(or '''lipidoses''') are a group of inherited
Metabolic disorders in which harmful amounts
Lipid s (fats) accumulate in some of the body’s
Cell s and tissues. People with these disorders either do not produce enough of one of the
Enzyme s 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 .
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
Nerve s. Lipids include
Oil s,
Fatty Acid s,
Wax es,
Steroid s (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
Lysosome s regularly convert, or metabolize, the lipids and
Protein s 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.
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:
- Autosomal Recessive inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent is affected by the Disorder . Each child born to these parents has a 25 % chance of inheriting both copies of the defective gene, a 50 % chance of being a carrier, and a 25 % chance of not inheriting either copy of the defective gene. Children of either gender can be affected by an autosomal recessive this pattern of inheritance.
- X-linked (or Sex -linked) recessive inheritance occurs when the mother carries the affected gene on the X Chromosome that determines the child’s gender and passes it to her son. Sons of carriers have a 50 % chance of inheriting the disorder. Daughters have a 50 % chance of inheriting the X-linked chromosome but usually are not severely affected by the disorder. Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.
Diagnosis is made through
Clinical Examination ,
Biopsy ,
Genetic Testing ,
Molecular Analysis of cells or tissue to identify inherited metabolic disorders and
Enzyme Assay s (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
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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,
Kidney s,
Lung s,
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 Node s and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin,
Anemia , low blood
Platelet s, 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 ,
Seizure s, 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 % 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 (
Xanthema s), 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.
Metoclopramide 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.
Corticosteroid s may be prescribed to relieve pain. Bone marrow transplants may improve
Granuloma s (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 . 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:
- Tay-Sachs Disease (also known as GM2 variant B). Tay-Sachs and its variant forms are caused by a deficiency in the enzyme beta-hexosaminidase A. The incidence is particularly high among Eastern European and Ashkenazi Jewish populations, as well as certain French Canadians and Louisianan Cajuns. Affected children appear to develop normally for the first few months of life. Symptoms begin by 6 months of age and include progressive loss of mental ability, Dementia , decreased eye contact, increased startle reflex to noise, progressive loss of hearing leading to deafness, difficulty in swallowing, blindness, cherry-red spots in the retinas, and some paralysis. Seizures may begin in the child’s second year. Children may eventually need a feeding tube and they often die by age 4 from recurring Infection . No specific treatment is available. Anticonvulsant medications may initially control seizures. Other supportive treatment includes proper nutrition and hydration and techniques to keep the airway open. A much rarer form of the disorder, which occurs in patients in their twenties and early thirties, is characterized by unsteadiness of gait and progressive neurological deterioration.
- Sandhoff Disease ( Variant AB ). This 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 symptoms may include progressive deterioration of the central nervous system, motor weakness, early blindness, marked startle response to sound, spasticity, Myoclonus (shock-like contractions of a muscle), seizures, Macrocephaly (an abnormally enlarged head), and cherry-red spots in the eye. Other symptoms may include frequent respiratory infections, murmurs of the heart, doll-like facial features, and an 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. Anticonvulsant medications may initially control seizures. Children generally die by age 3 from respiratory infections.
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
Arylsufatase 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 Ester s (normally a transport form of cholesterol) and
Triglyceride s (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 Gland s, 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.
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, some patients with type 3 Gaucher disease, and Fabry disease. Ongoing research is in place to provide enzyme replacement for other lipidoses as well as gene therapy. 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.
