Lipid storage diseases

Lipid storage diseases (also known as lipidoses) are a group of inherited metabolic disorders in which harmful amounts of fatty materials (lipids) accumulate in various cells and tissues in the body. People with these disorders either do not produce enough of one of the enzymes needed to break down (metabolize) lipids or they produce enzymes that do not work. Over time, excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system (the nerves from the spinal cord to the rest of the body), liver, spleen, and bone marrow.

Lipids. Lipids are fat-like substances that are important parts of the membranes found within and between cells and in the myelin sheath that coats and protects the nerves. Lipids include oils, fatty acids, waxes, steroids (e.g., cholesterol and estrogen), and other related compounds. These fatty materials are stored naturally in the body's cells, organs, and tissues.

Tiny bodies within cells called lysosomes regularly convert, or metabolize, the lipids and proteins into smaller components to provide energy for the body. Disorders in which intracellular material that cannot be metabolized is stored in lysosomes are called lysosomal storage diseases. In addition to lipid storage diseases, other lysosomal storage diseases include the:

• Mucolipidoses, in which excessive amounts of lipids with attached sugar molecules are stored in the cells and tissues
• Mucopolysaccharidoses, in which excessive amounts of large, complicated sugar molecules are stored

Types of lipid storage disease
Gaucher disease. Gaucher disease is caused by a deficiency of the enzyme glucocerebrosidase. Fatty material can collect in the brain, spleen, liver, kidneys, lungs, and bone marrow. Symptoms may include:

• Brain damage
• Enlarged spleen and liver
• Liver malfunction
• Skeletal disorders and bone lesions that may cause pain and fractures
• Distended abdomen

• Swelling of lymph nodes and occasionally adjacent joints
• A brownish tint to the skin, anemia
• Low blood platelets
• Yellow spots in the eyes

Individuals may also be more susceptible to infection. The disease affects males and females equally.

There are three common types of Gaucher disease:

1. Type 1 (nonneuronopathic type) is the most common form of the disease in the U.S. and Europe. The brain is not affected, but there may be lung and, rarely, kidney impairment.
2. Type 2 (acute infantile neuropathic Gaucher disease) typically begins within three months of birth.
3. Type 3 (chronic neuronopathic form) can begin at any time in childhood or even in adulthood. It is characterized by slowly progressive yet milder neurologic symptoms compared to type 2 Gaucher disease.

Niemann-Pick disease. Niemann-Pick disease is a group of autosomal recessive disorders caused by an accumulation of fat and cholesterol in cells of the liver, spleen, bone marrow, lungs, and, in some instances, brain. Neurological complications may include:

• Ataxia (lack of muscle coordination that can affect walking steadily, writing, eating)
• Eye paralysis
• Brain degeneration
• Learning problems
• Spasticity
• Feeding and swallowing difficulties
• Slurred speech
• Loss of muscle tone
• Hypersensitivity to touch
• Some clouding of the cornea due to excess buildup of materials

A characteristic cherry-red halo that can be seen by a physician using a special tool develops around the center of the retina in 50 percent of affected individuals.

Niemann-Pick disease is divided into three categories:

1. Type A, the most severe form, begins in early infancy. Infants develop profound brain damage by 6 months of age, an enlarged liver and spleen, swollen lymph nodes, and nodes under the skin (xanthomas).
2. Type B (juvenile onset) does not generally affect the brain but most children develop ataxia, damage to nerves exiting from the spinal cord (peripheral neuropathy), and pulmonary difficulties that progress with age. Enlargement of the liver and spleen characteristically occurs in the early adolescence. Niemann-Pick types A and B result from accumulation of the fatty substance called sphingomyelin, due to deficiency of an enzyme called sphingomyelinase.
3. Type C may appear early in life or develop in the teen or even adult years. Niemann-Pick disease type C is not caused by a deficiency of sphlingomyelinase but by a lack of the NPC1 or NPC2 proteins. As a result, various lipids and particularly cholesterol accumulate inside nerve cells and cause them to malfunction. Brain involvement may be extensive, leading to inability to look up and down, difficulty in walking and swallowing, progressive loss of hearing, and progressive dementia. People with type C only see a moderate enlargement of their spleens and livers.

Fabry disease. Fabry disease (also known as alpha-galactosidase-A deficiency) causes a buildup of fatty material in the autonomic nervous system (the part of the nervous system that controls involuntary functions such as breathing and heartbeat), eyes, kidneys, and cardiovascular system. Fabry disease is the only X-linked lipid storage disease. Males are primarily affected, although a milder and more variable form is common in females. Occasionally, affected females have severe manifestations similar to those seen in males with the disorder. Onset of symptoms is usually during childhood or adolescence. Neurological signs include:

• Burning pain in the arms and legs, which worsens in hot weather or following exercise
• Buildup of excess material in the clear layers of the cornea, resulting in clouding but no change in vision)

Fatty storage in blood vessel walls may impair circulation, putting the person at risk for stroke or heart attack. Other symptoms include:

• Heart enlargement
• Progressive kidney impairment leading to renal failure
• Gastrointestinal difficulties

• Decreased sweating
• Fever

Angiokeratomas (small, non-cancerous, reddish-purple elevated spots on the skin) may develop on the lower part of the trunk of the body and become more numerous with age.

Farber's disease. Farber's disease (also known as Farber's lipogranulomatosis) describes a group of rare autosomal recessive disorders that cause an accumulation of fatty material in the joints, tissues, and central nervous system. Farber's disease is caused by a deficiency of the enzyme called ceramidase. It affects both males and females. Disease onset is typically in early infancy but may occur later in life. Children who have the classic form of Farber's disease develop neurological symptoms within the first few weeks of life that may include increased lethargy and sleepiness, and problems with swallowing. The liver, heart, and kidneys may also be affected. Other symptoms may include:

• Joint contractures (chronic shortening of muscles or tendons around joints)
• Vomiting
• Arthritis
• Swollen lymph nodes

• Swollen joints
• Hoarseness
• Nodes under the skin which thicken around joints as the disease progresses

The gangliosidoses. The gangliosidoses are comprised of two distinct groups of genetic diseases. Both are autosomal recessive and affect males and females equally.

GM1 gangliosidoses are caused by a deficiency of the enzyme beta-galactosidase, resulting in abnormal storage of acidic lipid materials particularly in the nerve cells in the central and peripheral nervous systems. There are three clinical types of GM1 gangliosidosis:

1. GM1 is the most severe subtype, with onset shortly after birth. Children may be deaf and blind by age 1. About half of affected individuals develop cherry-red spots in the eye. Symptoms may include:
   • Neurodegeneration
   • Seizures
   • Liver and spleen enlargement
   • Coarsening of facial features
   • Skeletal irregularities
   • Joint stiffness
   • Distended abdomen
   • Muscle weakness
   • Exaggerated startle response
   • Problems with gait
     
2. Late infantile GM1 gangliosidosis typically begins between ages 1 and 3 years. Neurological symptoms include:
   • Ataxia
   • Seizures
   • Dementia
   • Difficulties with speech
     
3. GM1 gangliosidosis develops between ages 3 and 30. Symptoms include:
   • Decreased muscle mass (muscle atrophy),
   • Neurological complications that are less severe and progress at a slower rate than in other forms of the disorder
   • Corneal clouding in some people
   • Sustained muscle contractions that cause twisting and repetitive movements or abnormal postures (dystonia)

Angiokeratomas may develop on the lower part of the trunk of the body. The size of the liver and spleen in most affected individuals is normal.

GM2 gangliosidoses also cause the body to store excess acidic fatty materials in tissues and cells, most notably in nerve cells. These disorders are caused by a deficiency of the enzyme beta-hexosaminidase. The GM2 disorders include:

Tay-Sachs disease (also known as GM2 gangliosidosis-variant B) and its variant forms are caused by a deficiency in the enzyme hexosaminidase A. The incidence has been particularly high among Eastern European and Ashkenazi Jewish populations, as well as certain French Canadians and Louisianan Cajuns. Symptoms begin by 6 months of age and include:

• Progressive loss of mental ability
• Dementia
• Decreased eye contact
• Increased startle reflex response to noise
• Progressive loss of hearing leading to deafness
• Difficulty in swallowing
• Blindness
• Cherry-red spots in the retina
• Some paralysis

Seizures may begin at age 2. Children may eventually need a feeding tube. No specific treatment is available. Anticonvulsant medications may initially control seizures. A rare form of the disorder, called late-onset Tay-Sachs disease, occurs in people in their 20s and early 30s and is characterized by unsteadiness of gait and progressive neurological deterioration.

Sandhoff disease (variant AB) is a severe form of Tay-Sachs disease. Onset usually occurs at the age of 6 months and is not limited to any ethnic group. Neurological signs may include:

• Progressive deterioration of the central nervous system
• Motor weakness
• Early blindness
• Increased startle reflex response to noise
• Spasticity
• Shock-like or jerking of a muscle (myoclonus)
• Seizures

• Enlarged head (macrocephaly)
• Cherry-red spots in the eye
• Frequent respiratory infections
• Heart murmurs
• Doll-like facial features
• Enlarged liver and spleen

There is no specific treatment for Sandhoff disease. As with Tay-Sachs disease, supportive treatment includes keeping the airway open and proper nutrition and hydration. Anti-seizure medications may initially control seizures.

Krabbe disease (also known as globoid cell leukodystrophy and galactosylceramide lipidosis) is an autosomal recessive disorder caused by deficiency of the enzyme galactocerebrosidase. The disease most often affects infants, with onset before 6 months of age, but can occur in adolescence or adulthood.

The buildup of undigested fats affects the growth of the nerve's protective insulating sheath (myelin sheath) and causes severe deterioration of mental and motor skills. Other symptoms include:

• Muscle weakness
• Reduced ability of a muscle to stretch (hypertonia)
• Muscle stiffening (spasticity)
• Sudden shock-like or jerking of the limbs (myoclonic seizures)
• Irritability

• Unexplained fever
• Deafness
• Blindness
• Paralysis
• Difficulty when swallowing

Prolonged weight loss may also occur. No specific treatment for Krabbe disease has been developed, although early bone marrow transplantation may help some people.

Metachromatic leukodystrophy (MLD) is a group of disorders marked by storage buildup in the white matter of the central nervous system and in the peripheral nerves and to some extent in the kidneys. Similar to Krabbe disease, MLD affects the myelin that covers and protects the nerves. This autosomal recessive disorder is caused by a deficiency of the enzyme arylsulfatase A. Both males and females are affected by this disorder.

There are three characteristic forms of MLD:

• Late infantile MLD typically begins between 12 and 20 months following birth. Children experience difficulty when learning to walk and can have a tendency to fall, followed by:
  • Intermittent pain in the arms and legs
  • Progressive loss of vision leading to blindness
  • Developmental delays and loss of previously acquired milestones
  • Impaired swallowing
  • Convulsions
  • Dementia before age 2

Children also develop gradual muscle wasting and weakness and eventually lose the ability to walk.

• Juvenile MLD typically begins between ages 3 and 10. Symptoms, which are progressive, include:
  • Impaired school performance
  • Mental deterioration
  • Slurred speech and loss of balance (ataxia)
  • Dementia
• Adult symptoms begin after age 16 and may include:
  • Slurred speech and loss of balance (ataxia)
  • Seizures
  • Abnormal shaking of the limbs (tremor)
  • Impaired concentration
  • Depression
  • Psychiatric disturbances
  • Dementia

There is no cure for MLD. Treatment is symptomatic and supportive. Bone marrow transplantation may delay progression of the disease in some cases. Considerable progress has been made with regard to gene therapies in animal models of MLD and in clinical trials.

Acid lipase deficiency (also known as Wolman's disease) is a severe lipid storage disorder that is usually fatal by age 1. This autosomal recessive disorder is marked by accumulation of cholesteryl esters (a transport form of cholesterol) and triglycerides (a chemical form of fats in the body) that can build up significantly and cause damage in the cells and tissues. Both males and females are affected by this disorder. Infants are active at birth but quickly develop:

• Progressive developmental difficulties
• Enlarged liver and grossly enlarged spleen
• Distended abdomen
• Gastrointestinal problems
• Jaundice

• Anemia
• Vomiting
• Calcium deposits in the adrenal glands, causing them to harden

Another type of acid lipase deficiency is cholesteryl ester storage disease. This extremely rare disorder results from storage of cholesteryl esters and triglycerides in cells of the blood and lymph and lymphoid tissue. Children develop an enlarged liver leading to cirrhosis and chronic liver failure before adulthood. Children may also have calcium deposits in the adrenal glands and may develop jaundice late in the disorder.

Enzyme replacement for both diseases is currently under active investigation.

Who is more likely to get lipid storage diseases?

Lipid storage diseases are inherited from one or both parents who carry a defective gene that regulates a particular lipid-metabolizing enzyme. They can be inherited two ways:

1. Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the gene, but neither parent is affected by the disorder. Children can be affected by an autosomal recessive pattern of inheritance. Each child born to these parents has a:
   • 25 percent chance of inheriting both copies of the defective gene
   • 50 percent chance of being a carrier like the parents
   • 25 percent chance of not inheriting either copy of the defective gene
2. X-linked (or sex-linked) recessive inheritance occurs when the female parent carries the affected gene on the X chromosome. The X and Y chromosomes are involved in biological sex determination. Females have two X chromosomes and males have one X chromosome and one Y chromosome. Male children of female carriers have a 50 percent chance of inheriting and being affected with the disorder, as they receive one X chromosome from the female parent and a Y chromosome from the male parent. Female children have a 50 percent chance of inheriting the affected X chromosome from the female parent and are carriers or mildly affected. Affected men do not pass the disorder to their male children but their female children will be carriers for the disorder.

How are lipid storage diseases diagnosed and treated?

Diagnosing lipid storage diseases. In some states, some of these disorders (most notably and controversially Krabbe disease) are screened for at birth.

In older children, diagnosis is made through clinical examination, enzyme assays (laboratory tests that measure enzyme activity), genetic testing, biopsy, and molecular analysis of cells or tissues. In some forms of the disorder, urine analysis can identify the presence of stored material. In others, the abnormality in enzyme activity can be detected in white blood cells without tissue biopsy. Some tests can also determine if a person carries the defective gene that can be passed on to her or his children. This process is known as genotyping.

Treating lipid storage diseases. Currently there is no specific treatment available for most lipid storage disorders but highly effective enzyme replacement therapy is available for type 1 and type 3 Gaucher disease. Enzyme replacement therapy is also available for Fabry disease, although it is not as effective as it is for Gaucher disease.

Antiplatelet medications can help prevent strokes and medications for lowering blood pressure can slow the decline of kidney function in people with Fabry disease. The U.S. Food and Drug Administration (FDA) has approved the drug migalastat (Galafold) as an oral medication for adults with Fabry disease who have a certain genetic mutation. Eligustat tartrate is an oral drug approved for Gaucher treatment. Medications such as gabapentin and carbamazepine may be prescribed to help treat pain (including bone pain). Restricting one's diet does not prevent lipid buildup in cells and tissues.

What are the latest updates on lipid storage diseases?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. As part of its mission, the NINDS conducts and funds research on lipid storage diseases and other inherited metabolic disorders that affect the brain and nervous system.

In past research, investigators at NINDS made significant contributions to research on lipid storage disorders and their treatment. These scientists identified the enzymes affected in people with Gaucher and Fabry diseases. NINDS scientists also discovered a gene that is mutated in the majority of individuals with Niemann-Pick disease type C. NINDS researchers developed highly effective enzyme replacement therapy for Gaucher and Fabry diseases, as well as a mouse model of Fabry disease for use in research to understand the disease and develop treatments, which has enabled ongoing and promising research to develop gene therapy for this disease.

NINDS and other NIH institutes support the Lysosomal Disease Network (LDN), a network of centers that addresses some of the major challenges in the diagnosis, management, and therapy of rare diseases, including the lipid storage diseases. The LDN is a member of the NIH Rare Diseases Clinical Research Network, which supports collaborative consortia of rare disease researchers and disease community partners. Research on lipid storage disorders within the LDN includes longitudinal studies of the natural history and/or treatment of these disorders. Additional studies will emphasize the quantitative analysis of the central nervous system structure and function and develop biomarkers (signs that can indicate the diagnosis or progression of a disease) for these disorders.

Research funded by NINDS focuses on better understanding how neurological deficits arise in lipid storage disorders and on the development of new treatments targeting disease mechanisms, including gene therapies, cell-based therapies, and pharmacological approaches.

Mutations in the gene that provides instructions for the protein glucocerebrosidase cause Gaucher disease as well as an increased risk for Parkinson's disease and Lewy Body Dementia, all of which are marked by increased buildup of the protein alpha-synuclein. Using fly and mouse models of glucocerebrosidase deficiency, scientists hope to learn how this deficiency impairs the breakdown of lysosomal proteins, including the breakdown of alpha-synuclein. Other research is looking at anomalies in metabolic pathways that may contribute to neuronal dysfunction and degeneration in aging and sporadic Parkinson's disease. A better understanding of the mechanisms involved in these diseases could lead to the development of new treatments.

Hematopoietic stem cell transplant (HSCT)—using stem cells from umbilical cord blood or bone marrow—has been shown to benefit some individuals when given early in the course of Krabbe disease. For example, a small clinical study found that treating infants at high risk for developing early-onset Krabbe disease with HSCT before they were 7 weeks old led to improved quality of life and longer lifespans compared to untreated children or children who received HSCT after 6 weeks of age. Scientists plan to test hematopoietic stem cell transplantation plus gene therapy in an animal model of Krabbe disease to study disease mechanisms and any positive effects of combined therapy. Also in an animal model, NINDS-funded scientists are testing a combined treatment approach that uses a harmless virus to increase protein production, along with blood stem cell transplantation and small molecule-based drugs, to reduce neuroinflammation, cell death, and nerve cell degeneration seen in the disease.

A barrier to the development of therapies for Niemann-pick type C1 (NPC1) disease is the lack of outcome measures for clinical trials. NINDS-funded researchers will test if a cholesterol oxidation byproduct (“oxysterol”) is a biomarker that can be used to evaluate therapies as well as screen newborns for NPC1 disease.

NINDS-funded research on gangliosidosis is expanding the use of gene therapy delivered using an adeno-associated virus (AAV) to a larger area of the brain using an animal model of Tay-Sachs and Sandhoff diseases. A related project will study the effectiveness of whole-body AAV therapy in treating the disease.

NINDS-funded studies are developing new and improved treatments for Farber, Tay-Sachs, Sandhoff, Fabry, and Gaucher diseases, as well as cholesterol metabolism disorders. Among NIH-funded projects, researchers hope to improve imaging techniques that will aid in newborn screening for lysosomal storage diseases, and to correct cholesterol metabolism dysfunction and markedly increase the life of the animal models of cholesterol storage disease.

In addition to NINDS, other NIH Institutes and Centers conduct and support research on lipid storage diseases, including the National Institute on Aging (NIA), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Heart, Lung, and Blood Institute (NHLBI), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

More information on research on lipid storage diseases supported by NINDS and other NIH Institutes is available through the NIH RePORTER, a searchable database of current and previously funded research.

How can I or my loved one help improve care for people with lipid storage diseases?

Consider participating in a clinical trial so clinicians and scientists can learn more about lipid storage diseases and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with lipid storage diseases at Clinicaltrials.gov.

Where can I find more information on lipid storage diseases?

Information is available from the following organizations:

Ara Parseghian Medical Research Foundation (for Niemann-Pick Type C Disease)
Phone: 520-577-5106

Children's Gaucher Research Fund
Phone: 916-797-3700

Fabry Support & Information Group
Phone: 660-463-1355

Hide and Seek Foundation for Lysosomal Storage Disease Research
Phone: 877-621-1122

Hunter's Hope Foundation (for Krabbe Disease)
Phone: 716-667-1200

International Society for Mannosidosis and Related Disorders (ISMRD)
Phone: 734-449-1190

March of Dimes
Phone: 914-997-4488 or 888-663-4637

MedlinePlus

MLD Foundation (for Metachromatic Leukodystrophy)
Phone: 503-656-4808; 800-617-8387

National Fabry Disease Foundation
Phone: 800-651-9131

National Gaucher Foundation, Inc.
Phone: 800-504-3189

National Niemann-Pick Disease Foundation, Inc.
Phone: 920-563-0930 or 877-287-3672

National Organization for Rare Disorders (NORD)
Phone: 203-744-0100 or 800-999-6673

National Tay-Sachs and Allied Diseases Association
Phone: 800-906-8723

United Leukodystrophy Foundation
Phone: 815-748-3211 or 800-728-5483

Content source: https://www.ninds.nih.gov/health-information/disorders/lipid-storage-diseases Accessed July 13, 2023.

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