar syndrome in males between the ages of 10 and 35 years (108).
Diagnostic workup
There are a large number of known ataxia-causing genes; however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies and expression studies and an increased knowledge of ataxia pathways will aid in the identification of new ataxia genes (132). The European Pediatric Neurology Society published a clinical diagnostic algorithm for early-onset cerebellar ataxia. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuroimaging, laboratory investigations, genetic testing by array comparative genomic hybridization, and next generation sequencing (10; 18).
Friedreich ataxia. In addition to clinical findings, the most important tests for the diagnosis of Friedreich ataxia are DNA analysis showing expanded GAA expansion (107), normal vitamin E level in the blood, and normal motor, but abnormal sensory, nerve conduction studies. Expansion of the GAA trinucleotide repeat in the frataxin gene is diagnostic for Friedreich ataxia. This blood test is not necessary when Harding’s essential diagnostic criteria have been fulfilled because all such patients have had either homozygous or heterozygous GAA-repeat expansion (32; 107). Expansion of the GAA repeat is most helpful to confirm the diagnosis of Friedreich ataxia in patients who have the atypical features: age of onset later than 25 years, preservation of tendon reflexes, or spastic gait without ataxia or dysarthria. Lack of expansion of the GAA repeat (normal is 8 repeats to 22 repeats) excludes the diagnosis of all types of Friedreich ataxia (32; 107).
In Friedreich ataxia, routine hematology and chemistry studies are usually normal. Cerebrospinal fluid protein levels can be elevated, or there can be a mild pleocytosis; however, this is not a consistent finding. Electroencephalogram abnormalities, if found, are nonspecific. The most common electrographic abnormality is slowing of the background. Sensory nerve conduction studies, consistent with an axonal neuropathy, and somatosensory evoked responses are usually abnormal. Motor nerve conduction velocities should be greater than 40 meters per second.
Interestingly, other than the diagnostic GAA-repeat expansion, the most consistent laboratory abnormalities are non-neurologic. The incidence of ECG abnormalities ranges from 30% to more than 90%. The most common finding is the presence of inverted T-waves in several leads, especially inferior and lateral chest leads, but QRS axis changes, ventricular hypertrophy, arrhythmias, atrial hypertrophy, and other nonspecific abnormalities may also be seen (53). Echocardiographic examination of patients with Friedreich ataxia reveals interventricular septal hypertrophy, left ventricular free wall hypertrophy, and slight reduction of left ventricular dimension. There may also be abnormalities in the glucose tolerance test.
Assay of lysosomal enzymes is helpful for the exclusion of lipid storage disorders such as juvenile GM2 gangliosidosis (hexosaminidase deficiency), and it complements brain MRI for the exclusion of leukodystrophies, including metachromatic leukodystrophy (sulfatide lipidosis). Very long-chain fatty acids in blood or other tissues are abnormally elevated in adrenoleukodystrophy and its variant, adrenomyeloneuropathy.
Neuroimaging is most helpful for excluding other disorders. It may also increase our understanding of the pathogenesis of the disease. Atrophy of the vermis (17) and atrophy of the cervical spinal cord (155) occur in Friedreich ataxia. In a comparison among ataxias, one magnetic resonance imaging study found greater thinning of the cervical spinal cord and more posterior or lateral signal abnormalities in the spinal cord of patients with Friedreich ataxia (99). Some studies have shown no correlation between the degree of atrophy and clinical severity (155) whereas others have found that increasing atrophy of cerebellum, cerebral hemispheres, and brain stem identified by brain CT scan correlates with worsening clinical severity (69). Positron emission tomography studies using radio-labeled glucose suggest that early in the course of Friedreich ataxia diffuse cerebral hypermetabolism is present. As the disease worsens, regional decreases in glucose metabolism can be appreciated (43; 69).
Ataxia with primary vitamin E deficiency. Vitamin E levels should be obtained in every patient with chronic ataxia, especially if there is a history of malabsorption. An echocardiogram should also be obtained to screen for cardiomyopathy. The following results suggest abetalipoproteinemia: acanthocytes present in fresh blood samples, low serum cholesterol and triglycerides, and absent beta-lipoproteins. Nerve conduction studies may show axonal neuropathy. Electroretinography is abnormal in abetalipoproteinemia (102).
Ataxia-telangiectasia. This causes elevations in alpha-fetoprotein and carcinoembryonic antigen. Affected individuals also have low levels of IgA and IgE. X-ray sensitivity and radioresistant DNA synthesis can be screened in fibroblasts (119). Neuroimaging studies reveal cerebellar atrophy (133). An EMG may demonstrate evidence of denervation. Nerve conduction studies may show axonal degeneration (75). Lymphocytopenia in newborns can be a feature of ataxia-telangiectasia, as revealed by newborn screening and exome sequencing (95).
Congenital ataxias. These disorders can be diagnosed and distinguished using MRI of the brain.
Early-onset cerebellar ataxia. Evaluation for a mitochondrial cytopathy includes serum and cerebrospinal fluid lactate, urine organic acid profile, muscle biopsy to screen for ragged-red fibers, and mitochondrial DNA analysis. The juvenile form of dentatorubral-pallidoluysian atrophy can be diagnosed by testing for the specific trinucleotide repeat.
Cerebellar atrophy is seen in congenital or infantile olivopontocerebellar atrophy (01) and in some forms of progressive myoclonic ataxia.
Inborn errors of metabolism. The following table lists the metabolic disorders that can cause ataxia, the underlying enzyme defect, and the diagnostic test that aids in diagnosing each disorder (37).
Table 5. Ataxia-Causing Metabolic Disorders
|
Disease |
Enzyme defect |
Diagnostic test |
|
Amino acid and organic acid metabolism | ||
|
Biotinidase deficiency |
Biotinidase deficiency |
Neonatal screen, typical organic aciduria, biotinidase activity |
|
Gamma glutamylcysteine synthetase |
Gamma glutamylcysteine synthetase deficiency |
Amino acid profile, enzyme activity in leukocytes or fibroblasts |
|
Hartnup |
Renal neutral amino acid transporter defect |
Elevated neutral monoamino and monocarboxylic acid levels in urine |
|
L-2-hydroxyglutaric aciduria |
Unknown |
Increased urinary L-2 hydroxyglutaric acid in organic acid profile |
|
Isovaleric acidemia |
Isovaleryl-CA dehydrogenase |
Accumulation of isovaleryl-CoA derivatives in plasma and urine |
|
Maple syrup urine disease |
Branched chain ketoacid dehydrogenase |
Elevated branch chain amino acids and their ketoacids |
|
Methylmalonic acidemia |
Methylmalonyl-CoA mutase |
Elevated methylmalonic acid and propionyl-CoA in plasma and urine |
|
Propionic acidemia |
Propionyl-CoA carboxylase |
Characteristic organic acid profile |
|
Dyslipoproteinemias | ||
|
Abetalipoproteinemia |
Abnormal triglyceride transfer protein |
Acanthocytosis |
|
Cerebrotendinous xanthomatosis |
Sterol 27 hydroxylase (bile salt metabolism) |
Elevated cholestanol |
|
Leukodystrophies | ||
|
Adrenoleukodystrophy |
Disorder of very long chain fatty acid peroxisomal metabolism |
Elevated very long chain fatty acids |
|
Krabbe (globoid cell) |
Galactocerebrosidase |
Direct enzyme assay |
|
Metachromatic leukodystrophy |
Sulfatidase |
Arylsulfatase-A enzyme analysis |
|
Lysosomal disorders | ||
|
Fabry |
Alpha-galactosidase A |
Direct enzyme assay |
|
GM2 gangliosidosis |
Hexosaminidase A |
Direct enzyme assay |
|
Galactosialidosis |
Neuraminidase and beta-galactosidase |
Excess urinary excretion of oligosaccharides |
|
Gaucher Type 3 |
Beta-glucosidase glucocerebrosidase |
Glucocerebrosidase activity in leukocytes, bone marrow |
|
Multiple sulfatase deficiency |
Multiple sulfatase deficiencies |
Enzyme assay of arylsulfatase A, B, and C activity |
|
Niemann-Pick Type C |
Unknown |
Fibroblasts LDL-derived intracellular cholesterol esterification measurement. Sea blue histiocytes in bone marrow |
|
Mitochondrial | ||
|
Kearns-Sayre syndrome |
Large mtDNA deletions |
± Lactic acidosis, elevated CSF protein, mitochondrial DNA, enzyme assay |
|
MELAS |
tRNALeu, COX III |
± Lactic acidosis, ragged red fibers, mitochondrial DNA, enzyme assay |
|
Myoclonic epilepsy with ragged red fibers |
tRNALys mutations |
± Lactic acidosis, ragged red fibers, mitochondrial DNA, enzyme assay |
|
Neuropathy, ataxia, retinitis, and pigmentosa |
ATPase 6 mutations |
± Lactic acidosis, mitochondrial DNA, enzyme assay |
|
Other | ||
|
Aceruloplasminemia |
Mutations in ceruloplasmin gene |
Ceruloplasmin undetectable, low copper and iron, elevated ferritin, normal transferring |
|
Cobalamin (vitamin B12) deficiency |
Intrinsic factor transporter defect |
Low cobalamin in plasma |
|
Congenital disorders of glycosylation |
Defective glycosylation of glycoconjugates |
Isoelectrofocusing or Western-blot analysis |
|
Giant axonal neuropathy |
Disorder of intermediate filaments due to mutations in gigaxonin (08) |
Accumulation of neurofilaments in axons (sural nerve biopsy, skin biopsy) |
|
Neuronal ceroid lipofuscinosis |
Multiple mutations |
Inclusions on conjunctival, rectal, or skin biopsy; DNA testing |
|
Pyruvate dehydrogenase |
One of the subunits of pyruvate dehydrogenase complex |
Lactic acidosis, characteristic amino and organic acid profile, enzyme assay |
|
Refsum disease |
Defective phytanic acid oxidation due to mutations in PHYH or PEX7 (150) |
Elevated phytanic acid |
|
Urea cycle defects |
Multiple |
Hyperammonemia, characteristic urine organic acid profile for each defect |
|
Wilson disease |
Copper transporting ATPase defect |
Low ceruloplasmin, elevated 24-hour urine copper, ophthalmology exam |
Management
Friedreich ataxia. The United States Federal Drug Administration (US FDA) has approved the first drug treatment for Friedreich ataxia, omaveloxolone, a NRF2 agonist (109; 126). The precise mechanism of therapeutic action is unknown, but the drug activates the NRF2 pathway involved in the cellular response to oxidative stress and may help protect neurons. There remains no curative treatment. Dyspnea, palpitations, or chest pain may herald worsening cardiomyopathy. In patients with cardiac involvement, propranolol and digoxin may be used. In patients with diabetes, insulin or oral hypoglycemic agents might be required. However, if insulin is used, propranolol should be avoided. Physical therapy and wheelchairs are usually needed for mobility. Surgical intervention to correct bone and joint deformities may be needed, especially when respiratory compromise is present.
The antioxidant idebenone, a homologue of ubiquinone that inhibits iron-induced cardiac injury, has been shown to decrease or stabilize cardiac hypertrophy (57; 98). Although early studies failed to show a benefit of idebenone therapy (88; 137), current trials show promise (92). A phase 3 double-blinded, randomized, placebo-controlled trial showed that patients who received idebenone (n=24) improved by 2.5 points on mean International Cooperative Ataxia Rating Scale (ICARS) score compared with baseline, whereas patients in the placebo group (n=24) improved by 1.3 points (92). Patients on idebenone improved by 1.6 points on the Friedreich Ataxia Rating Scale (FARS), whereas patients on placebo declined by 0.6 points. For both endpoints, the difference between groups was not significant, demonstrating that further studies are required. The recognition of iron accumulation in mitochondria may lead to other therapeutic approaches, including iron or calcium chelation, other antioxidant compounds, or apoptosis inhibitors (25; 157; 117). Personal FM-hearing devices have been shown to improve everyday hearing situations for patients with auditory neuropathy and Friedreich ataxia (129). Primary and secondary high-throughput drug screening assays have been applied in the yeast frataxin orthologue, and of the 101,200 compounds screened, 302 were identified that effectively rescue mitochondrial function (21). These findings require further confirmatory studies in mammalian cells to evaluate efficacy and to understand mechanisms of action before they are suggested to have relevance for neurodegenerative disorders associated with mitochondrial dysfunction.
Cloning of the disease gene for Friedreich ataxia and elucidation of many aspects of the biochemical defects underlying the disorder have led to several major therapeutic initiatives aimed at increasing frataxin expression, reversing mitochondrial iron accumulation, and alleviating oxidative stress. These initiatives are in preclinical and clinical development and are reviewed herein (156). In the 15 years since the discovery of the frataxin gene, vigorous international efforts have resulted in 21 agents or classes of therapeutic agents in the research pipeline, 24 current clinical trials, 27 published works discussing clinical trial results, and millions of dollars from private, public, and industry-based initiatives, and yet, there is no proven disease-modifying therapy (121). Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy has been reported in a mouse model of Friedreich ataxia (120).
Khonsari and colleagues reported the identification of elevated levels of DNA double strand breaks in Friedreich ataxia patient and YG8sR Friedreich ataxia mouse model fibroblasts compared to normal fibroblasts (72). Using lentivirus FXN gene delivery to Friedreich ataxia patient and YG8sR cells, they obtained long-term overexpression of FXN mRNA and frataxin protein levels with reduced double strand break levels towards normal. Furthermore, γ-irradiation of Friedreich ataxia patient and YG8sR cells revealed impaired double strand break repair that was recovered on FXN gene transfer. This suggests that frataxin may be involved in double strand break repair, either directly by an unknown mechanism or indirectly via iron-sulfur cluster biogenesis for DNA repair enzymes, which may be essential for the prevention of neurodegeneration.
TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory (41). Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression.
The Friedreich Ataxia Caregiver-Reported Health Index (FACR-HI) was designed to measure total disease burden and disease burden in 18 symptomatic domains. The FACR-HI is valid as a caregiver-reported outcome measure for assessing how pediatric individuals with Friedreich ataxia feel and function (138).
Currently, the only approved treatment for Friedreich ataxia is an Nrf2 activator called omaveloxolone (Skyclarys). Patients with FRDA also rely on various symptomatic medications for treatment. The approval of omaveloxolone provides a major advance in therapeutics that is likely to be beneficial in the majority of patients with Friedreich ataxia. Although well tolerated, it is not curative. Reversal of deficient frataxin levels with gene therapy, protein replacement, or epigenetic approaches provides the most likely prospect for enduring disease-modifying therapy in the future (49; 91).
Ataxia with primary vitamin E deficiency. Treatment with vitamin E supplementation can halt the progression of symptoms in patients with ataxia with primary vitamin E deficiency or abetalipoproteinemia (48). In abetalipoproteinemia, the patient should replace long chain fatty acid consumption with polyunsaturated fats in an effort to minimize malabsorption (33).
Ataxia-telangiectasia. Infections should be treated aggressively. Noninvasive quantitative measures of respiratory-swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia (84). Changes in respiratory-swallow coupling observed with advancing age in control participants were not seen in participants with ataxia-telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae.
Congenital ataxias. There is no curative treatment for these malformations. Associated symptoms, such as hydrocephalus and seizures, should be treated when indicated. Patients with developmental delays should receive appropriate therapeutic interventions, such as physical therapy, occupational therapy, and speech therapy. A consensus paper on management of degenerative cerebellar disorders recommends that, up to date, no medication has been proven effective (62). Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy.
Early-onset cerebellar ataxia. Valproate, clonazepam, or levetiracetam may diminish the myoclonus in progressive myoclonic ataxias and progressive myoclonic epilepsies. However, if progressive myoclonic ataxia is due to a mitochondrial disorder, valproate is contraindicated.
Metabolic disease. Enzyme replacement therapy (alpha galactosidase A) for Fabry disease is currently under investigation.
There is a clinical trial repurposing riluzole as a treatment of hereditary cerebellar ataxias (158).
Special considerations
Pregnancy
Medical advances have improved the average life expectancy of Friedreich ataxia patients, and, as such, many female patients contemplate pregnancy (94; 39). A retrospective study examined 31 women with Friedreich ataxia who had 65 pregnancies, resulting in 56 live offspring. Nearly four of five births were vaginal. Pregnancy and delivery did not complicate disease severity. Friedreich ataxia did not increase the risk of spontaneous abortion, preeclampsia, or preterm birth (39).
Anesthesia
For Friedreich ataxia, both general and spinal anesthesia have been successfully used (12; 79). Rocuronium was used safely in two girls with Friedreich ataxia who were undergoing spinal surgery (135).
Lockman and colleagues were the first to describe perioperative risk for patients with ataxia-telangiectasia and showed that general anesthesia, airway manipulation, and perioperative mechanical ventilation may be tolerated with only minor postoperative anesthetic concerns (86).
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Ryan W Y Lee MD
Dr. Lee of the John A Burns School of Medicine at the University of Hawaii has no relevant financial relationships to disclose.
See Profile
Editor
-
Ann Tilton MD
Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
See Profile
Former Authors
- Michael V Johnston MD†
- Tyler Reimschisel MD
- Raymond S Kandt MD
- Deivasumathy Muthugovindan MD
Patient Profile
- Age range of presentation
-
- 1 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- heredity typical
- autosomal dominant
- autosomal recessive
- sex-linked recessive
- 11
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Abetalipoproteinemia: E78.6
- Ataxia-telangiectasia: G11.3
- Baltic myoclonus: G25.3
- Friedreich ataxia: G11.1
- Ramsay Hunt syndrome: B02.2+ G53.0* or G111
- ICD-11
-
- Hypobetalipoproteinaemia: 5C81.1
- DNA repair defects other than combined T-cell or B-cell immunodeficiencies: 4A01.31
- Friedreich ataxia: 8A03.10
- Other specified disorders of facial nerve: 8B88.Y
- OMIM
-
- Abetalipoproteinemia: #200100
- Ataxia telangiectasia: #208900
- Ataxia-oculomotor apraxia syndrome: #208920
- Behr syndrome: #210000
- Cerebellar ataxia, early-onset, with retained tendon reflexes: %212895
- Cockayne syndrome: #216400
- Friedreich ataxia, 1: #229300
- Kearns-Sayre syndrome: #530000
- Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like epdisodes: #540000
- Myoclonic epilepsy associated with ragged red fibers: #545000
- Myoclonic epilepsy of Unverricht and Lundborg: #254800
- Neuropathy, ataxia, and retinitis pigmentosa: #551500
- Spastic ataxia, Charlevoix-Saguenay type: #270550
- Vitamin E, familial isolated deficiency of: #277460
- Xeroderma pigmentosa: #278720
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