Lipid Storage Diseases

Lipid Storage Diseases

Lipid storage diseases are a group of inherited metabolic disorders in which harmful amounts of fatty materials (lipids) accumulate in various tissues and cells in the body.  Lipids are important parts of the membranes found within and between each cell and in the myelin sheath that coast and protects the nerves.  Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow.  Lipid storage diseases are inherited from one or both parents who carry a defective gene.   Symptoms may appear early in life or develop in the teen or even adult years.  Neurological complications of the lipid storage diseases may include ataxia, eye paralysis, brain degeneration, seizures, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity to touch, pain in the arms and legs, and clouding of the cornea. 

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:

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.

Type 2 (acute infantile neuropathic Gaucher disease) typically begins within three months of birth.

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:

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).

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.

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:

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

Late infantile GM1 gangliosidosis typically begins between ages 1 and 3 years. Neurological symptoms include:

Ataxia

Seizures

Dementia

Difficulties with speech

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.

Symptoms

Neurological: Brain degeneration, seizures, learning problems, ataxia (loss of coordination), eye movement disorders, spasticity, and speech difficulties. 

Organ Enlargement: Enlarged spleen and liver, sometimes with swollen lymph nodes and joints. 

Skeletal: Bone pain, fractures, and skeletal abnormalities (dysostosis multiplex). 

Blood: Easy bruising and bleeding, fatigue due to anemia, and low platelet counts. 

Other: Breathing problems, feeding and swallowing difficulties, and skin abnormalities (ichthyosis). 

Eye: Abnormal eye movements, cataracts, and cherry-red spots on the retina. 

Causes

Genetic Mutations:

Lipid storage diseases are typically inherited, meaning they are passed down from parents to children through faulty genes.

Enzyme Deficiency:

These genetic mutations often lead to a deficiency or malfunction of enzymes that are crucial for breaking down lipids (fats) within cells.

Lipid Accumulation:

As a result of the enzyme deficiency, lipids accumulate in cells and tissues, particularly in the brain, liver, spleen, and other organs.

Tissue Damage:

The excessive buildup of lipids can cause progressive damage to cells and tissues, leading to various symptoms and health problems.

Diagnosis

Lipid storage diseases begin differently for different people, and there are several forms of the disorders with similar symptoms. Therefore, it may be difficult to diagnose lipid storage diseases in the earliest stages.

Some U.S. states require screening for some of these disorders (most notably Krabbe disease) 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, abnormal enzyme activity can be detected in blood tests. 

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. A genetic counselor can help explain the risks of passing along these disorders. 

Treating lipid storage diseases 

Treating lipid storage diseases depends on the specific disorder and subtype. For some, including Niemann-Pick disease, the gangliosidoses, Tay-Sachs disease, Sandhoff disease, Krabbe disease, metachromatic leukodystrophy, and acid lipase disease, only supportive treatments are available. For example, proper nutrition, hydration, and keeping the airway open, may help people with the gangliosidoses, including Tay-Sachs disease and Sandhoff disease. Also, people with cholesteryl ester storage disease (CESD) may benefit from a low cholesterol diet.       

The U.S. Food and Drug Administration (FDA) has approved enzyme replacement therapies (ERTs) and substrate reduction therapies (SRTs) for Gaucher Type 1 disease, such as eliglustat tartrate. ERTs are typically used to replace a missing or deficient enzyme in a person with an inherited enzyme deficiency syndrome. SRTs reduce the production or buildup of harmful substances in the body. Rarely, surgery to remove the whole or part of the spleen may be required. Blood transfusions may benefit some people who are anemic. Other people may need joint replacement surgery to improve mobility and quality of life. There is no effective treatment for severe brain damage that may affect people with Gaucher Types 2 and 3 disease.

The FDA has also approved ERT to treat non-central nervous system symptoms in Niemann-Pick Type B disease. 

Intravenous ERTs for Fabry disease, including agalsidase alfa (Replagal), agalsidase beta (Fabrazyme), and pegunigalsidase alfa-iwxj (Elfabrio), can reduce lipid storage, ease pain, and preserve organ function in some people with the disease. Drugs are often prescribed to treat pain and gastrointestinal distress that accompanies Fabry disease but do not treat the disease. The FDA has approved migalastat (Galafold), an SRT, as an oral medication for adults with Fabry disease who have a certain genetic mutation. Anti-platelet medications can help prevent strokes and medications that lower blood pressure can slow the decline of kidney function in people with the disease. Some people may require kidney transplants or dialysis. 

Hematopoietic stem cell transplantation (HSCT) (also called bone marrow or stem cell transplantation) has been attempted in a few people with Niemann-Pick Type B disease, with mixed results. HSCT has also been examined in Farber Disease. HSCT is also used to treat early-infantile and late-infantile Krabbe. It has been shown to increase lifespan and improve clinical outcomes.

The FDA has approved the first and only gene therapy for metachromatic leukodystrophy (MLD), atidarsagene autotemecel (Lenmeldy). It is a one-time, single dose infusion made from a person’s own blood stem cells which have been genetically modified to include copies of the patient’s ARSA gene. The modified stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow. The modified stem cells supply the body with myeloid (immune) cells that produce the ARSA enzyme, which helps break down the harmful buildup of lipids and may stop the progression of MLD.  

Anticonvulsants may initially control seizures in people with Niemann-Pick disease and the gangliosidoses, including Tay-Sachs disease and Sandhoff disease. 

Corticosteroids may be prescribed to relieve pain in people with Farber’s disease. Older people with the disease may have granulomas surgically reduced or removed. 

Bone marrow transplantation may delay progression of MLD in some cases. Considerable progress has been made in gene therapies in animal models of MLD and in clinical trials. 

Type of Doctor Department: Lipidologist, geneticist, and potentially a neurologist or cardiologist