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What are lipid storage diseases?What are lipid storage diseases? Lipid storage diseases, or the lipidoses, are a group of inherited metabolic disorders in which harmful amounts of fatty materials called lipids accumulate in some
of the body’s cells and tissues. People with these disorders either do not produce enough of one of the enzymes needed to
metabolize lipids or they produce enzymes that do not work properly. 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.
What are lipids? Lipids are fat-like substances that are important parts of the membranes found within and between each cell and in the myelin
sheath that coats and protects the nerves. Lipids include oils, fatty acids, waxes, steroids (such as cholesterol and estrogen),
and other related compounds.
These fatty materials are stored naturally in the body’s cells, organs, and tissues. Minute bodies within the cells called
lysosomes regularly convert, or metabolize, the lipids and proteins into smaller components to provide energy for the body.
Disorders that store this intracellular material are called lysosomal storage diseases. In addition to lipid storage diseases,
other lysosomal storage diseases include the mucolipidoses, in which excessive amounts of lipids and sugar molecules are stored
in the cells and tissues, and the mucopolysaccharidoses, in which excessive amounts of sugar molecules are stored.
How are lipid storage diseases inherited? Lipid storage diseases are inherited from one or both parents who carry a defective gene that regulates a particular protein
in a class of the body’s cells. They can be inherited two ways:
How are these disorders diagnosed? Diagnosis is made through clinical examination, biopsy, genetic testing, molecular analysis of cells or tissue to identify
inherited metabolic disorders, and enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency).
In some forms of the disorder, a urine analysis can identify the presence of stored material. 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.
Biopsy for lipid storage disease involves removing a small sample of the liver or other tissue and studying it under a microscope.
In this procedure, a physician will administer a local anesthetic and then remove a small piece of tissue either surgically
or by needle biopsy (a small piece of tissue is removed by inserting a thin, hollow needle through the skin). The biopsy
is usually performed at an outpatient testing facility.
Genetic testing can help individuals who have a family history of lipid storage disease determine if they are carrying a mutated
gene that causes the disorder. Other genetic tests can determine if a fetus has the disorder or is a carrier of the defective
gene. Prenatal testing is usually done by chorionic villus sampling, in which a very small sample of the placenta is removed and tested during early pregnancy. The sample, which contains the
same DNA as the fetus, is removed by catheter or fine needle inserted through the cervix or by a fine needle inserted through
the abdomen. Results are usually available within 2 weeks.
What are the types of lipid storage disease? Gaucher disease is the most common of the lipid storage diseases. It is caused by a deficiency of the enzyme glucocerebrosidase. Fatty
material can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow. Symptoms may include enlarged spleen and
liver, liver malfunction, skeletal disorders and bone lesions that may cause pain, severe neurologic complications, swelling
of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets,
and yellow spots in the eyes. Persons affected most seriously may also be more susceptible to infection. The disease affects
males and females equally.
Gaucher disease has three common clinical subtypes. Type 1 (or nonneuropathic type) is the most common form of the disease. It occurs most often among persons of Ashkenazi Jewish heritage. Symptoms
may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen, which can rupture and cause
additional complications. Skeletal weakness and bone disease may be extensive. The brain is not affected, but there may
be lung and, rarely, kidney impairment. Patients in this group usually bruise easily and experience fatigue due to low blood
platelets. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild
form of the disease or may not show any symptoms. Type 2 (or acute infantile neuropathic Gaucher disease) typically begins within 3 months of birth. Symptoms include an enlarged liver and spleen, extensive and
progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow.
Affected children usually die by age 2. Type 3 (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood. It is characterized by slowly progressive but milder neurologic
symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor
coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia, and respiratory problems.
Patients often live to their early teen years and often into adulthood.
For type 1 and most type 3 patients, enzyme replacement treatment given intravenously every two weeks can dramatically decrease
liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. Successful bone marrow transplantation
cures the non-neurological manifestations of the disease. However, this procedure carries significant risk and is rarely
performed in Gaucher patients. Surgery to remove the spleen may be required on rare occasions (if the patient is anemic or
when the enlarged organ affects the patient’s comfort). Blood transfusion may benefit some anemic patients. Other patients
may require joint replacement surgery to improve mobility and quality of life. There is currently no effective treatment
for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.
Niemann-Pick disease is actually 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 patients, brain. Neurological complications may include ataxia, eye paralysis, brain
degeneration, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity
to touch, and some corneal clouding. A characteristic cherry-red halo develops around the center of the retina in 50 percent
of patients.
Niemann-Pick disease is currently subdivided into four categories. Onset of type A, the most severe form, is in early infancy. Infants appear normal at birth but develop an enlarged liver and spleen, swollen
lymph nodes, nodes under the skin (xanthemas), and profound brain damage by 6 months of age. The spleen may enlarge to as
much as 10 times its normal size and can rupture. These children become progressively weaker, lose motor function, may become
anemic, and are susceptible to recurring infection. They rarely live beyond 18 months. This form of the disease occurs most
often in Jewish families. In the second group, called type B (or juvenile onset), enlargement of the liver and spleen characteristically occurs in the pre-teen years. Most patients
also develop ataxia, peripheral neuropathy, and pulmonary difficulties that progress with age, but the brain is generally
not affected. Type B patients may live a comparatively long time but many require supplemental oxygen because of lung involvement.
Niemann-Pick types A and B result from accumulation of the fatty substance called sphingomyelin, due to deficiency of acid
sphingomyelinase.
Niemann-Pick disease also includes two other variant forms called types C and D. These may appear early in life or develop in the teen or even adult years. Niemann-Pick disease types C and D are not
caused by a deficiency of sphlingomyelinase but by a lack of the NPC1 or NPC2 proteins. As a result, various lipids and cholesterol
accumulate inside nerve cells and cause them to malfunction. Patients with types C and D have only moderate enlargement of
their spleens and livers. Brain involvement may be extensive, leading to inability to look up and down, difficulty in walking
and swallowing, and progressive loss of vision and hearing. Type D patients typically develop neurologic symptoms later than
those with type C and have a progressively slower rate of loss of nerve function. Most type D patients share a common ancestral
background in Nova Scotia. The life expectancies of patients with types C and D vary considerably. Some patients die in
childhood while others who appear to be less severely affected live into adulthood.
There is currently no cure for Niemann-Pick disease. Treatment is supportive. Children usually die from infection or progressive
neurological loss. Bone marrow transplantation has been attempted in a few patients with type B. Patients with types C and
D are frequently placed on a low-cholesterol diet and/or cholesterol lowering drugs, although research has not shown these
interventions to change cholesterol metabolism or halt disease progression.
Fabry disease, also known as alpha-galactosidase-A deficiency, causes a buildup of fatty material in the autonomic nervous system, eyes,
kidneys, and cardiovascular system. Fabry disease is the only x-linked lipid storage disease. Males are primarily affected
although a milder form is common in females, some of whom may have severe manifestations similar to those seen in affected
males. Onset of symptoms is usually during childhood or adolescence. Neurological symptoms include burning pain in the arms
and legs, which worsens in hot weather or following exercise, and the 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 patient at risk for stroke or heart attack. Other symptoms include heart enlargement, progressive kidney impairment leading
to renal failure, gastrointestinal difficulties, decreased sweating, and 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.
Patients with Fabry disease often die prematurely of complications from heart disease, renal failure, or stroke. Drugs such
as phenytoin and carbamazepine are often prescribed to treat pain that accompanies Fabry disease. Metoclopramaide or Lipisorb
(a nutritional supplement) can ease gastrointestinal distress that often occurs in Fabry patients, and some individuals may
require kidney transplant or dialysis. Recent experiments indicate that enzyme replacement can reduce storage, ease pain,
and improve organ function in patients with Fabry disease.
Farber’s disease, also known as Farber’s lipogranulomatosis or ceramidase deficiency, describes a group of rare autosomal recessive disorders
that cause an accumulation of fatty material in the joints, tissues, and central nervous system. The disorder 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. These symptoms may include moderately
impaired mental ability and problems with swallowing. The liver, heart, and kidneys may also be affected. Other symptoms
may include vomiting, arthritis, swollen lymph nodes, swollen joints, joint contractures (chronic shortening of muscles or
tendons around joints), hoarseness, and xanthemas which thicken around joints as the disease progresses. Patients with breathing
difficulty may require insertion of a breathing tube. Most children with the disease die by age 2, usually from lung disease.
In one of the most severe forms of the disease, an enlarged liver and spleen (hepatosplenomegaly) can be diagnosed soon after
birth. Children born with this form of the disease usually die within 6 months.
There is no specific treatment for Farber’s disease. Corticosteroids may be prescribed to relieve pain. Bone marrow transplants
may improve granulomas (small masses of inflamed tissue) on patients with little or no lung or nervous system complications.
Older patients may have granulomas surgically reduced or removed.
The gangliosidoses are two distinct genetic groups of diseases. Both are autosomal recessive and affect males and females equally.
The GM1 gangliosidoses are caused by a deficiency of beta-galactosidase, with resulting abnormal storage of acidic lipid materials in cells of the
central and peripheral nervous systems, but particularly in the nerve cells. GM1 has three forms: early infantile, late
infantile, and adult. Symptoms of early infantile GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver and spleen enlargement,
coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle
response to sound, and problems with gait. About half of affected patients develop cherry-red spots in the eye. Children
may be deaf and blind by age 1 and often die by age 3 from cardiac complications or pneumonia. Onset of late infantile GM1 is typically between ages 1 and 3 years. Neurological symptoms include ataxia, seizures, dementia, and difficulties
with speech. Onset of adult GM1 is between ages 3 and 30. Symptoms include 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 patients, and dystonia (sustained muscle contractions
that cause twisting and repetitive movements or abnormal postures). Angiokeratomas may develop on the lower part of the trunk
of the body. Most patients have a normal size liver and spleen.
The GM2 gangliosidoses also cause the body to store excess acidic fatty materials in tissues and cells, most notably in nerve cells. These disorders
result from a deficiency of the enzyme beta-hexosaminidase. The GM2 disorders include:
Krabbé disease (also known as globoid cell leukodystrophy and galactosylceramide lipidosis) is an autosomal recessive disorder caused by
deficiency of the enzyme galactosylceramidase. The disease most often affects infants, with onset before age 6 months, but
can occur in adolescence or adulthood. The buildup of undigested fats affects the growth of the nerve’s protective myelin
sheath and causes severe degeneration of mental and motor skills. Other symptoms include muscle weakness, hypertonia (reduced
ability of a muscle to stretch), myoclonic seizures (sudden, shock-like contractions of the limbs), spasticity, irritability,
unexplained fever, deafness, optic atrophy and blindness, paralysis, and difficulty when swallowing. Prolonged weight loss
may also occur. The disease may be diagnosed by its characteristic grouping of certain cells, nerve demyelination and degeneration,
and destruction of brain cells. In infants, the disease is generally fatal before age 2. Patients with a later onset form
of the disease have a milder course of the disease and live significantly longer. No specific treatment for Krabbé disease
has been developed, although early bone marrow transplantation may help some patients.
Metachromatic leukodystrophy, or 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 Krabbé 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.
MLD has three characteristic phenotypes: late infantile, juvenile, and adult. The most common form of the disease is late infantile, with onset typically between 12 and 20 months following birth. Infants may appear normal at first but develop difficulty
in walking and a tendency to fall, followed by intermittent pain in the arms and legs, progressive loss of vision leading
to blindness, developmental delays, impaired swallowing, convulsions, and dementia before age 2. Children also develop gradual
muscle wasting and weakness and eventually lose the ability to walk. Most children with this form of the disorder die by
age 5. Symptoms of the juvenile form typically begin between ages 3 and 10. Symptoms include impaired school performance, mental deterioration, ataxia,
seizures, and dementia. Symptoms are progressive with death occurring 10 to 20 years following onset. In the adult form, symptoms begin after age 16 and may include impaired concentration, depression, psychiatric disturbances, ataxia, seizures,
tremor, and dementia. Death generally occurs within 6 to 14 years after onset of symptoms.
There is no cure for MLD. Treatment is symptomatic and supportive. Bone marrow transplantation may delay progression of
the disease in some cases.
Wolman’s disease, also known as acid lipase deficiency, is a severe lipid storage disease that is usually fatal by age 1. This autosomal
recessive disorder is marked by accumulation of cholesteryl esters (normally a transport form of cholesterol) and triglycerides
(a chemical form in which fats exist in the body) that can build up significantly and cause damage in the cells and tissues.
Both males and females are affected by this severe disorder. Infants are normal and active at birth but quickly develop progressive
mental deterioration, enlarged liver and grossly enlarged spleen, distended abdomen, gastrointestinal problems including steatorrhea
(excessive amounts of fats in the stools), jaundice, anemia, vomiting, and 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 in 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.
There is no specific treatment for Wolman’s disease or cholesteryl ester storage disease.
How are these disorders treated? Currently there is no specific treatment available for most of the lipid storage disorders but highly effective enzyme replacement
therapy is available for patients with type 1 Gaucher disease and some patients with type 3 Gaucher disease. Patients with anemia may require blood transfusions. In some patients, the enlarged spleen must be removed to
improve cardiopulmonary function. The drugs phenytoin and carbamazepine may be prescribed to help treat pain (including bone pain) for patients with Fabry disease. Restricting one’s diet does not prevent lipid buildup in cells and tissues.
What research is being done? Within the Federal government, the primary supporter of research on neurological disorders is the National Institute of Neurological
Disorders and Stroke (NINDS), a part of the National Institutes of Health within the U.S. Department of Health and Human Services.
As part of its mission, the NINDS conducts research on lipid storage diseases and other inherited neurometabolic disorders.
Investigators at the NINDS identified the gene that is altered in the majority of patients with type C and D Niemann-Pick
disease. In the year 2000, scientists discovered a second gene that is mutated in a minority of patients with type C Niemann-Pick
disease. NINDS researchers have developed highly effective enzyme replacement therapy for Gaucher and Fabry diseases. These
researchers are now developing improved research techniques, including a mouse model of Fabry disease. Gene therapy in this
model appears to be especially encouraging.
Among other potential therapies for lipid storage diseases under way, NINDS scientists are studying the effectiveness and
safety of the medicine called OGT-918, which has been shown to slow the production of the lipid that builds up in Gaucher
disease. Scientists hope the drug, which passes through the blood-brain barrier into the brain, will reduce lipid storage
and therefore the neurological symptoms of the disease. Other NINDS investigators are evaluating the safety and effectiveness
of continued replacement of the enzyme alpha-galactosidase-A in patients with Fabry disease. In a preliminary 24-week clinical
trial, this therapy was found to reduce pain, improve renal function, and reverse heart problems among Fabry patients.
NINDS scientists are also studying the mechanisms by which the lipids accumulating in these storage diseases cause harm to
the body. The goal of this research is to develop novel approaches to the treatment of these disorders.
Among several current projects being funded by the NINDS, scientists are studying ways to deliver genes and proteins into
the brain in animal models of Krabbé disease. Other NINDS-sponsored scientists are examining the possible role of the protein
psychosine in the neuroinflammatory response seen in this disease and hope to identify potential therapeutic drugs for use
in human trials. Researchers are investigating the mechanisms of intracellular cholesterol delivery and metabolism in Niemann-Pick
type C disease and hope to develop a diagnostic tool for the disorder. Other researchers are studying dysfunctional cholesterol
processing (seen in Niemann-Pick disease) as a key feature in the development of several neurodegenerative disorders.
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:
BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov
Information also is available from the following organizations:
Fabry Support & Information Group 108 NE 2nd Street, Ste. C P.O. Box 510 Concordia, MO 64020-0510 info@fabry.org http://www.fabry.org Tel: 660-463-1355 Fax: 660-463-1356 |
National Gaucher Foundation 2227 Idlewood Road, Suite 12 Tucker, GA 30084 ngf@gaucherdisease.org http://www.gaucherdisease.org Tel: 800-504-3189 Fax: 770-934-2911 |
Children's Gaucher Research Fund P.O. Box 2123 Granite Bay, CA 95746-2123 research@childrensgaucher.org http://www.childrensgaucher.org Tel: 916-797-3700 Fax: 916-797-3707 |
United Leukodystrophy Foundation 2304 Highland Drive Sycamore, IL 60178 office@ulf.org http://www.ulf.org Tel: 815-895-3211 800-728-5483 Fax: 815-895-2432 |
National Niemann-Pick Disease Foundation, Inc. P.O. Box 49 Ft. Atkinson, WI 53538 nnpdf@idcnet.com http://www.nnpdf.org Tel: 920-563-0930 877-CURE-NPC (287-3672) Fax: 920-563-0931 |
Ara Parseghian Medical Research Foundation
[For Niemann-Pick Type C Disease] 3530 East Campo Abierto Suite 105 Tucson, AZ 85718-3327 victory@parseghian.org http://www.parseghian.org Tel: 520-577-5106 Fax: 520-577-5212 |
National Tay-Sachs and Allied Diseases Association 2001 Beacon Street Suite 204 Brighton, MA 02135 info@ntsad.org http://www.ntsad.org Tel: 617-277-4463 800-90-NTSAD (906-8723) Fax: 617-277-0134 |
March of Dimes Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 askus@marchofdimes.com http://www.marchofdimes.com Tel: 914-428-7100 888-MODIMES (663-4637) Fax: 914-428-8203 |
National Organization for Rare Disorders (NORD) P.O. Box 1968 (55 Kenosia Avenue) Danbury, CT 06813-1968 orphan@rarediseases.org http://www.rarediseases.org Tel: 203-744-0100 Voice Mail 800-999-NORD (6673) Fax: 203-798-2291 |
Hide and Seek Foundation for Lysosomal Storage Disease Research 4123 Lankershim Boulevard Suite 302 No. Hollywood, CA 91602-2828 info@hideandseek.org http://www.hideandseek.org Tel: 818-762-8621 Fax: 818-762-2502 |
ISMRD-International Advocate For Glycoprotein Storage Diseases P.O. Box 328 Dexter, MI 48130 info@ismrd.org http://www.ismrd.org Tel: 734-449-1190 Fax: 734-449-9038 |
NIH Publication No. 05-2628
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Last updated August 13, 2008