lipid storage diseases

Lipid storage disorders

Lipid storage diseases also called 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 1). Lipids are important parts of the myelin sheath that coats and protects the nerves. People with lipid storage diseases either do not produce enough of one of the enzymes needed to break down (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 (the nerves from the spinal cord to the rest of the body), liver, spleen, and bone marrow.

Lipid storage disease symptoms may appear early in life or develop in the teen or even adult years. Neurological complications of the lipid storage diseases may include:

  • lack of muscle coordination,
  • brain degeneration,
  • seizures,
  • loss of muscle tone,
  • learning problems,
  • spasticity,
  • feeding and swallowing difficulties,
  • slurred speech,
  • increased sensitivity to touch,
  • pain in the arms and legs, and
  • clouding of the cornea.

Lipid storage diseases are rare and complex. Natural history data for most conditions are limited, and scant long-term follow-up data are available on the efficacy of different therapeutic approaches. The evidence bases for these rare disorders are poorly organized and statistically weak. Efforts to capture diagnostic and long-term follow-up data to improve understanding are urgently needed. Biospecimen repositories are needed for future research studies of biomarkers and modifier genes. In this regard, the creation of ACMG/NIH Newborn Screening Translational Research Network301 is timely and will play an important role in improving the knowledge base in the coming years.

Patients with lipid storage diseases often need multidisciplinary care that should ideally be provided through a team approach, including medical geneticists, hematologists, cardiologists, neurologists, ophthalmologists, and anesthesiologists, among other specialists. As newborn screening for lipid storage diseases becomes more widespread, there will be an increasing need for physicians trained in the care of these patients, particularly biochemical geneticists.

Currently there is no specific treatment available for most of the lipid storage diseases 2). Enzyme replacement therapy is available for Gaucher and Fabry diseases. The U.S. Food and Drug Administration has approved migalastat (Galafold) as an oral drug to treat adults with Fabry disease who have a certain genetic mutation. Antiplatelet drugs used to treat stroke can slow the decline of kidney function seen in Fabry disease. Medications may be prescribed to help treat pain.

What are 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 (such as 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 the 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, and the mucopolysaccharidoses, in which excessive amounts of large, complicated sugar molecules are stored.

Lipid storage disease types

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

Gaucher disease has three common clinical subtypes:

  1. Type 1 (or 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. 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. People in this group usually bruise easily due to low blood platelet count. They may also experience fatigue due to anemia. Depending on disease onset and severity, individuals with type 1 may live well into adulthood. Many affected individuals have a mild form of the disease or may not show any symptoms. Although Gaucher type 1 occurs often among persons of Ashkenazi Jewish heritage, it can affect individuals of any ethnic background.
  2. Type 2 (or acute infantile neuropathic Gaucher disease) typically begins within 3 months of birth. Symptoms include extensive and progressive brain damage, spasticity, seizures, limb rigidity, enlarged liver and spleen, abnormal eye movement, and a poor ability to suck and swallow. Affected children usually die before age 2.
  3. 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 Gaucher disease. Major symptoms include eye movement disorders, cognitive deficit, poor coordination, seizures, an enlarged spleen and/or liver, skeletal irregularities, blood disorders including anemia, and respiratory problems. Nearly everyone with type 3 Gaucher disease who receives enzyme replacement therapy will reach adulthood.

For type 1 and most type 3 individuals, 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 individuals with Gaucher disease. Surgery to remove all or part of the spleen may be required on rare occasions (if the person has very low platelet counts or when the enlarged organ severely affects the person’s comfort). Blood transfusion may benefit some anemic individuals. Others may require joint replacement surgery to improve mobility and quality of life. There is currently no effective treatment for the brain damage that may occur in people with types 2 and 3 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, and eating, among other functions), eye paralysis, brain degeneration, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity to touch, and 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 subdivided into three categories:

  1. Type A, the most severe form, begins in early infancy. Infants appear normal at birth but develop profound brain damage by 6 months of age, an enlarged liver and spleen, swollen lymph nodes, and nodes under the skin (xanthomas). The spleen may enlarge to as great as 10 times its normal size and can rupture, causing bleeding. 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.
  2. Type B (or 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 pre-teen years. Individuals with type B 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 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 have only moderate enlargement of their spleens and livers. Those individuals with Niemann-Pick type C who share a common ancestral background in Nova Scotia were previously referred to as type D. The life expectancies of people with type C vary considerably. Some individuals die in childhood while others who appear to be less severely affected can 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 individuals with type B with mixed results.

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 heart beat), 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, 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 person 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.

People 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 but do not treat the disease. Metoclopramide or Lipisorb (a nutritional supplement) can ease gastrointestinal distress that often occurs in people with Fabry disease, and some individuals may require kidney transplant or dialysis. Enzyme replacement can reduce storage, ease pain, and preserve organ function in some people with Fabry disease.

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. 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, and nodes under the skin which thicken around joints as the disease progresses. Affected individuals with breathing difficulty may require 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 can be diagnosed soon after birth. Children born with this form of the disease usually die within 6 months.

Farber’s disease is caused by a deficiency of the enzyme called ceramidase. Currently 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 people with little or no lung or nervous system complications. Older persons may have granulomas surgically reduced or removed.

Gangliosidoses

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

GM1 gangliosidoses

The 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. GM1 gangliosidosis has three clinical presentations:

  • 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, and problems with gait. About half of affected individuals develop cherry-red spots in the eye. Children may be deaf and blind by age 1 and often die by age 3 from either cardiac complications or pneumonia.
  • Late infantile GM1 gangliosidosis typically begins between ages 1 and 3 years. Neurological symptoms include ataxia, seizures, dementia, and 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, and 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

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:

  1. 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. 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 response to noise, progressive loss of hearing leading to deafness, difficulty in swallowing, blindness, cherry-red spots in the retina, 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 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.
  2. 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, marked startle response to sound, spasticity, shock-like or jerking of a muscle (myoclonus), seizures, abnormally enlarged head (macrocephaly), and cherry-red spots in the eye. Other symptoms may include frequent respiratory infections, heart murmurs, 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. Anti-seizure medications may initially control seizures. Children generally die by age 3 from respiratory infections.

Krabbe disease

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 age 6 months, 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, and difficulty when swallowing. Prolonged weight loss may also occur. The disease may be diagnosed by enzyme testing and by identification of its characteristic grouping of cells into globoid bodies in the white matter of the brain, demyelination of nerves and degeneration, and destruction of brain cells. In infants, the disease is generally fatal before age 2. Individuals with a later onset form of the disease have a milder course of the disease and live significantly longer. No specific treatment for Krabbe disease has been developed, although early bone marrow transplantation may help some people.

Metachromatic leukodystrophy

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 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.

Metachromatic leukodystrophy has three characteristic forms: late infantile, juvenile, and adult.

  1. Late infantile MLD typically begins 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 and loss of previously acquired milestones, 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.
  2. Juvenile MLD typically begins 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.
  3. Adult symptoms begin after age 16 and may include ataxia, seizures, abnormal shaking of the limbs (tremor), impaired concentration, depression, psychiatric disturbances and dementia. Death generally occurs within 6 to 14 years after onset of symptoms.

There is no cure for metachromatic leukodystrophy. 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.

Wolman’s disease

Wolman’s disease also known as acid lipase deficiency, is a severe lipid storage disorder 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 disorder. Infants are normal and active at birth but quickly develop progressive mental deterioration, enlarged liver and grossly enlarged spleen, distended abdomen, gastrointestinal problems, 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.

Enzyme replacement for both Wolman’s disease and cholesteryl ester storage disease is currently under active investigation.

Lipid storage disease causes

Each lipid storage disorder results from deficiency of a specific enzymatic activity. With exception of Fabry disease, which is X-linked, each is inherited in an autosomal recessive fashion.

GM1 gangliosidoses

Type 1 disease frequently presents in early infancy, but patients with type 2 have been described with juvenile onset.

Both forms result from deficient activity of beta-galactosidase, a lysosomal enzyme encoded on chromosome 3 (band 3p21.33).

Although it is characterized by pathologic accumulation of GM1 gangliosides in the lysosomes of both neural and visceral cells, its accumulation is most marked in the brain. In addition, keratan sulfate, a mucopolysaccharide, accumulates in liver and is excreted in urine.

GM2 gangliosidoses

Tay-Sachs disease and Sandhoff disease both result from deficiency of hexosaminidase activity and lysosomal accumulation of GM2 gangliosides, particularly in central nervous system.

Both disorders have been classified into infantile, juvenile, and adult onset, with chronic forms based on age of onset and clinical features.

Hexosaminidase occurs as two isozymes, hexosaminidase A, which is composed of a and b subunits, and hexosaminidase B, which has two b subunits. Hexosaminidase A deficiency results from mutations in the a subunit and causes Tay-Sachs disease; mutations in the b subunit gene result in deficiency of both hexosaminidase A and B and cause Sandhoff disease.

Complementary DNA (cDNA) for both a and b subunits of hexosaminidase have been isolated and genes cloned. The a subunit is encoded by the HEXA gene on 15q23-q24 and the b subunit by the HEXB gene on 15q13. To date, more than 50 mutations have been identified, most associated with infantile forms of the disease. Three mutations account for more than 95% of mutant alleles among Ashkenazi Jewish carriers of Tay-Sachs disease, including 1 allele associated with the adult-onset form. Mutations that cause the subacute or chronic forms are associated with higher residual enzymatic activity levels, which correlate with decreased severity of symptoms.

A small number of patients accumulate GM2 gangliosides despite the presence of increased amounts of hexosaminidase A and B activity. These patients demonstrate complete absence of GM2 activator protein, which is encoded by the GM2A gene on 5q31.3-q33.1, and is necessary for the interaction of lipid substrates with the water-soluble enzyme hexosaminidase A.

Gaucher disease

Three clinical subtypes are delineated by the presence and progression of neurologic manifestations. All three subtypes are inherited as autosomal recessive traits

  • Type 1 – Adult, non-neuronopathic form
  • Type 2 – Infantile, acute neuronopathic form
  • Type 3 – Juvenile, Norrbotten form

Type 1, which accounts for 99% of cases, has a striking Ashkenazi Jewish predilection with an incidence of about 1 in 1000 and a carrier frequency of 1 in 18.

Gaucher disease results from deficient activity of lysosomal hydrolase, acid beta-glucosidase, which is encoded by a gene on chromosome 1 (q21 to q31). Enzymatic defects result in accumulation of undegraded glycolipid substrates, particularly glucosylceramide, in cells of reticuloendothelial system. This progressive deposition results in infiltration of bone marrow, progressive hepatosplenomegaly, and skeletal complications.

Acid beta-glucosidase cDNA has been cloned and mutant alleles have been identified including missense, insertion, and deletion mutations. Four of these mutations, N370S, L444P, 84insG, and IVS2, account for 90-95% of mutant alleles among Ashkenazi Jewish patients permitting screening for this disorder in this population.

Genotype-phenotype correlations have been noted, providing molecular basis for clinical heterogeneity seen in Gaucher disease type 1, which has a wide range of severity and age of onset. For example, patients who are homozygous for N370S mutations tend to have later onset of disease manifestations with a more indolent course than patients with one copy of N370S and another common allele.

Sphingomyelinase deficiency (NPD types A and B)

These disorders result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by a gene located on chromosome 11 (11p15.1 to p15.4). Enzymatic defects result in pathologic accumulation of sphingomyelin, a ceramide phospholipid, and other lipids in monocyte-macrophage systems, the primary site of pathology.

Progressive deposition of sphingomyelin in central nervous system results in a neurodegenerative course, seen in type A and in systemic disease manifestations of type B, including progressive lung disease. Complete sphingomyelinase genomic regions have been isolated and sequenced, and a number of mutations that cause NPD types A and B are identified, including single base substitutions and small deletions.

NPD type C

This disorder results from the egress of lipids, and particularly cholesterol, from late endosomes or lysosomes. Most cases of NPD type C result from mutations in the NPC1 gene on 18q11-q12. A small number of cases result from mutations in the NPC2 gene on chromosome 14q24.3. The NPC1 and NPC2 genes provide instructions for producing protein that are involved in the movement of cholesterol and lipids within cells. The term Niemann-Pick disease type D is no longer used; it describes the Nova Scotian variant, which results from mutations of the NPC1 gene.

Fabry disease

This disorder results from deficient activity of alpha-galactosidase A, a lysosomal enzyme encoded by a gene located on long arm of chromosome X (Xq22). [23]

Enzymatic defects lead to systemic accumulation of neutral glycosphingolipids, primarily globotriaosylceramide (GL-3), particularly in plasma and lysosomes of vascular endothelial and smooth muscle cells.

Progressive vascular glycosphingolipid deposition in affected males results in ischemia and infarction, which leads to major disease manifestations. Affected males who have type B or AB blood have a more severe disease course, since blood group B substance also accumulates, as it is normally degraded by alpha-galactosidase A.

Both cDNA and genomic sequences, encoding alpha-galactosidase A, are isolated and characterized. Molecular studies have identified a variety of different mutations in alpha-galactosidase A gene that are responsible for this lysosomal storage disease, including amino acid substitutions, gene rearrangements and messenger RNA (mRNA) splicing defects.

Fucosidosis

This rare, autosomal recessive disorder results from deficient activity of alpha-fucosidase and accumulation of fucose containing glycosphingolipids, glycoproteins, and oligosaccharides in lysosomes of the liver, brain, and other organs.

The alpha-fucosidase gene is localized to chromosome 1 (band 1p24), and specific mutations are been identified.

Schindler disease

This autosomal recessive neurodegenerative disorder results from deficient activity of alpha-N-acetylgalactosaminidase, and accumulation of sialylated, asialio-glycopeptides, and oligosaccharides.

The gene for the enzyme is cloned and mapped to chromosome 22 (bands 22q13.1-13.2).

Metachromatic leukodystrophy (MLD)

This is an autosomal recessive white matter disease caused by deficiency of arylsulfatase A (ASA), which is required for hydrolysis of sulfated glycosphingolipids. Another form is caused by a deficiency of a sphingolipid activator protein (SAP-1), a protein required for formation of substrate-enzyme complex.

Deficiency of enzymatic activity results in white matter storage of sulfated glycosphingolipids, which then leads to demyelination and a neurodegenerative course.

The ASA gene is localized to chromosome band (22q13.31-qter) and specific mutations are identified. They fall into two groups, which correlate with disease severity.

Multiple sulfatase deficiency

This is an autosomal recessive disorder resulting from mutations in the sulfatase-modifying factor-1 gene (SUMF1) localized to chromosome 3p26. The activities of all sulfatases are impaired due to a defect in their post-translational modification by the protein encoded by SUMF1.

Sulfatides, mucopolysaccharides, steroid sulfates, and gangliosides accumulate in cerebral cortex and visceral tissues. This results in a clinical phenotype with features of leukodystrophy and mucopolysaccharidoses.

Krabbe disease

This autosomal recessive, fatal disorder of infancy is also known as globoid cell leukodystrophy.

It results from deficiency of enzymatic activity, galactocerebroside, and white matter accumulation of galactosylceramide, which is normally found exclusively in myelin sheath.

The galactocerebroside gene is localized to chromosome 14 (band14q31) and specific disease-causing mutations have been identified.

Farber disease

This autosomal recessive disorder results from deficiency of lysosomal enzyme, ceramidase, and accumulation of ceramide in various tissues, especially the joints.

Ceramidase is encoded by the gene ASAH localized to chromosome 8p22-p21.3.

Schindler disease

The 3 forms of Schindler disease result from deficiency in the alpha-N-acetylgalactosaminidase encoded by the NAGA gene on 22q11.

Wolman disease and CESD both result from deficiency of lysosomal acid lipase, an acid cholesteryl ester hydrolase encoded by the LIPA gene on chromosome 10q24-q25. Wolman patients have no enzyme activity, and patients with the milder CESD demonstrate residual enzyme activity.

Lipid storage diseases inheritance pattern

Lipid storage diseases are inherited from one or both parents who carry a defective gene that regulates a particular lipid-metabolizing enzyme in a class of the body’s cells. They can be inherited two ways:

  1. 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 percent chance of inheriting both copies of the defective gene, a 50 percent chance of being a carrier like the parents, and a 25 percent chance of not inheriting either copy of the defective gene. Children of either gender can be affected by an autosomal recessive pattern of inheritance.
  2. X-linked (or sex-linked) recessive inheritance occurs when the mother carries the affected gene on the X chromosome. The X and Y chromosomes are involved in gender determination. Females have two X chromosomes and males have one X chromosome and one Y chromosome. Sons of female carriers have a 50 percent chance of inheriting and being affected with the disorder, as the sons receive one X chromosome from the mother and a Y chromosome from the father. Daughters have a 50 percent chance of inheriting the affected X chromosome from the mother and are carriers or mildly affected. Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.

Lipid storage disease symptoms

Progressive lysosomal accumulation of glycosphingolipids results in clinical symptoms in patients with lipid storage disorders.

Storage in CNS can lead to a neurodegenerative course, with loss of skills or failure to attain developmental milestones. Loss of milestones, in any infant or child, should prompt an evaluation for presence of a storage disorder.

Storage in visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, pulmonary infiltration, and other manifestations.

Patterns of abnormalities and clinical history vary among different lipidoses. Symptoms depend on the underlying enzymatic deficiency and the particular substrate that is accumulated.

Neurologic findings

Accumulation of lipid substrates in CNS leads to neurodegeneration, which frequently manifests as loss of previously attained milestones in an infant or young child. Neurodegeneration is characteristic of many lipidoses.

GM1 gangliosidoses type 1

Infantile forms in newborns present with hepatosplenomegaly, edema, and skin eruptions. They also can present within the first 6 months of life, with developmental arrest followed by progressive psychomotor retardation and tonic-clonic seizures. As many as 50% of affected infants have a cherry-red spot in the macula.

By the end of the first year of life, most patients are blind and deaf, with severe neurologic impairment characterized by decerebrate rigidity. Death usually occurs by age 3-4 years.

GM2 gangliosidoses type 2

These include Tay-Sachs disease and Sandhoff disease. Each results from deficiency of hexosaminidase activity and lysosomal accumulation, particularly in the CNS. Both disorders have been classified into infantile, juvenile, and adult onset.

Patients with infantile forms of Tay-Sachs disease present in infancy with loss of motor skills, increased startle reaction, and presence of a cherry-red spot on slit lamp examination.

Affected infants usually develop normally until about age 5 months, when decreased eye contact and exaggerated startle response to noise is noted. Macrocephaly may develop but is not associated with hydrocephalus. In the second year of life, seizures usually develop and require anticonvulsant therapy. Neurodegeneration is relentless, death occurs by age of 4-5 years.

Juvenile-onset disease presents with ataxia and dysarthria and is not associated with a cherry-red spot of the macula. Clinical manifestations of Sandhoff disease are similar to Tay-Sachs disease. Juvenile forms present with ataxia, dysarthria, and mental deterioration but without visceral enlargement or a macular cherry-red spot.

Gaucher disease type 1

Gaucher disease type 1 is less severe than type 2.

Patients who present in childhood tend to have more pronounced visceral and bony disease manifestations than those who present in adulthood.

Physical findings include growth retardation, delayed puberty, leukopenia, impairment of pulmonary gas exchange, and destruction of vertebral bodies with secondary neurologic complications 3). Retinoblastoma has been noted in an infant with Gaucher disease 4).

Gaucher disease type 2

This condition is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within first 2 years of life. It presents in infancy with increased tone, strabismus and organomegaly. Failure to thrive and stridor due to laryngospasm are typical.

After several years of psychomotor retrogression, death usually occurs secondary to respiratory compromise.

Sphingomyelinase deficiency (NPD type A)

Clinical presentation and course are relatively uniform and characterized by normal appearance at birth. Hepatosplenomegaly and psychomotor retardation are evident by age 6 months, followed by regression.

With advancing age, loss of motor function and deterioration of intellectual capabilities are progressively debilitating. In later stages, spasticity and rigidity are evident, with affected infants experiencing complete loss of contact with environment.

Sphingomyelinase deficiency (NPD type B)

Patients usually have normal neurologic findings and intelligence, although some have reported cherry-red maculae or haloes and subtle neurologic symptoms (eg, peripheral neuropathy). Skeletal involvement is more prevalent than previously recognized 5).

NPD type C

The clinical presentation and course is relatively uniform and characterized by normal appearance at birth, hepatosplenomegaly and psychomotor retardation by age 6 months, followed by regression and progressive debilitation. In later stages, spasticity and rigidity are evident, with affected infants experiencing complete loss of contact with the surrounding environment.

Fucosidosis

Wide variability is observed, with severely affected patients presenting in the first year of life. Developmental delay and somatic features are similar to those for mucopolysaccharidoses. These include frontal bossing, hepatosplenomegaly, coarse facial features, and macroglossia.

CNS storage results in a relentless neurodegenerative course with death in childhood.

Fabry disease

The typical presentation is acute, episodic pain crises followed by chronic acroparesthesias 6).

Schindler disease type 1

This disease is an infantile-onset neuroaxonal dystrophy. Affected infants have normal development for the first months of life, followed by a rapid neurodegenerative course that results in severe psychomotor retardation, cortical blindness, and frequent myoclonic seizures.

Metachromatic leukodystrophy (MLD)

Late infantile forms are most common. Patients usually present when aged 12-18 months with irritability, inability to walk, and hyperextension of knee, causing genu-recurvatum. Deep tendon reflexes are diminished or absent. Gradual muscle wasting, weakness, and hypotonia become evident and lead to a debilitated state. As disease progresses, nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear. Death occurs within the first decade of life.

Krabbe disease

The infantile form is rapidly progressive and presents in early infancy with irritability, seizures, and hypertonia.

Optic atrophy is evident in the first year of life, and mental development is severely impaired. As disease progresses, optic atrophy and severe developmental delay become apparent.

Death typically occurs within the first 2 years of life because of respiratory complications 7).

Niemann-Pick disease

Type A: Hypotonia at age 7 months, cognitive progression up to 8 months, cognitive stagnation and regression, loss of deep tendon reflexes, eventual loss of interaction with environment, dysphagia, and aspiration 8).

Multiple sulfatase deficiency

Affected individuals may display developmental delay and ataxia. Some patients develop rapid neurologic deterioration.

Organomegaly

Organomegaly is caused by storage of lipid substrates in visceral cells and development of symptoms of hypersplenism, which include anemia, leukopenia, and thrombocytopenia.

Splenomegaly can be massive and life threatening; however, removal of spleen should be delayed as long as possible because patients frequently have exacerbation of other symptoms due to loss of the spleen as a reservoir for substrate storage.

Organomegaly is a feature of the infantile form of GM1 gangliosidosis, Sandhoff disease, but not Tay-Sachs disease, Gaucher disease, sphingomyelinase deficiency (NPD types A and B), or fucosidosis. For example, patients with NPD type B disease who undergo splenectomy frequently have worsening of pulmonary symptoms. Hepatosplenomegaly is prominent in childhood, but with increasing linear growth, abdominal protuberance decreases and becomes less conspicuous. In mildly affected patients, splenomegaly may not be noted until adulthood and disease manifestations may be minimal.

In Gaucher disease, splenomegaly is progressive and can become massive.

Skeletal abnormalities

These result from substrate accumulation and are present in several lipidoses.

In GM1 gangliosidosis, skeletal abnormalities are similar to those of mucopolysaccharidoses. There is anterior beaking of vertebrae, enlargement of sella turcica, and thickening of calvaria.

Clinical manifestations of Gaucher disease type 1 include clinically apparent bony involvement. It occurs in more than 20% of patients and can present as bone pain or pathologic fractures. More than half of patients have radiological evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur. In patients with symptomatic bone disease, lytic lesions can develop in long bones including the femur, ribs, and pelvis, and osteosclerosis occurs at an early age. Bone crises with severe pain and swelling can occur.

Patients with Farber disease develop nodular, erythematous swelling of the wrists and at other sites of trauma.

Pulmonary infiltration

Accumulation of substrate in pulmonary tissue occurs in several lipidoses.

Occasionally, patients with Gaucher disease type 1 have pulmonary involvement at time of presentation.

At diagnosis, most patients with sphingomyelinase deficiency (NPD type B) also have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on chest roentgenogram. In most type B patients, decreased pulmonary diffusion, due to alveolar infiltration, becomes evident in late childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by age 15-20 years. Such patients have low pO2 values and dyspnea on exertion. Life-threatening bronchopneumonias may occur and cor pulmonale is described.

Dermatologic findings

Findings include presence of edema and skin eruptions in infantile forms of GM1 gangliosidosis.

Patients with Fabry disease have angiokeratomas that usually appear in childhood and lead to early diagnosis. They increase in size and number with age and range from barely visible to several millimeters in diameter. Lesions are punctate, dark red to blue-black, and flat or slightly raised. They do not blanch with pressure and larger ones may show slight hyperkeratosis. Lesions are most dense between umbilicus and knees, in “bathing trunk area,” but may occur anywhere, including oral mucosa. Hips, thighs, buttocks, umbilicus, lower abdomen, scrotum, and glans penis are common sites, and there is a tendency toward bilateral symmetry. Variants without skin lesions are described.

Angiokeratoma are also found in patients with Schindler disease, fucosidosis, and GM1 gangliosidosis.

Ichthyosis and dry, scaly, itchy skin occurs in patients with multiple sulfatase deficiency and the congenital form of Gaucher disease.

Painful crises

Pain is the most debilitating symptom of Fabry disease in childhood and adolescence. Fabry crises last from minutes to several days. They consist of agonizing, burning pain in hands, feet, and proximal extremities. Pains are usually associated with exercise, fatigue, and fever. Painful acroparesthesias usually become less frequent in the third to fourth decades of life, although in some men they may become more frequent and severe. Attacks of abdominal or flank pain may simulate appendicitis or renal colic.

Vascular disease

With increasing age, major morbid symptoms of Fabry disease result from progressive involvement of vascular system. Early in disease, casts, red cells, and lipid inclusions, with characteristic birefringent “Maltese crosses,” appear in urinary sediment.

Proteinuria, isosthenuria, gradual deterioration of renal function, and development of azotemia occur in the second through fourth decades of life. Cardiovascular findings may include hypertension, left ventricular hypertrophy, anginal chest pain, myocardial ischemia or infarction, and congestive heart failure. Mitral insufficiency is the most common valvular lesion. Abnormal electrocardiographic and echocardiographic findings are common. Cerebrovascular manifestations result primarily from multifocal small vessel involvement.

Other features are chronic bronchitis and dyspnea, lymphedema of legs without hypoproteinemia, episodic diarrhea, osteoporosis, retarded growth, and delayed puberty. Death often results from uremia or vascular disease of heart or brain. Prior to hemodialysis or renal transplantation, mean age of death for affected men was 41 years.

Atypical male variants with residual alpha -galactosidase A activity that are asymptomatic or produce mild symptoms have been described. More recently, several patients with late-onset, isolated cardiac or cardiopulmonary disease have been reported. These patients do not have early classic manifestations. These cardiac variants include cardiomegaly, usually involving left ventricular wall, interventricular septum and electrocardiographic abnormalities consistent with a cardiomyopathy. Others have had hypertrophic cardiomyopathy and myocardial infarction.

Lipid storage disease complications

Myoclonic jerks, developmental regression, vision loss, macrocephaly, seizures, and spasticity are potential complications of Tay-Sachs disease 9).

Neurodegeneration, hypertonia, fevers of unknown etiology, seizures, vision loss, and developmental regression are all potential complications of Krabbe disease 10).

Anemia, thrombocytopenia, splenic rupture, hepatosplenomegaly, and bone pain are all potential complications of Gaucher disease. In addition, while the brain is not notably affected, an association between Parkinson disease and Gaucher disease has been demonstrated 11).

Splenic rupture is a potential complication of sphingomyelinase deficiency (NPD types A and B).

Aspiration that results in neurologic deficits is possible in individuals with infantile forms of lipid storage disorders.

If untreated, Pompe disease can lead to complications such as respiratory insufficiency and heart failure 12).

Acroparesthesias, stroke, and renal failure may result from Fabry disease 13).

Lipid storage disease diagnosis

Diagnosis of lipid storage disorders depends on demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

In some states, some of these lipid storage diseases (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.

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).

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 inserted through the cervix or by a fine needle inserted through the abdomen. Results are usually available within 2-4 weeks.

Prenatal diagnosis

If an index case has been identified, an attempt at prenatal diagnosis is warranted. Amniotic fluid can be evaluated by assaying cultured cells from the amniotic fluid or from chorionic villus for the targeted enzymatic activity. For some disorders, molecular genetic testing can be used to detect enzyme mutation detection or linkage analysis 14).

Newborn screening

The first large-scale pilot was conducted in Taiwan for Pompe disease (glycogen-storage disease type 2). Pseudodeficiencies for Pompe disease are common in Asian populations 15). A fluorescence assay was used to measure alpha glucosidase activity at three different pH levels.

In another large pilot study conducted in New York State and Washington State, tandem mass spectrometry (MS/MS) was used in newborn screening to assess enzyme activity for Pompe disease, mucopolysaccharidosis type 1, and Fabry disease, finding a lower number of screen positives 16).

Abdominal examination

This examination may reveal hepatosplenomegaly. Marked splenomegaly is sometimes overlooked when the spleen edge is in the pelvis, and abdominal contour also should be assessed. Hepatosplenomegaly may be evident at birth in neonates with GM1 gangliosidosis, sphingomyelinase deficiency (NPD type A), and Sandhoff disease.

Ophthalmologic examination

Ophthalmologic examination reveals findings in several lipidoses. A cherry-red macula can be identified by slit lamp examination in patients with GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease), Farber disease, and sphingomyelinase deficiency (NPD types A and B). The cherry red spot is the only normal part of the retina and is accentuated by the deposition of gangliosides in the surrounding retinal ganglion cells.

Neurologic examination

Neurologic examination documents presence and extent of neuropathology.

Imaging studies

Brain imaging

Brain imaging studies are frequently obtained during evaluation of infants and children with developmental delay or retrogression. However, they are not essential to diagnosis, which depends on demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

For many of the lipid storage disorders, MRI findings are either normal or not specific enough to be diagnostic. However, T2 hypointensity with T1 hyperintensity has been noted in patients with Tay-Sachs disease. In contrast, with infantile Krabbe, T1 hypointensity can be seen with T2 hyperintensity. In Niemann-Pick disease type C, frontal lobe and/or brainstem/cerebellar atrophy may be seen 17).

Findings vary with different disorders.

Skeletal radiography

In GM1 gangliosidosis, skeletal abnormalities are similar to those associated with mucopolysaccharidoses. They include anterior beaking of vertebrae, enlargement of sella-turcica and thickening of calvaria.

In Gaucher disease type 1, more than half of patients have radiological evidence of skeletal involvement including an Erlenmeyer flask deformity of the distal femur.

In patients with symptomatic bone disease, lytic lesions can develop in long bones like the femur, ribs, and pelvis. Osteosclerosis may be evident at an early age.

Chest radiography

Patients with sphingomyelinase deficiency (NPD types A and B) typically have fine reticular-nodular infiltrates.

Findings are not associated with clinical pulmonary disease in young patients but can be accompanied by pulmonary dysfunction later in life.

Abdominal radiography

Patients with Wolman disease typically have calcification of the adrenal noted on abdominal radiograph.

Genetic testing

For most disorders, carrier identification and prenatal diagnosis are available. Making a specific diagnosis in an affected child is important in order to provide genetic counseling.

More recently, investigators have focused efforts on determining molecular basis. These studies have resulted in identification of specific disease-causing mutations, allowing for improved diagnosis, prenatal diagnosis and carrier identification.

For some disorders (eg, Gaucher disease), it is possible to make genotype-phenotype correlations that predict disease severity and allow more precise genetic counseling. Thus, determination of genotype is recommended when possible 18).

Disease-specific molecular analysis

Fabry disease

Most pathogenic GLA mutations are “private” and nonrecurrent; more than 300 mutations have been described. In general, mutations that result in prematurely truncated α-gal A, which are approximately 45% of those reported, result in a classic Fabry phenotype in a hemizygote 19). Missense mutations that result in very low leukocyte α-gal A levels also result in a classic phenotype.

Gaucher disease

Sequencing of the GBA gene is the definitive method in the diagnosis of Gaucher disease. Within the Ashkenazi Jewish population, four common mutations (p.N370S, p.L444P, c.84insG, and c.IVS2 1) account for 90% of the disease-causing alleles; these same mutations account for 50%-60% of disease-causing alleles in non-Jewish patients 20).

Krabbe disease

The diagnosis can be confirmed via molecular analysis of the GALC gene 21). Genotype-phenotype correlation is limited and may be possible only if the clinical impact of a particular genotype is known in a larger set of patients with Krabbe disease.

Metachromatic leukodystrophy

The diagnosis of MLD can also be confirmed with molecular genetic analysis of the ARSA gene. To date, more than 140 disease-relevant mutations have been identified. Several recurrent mutations account for up to 60% of disease-relevant alleles in certain populations 22). ARSA mutations characterized in more detail have been divided into two groups: (1) “null alleles” such as c.459 1g>a (25% of disease alleles) and c.1204 1g>a, which result in complete loss of enzymatic activity, and (2) “R alleles” such as p.P426L (25% of disease alleles) and p.I179S (12.5% of disease alleles), which allow the synthesis of ARSA enzyme with residual catalytic activity of up to 5% of normal 23).

Niemann-Pick disease, types A and B

Sequencing of the SMPD1 gene is the most reliable method to confirm a diagnosis of NPD. In the Ashkenazi Jewish population, three founder mutations, p.R496L, p.L302P, and fsP330, account for more than 95% of mutant alleles and are associated with the NPA phenotype 24). Biomarkers may play a role in confirming a diagnosis of Niemann-Pick disease type C1 (isolation of abundant N-palmitoyl-O-phosphocholineserine [PPCS] levels urine) 25).

Tay-Sachs disease

HEXA gene DNA analysis or enzymatic assay of leukocyte beta-hexosaminidase A are approaches for diagnosis of Tay-Sachs disease 26).

Lipid storage disease treatment

Currently there is no specific treatment available for most of the 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 for Gaucher disease. However, anti-platelet medications can help prevent strokes and medications that lower blood pressure can slow the decline of kidney function in people with Fabry disease. The U.S.Food and Drug Administration has approved the drug migalastat (Galafold) as an oral medication for adults with Fabry disease who have a certain genetic mutation. Eligustat tartrate, an oral drug approved for Gaucher treatment, works by administering small molecules that reduce the action of the enzyme that catalyzes glucose to ceramide. 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.

Fabry disease

Until recently, treatment for Fabry disease has been nonspecific and limited to supportive care. These measures included the use of phenytoin and carbamazepine, which have been shown to decrease the frequency and severity of the chronic acroparesthesias and the periodic crises of excruciating pain. Renal transplantation and long-term hemodialysis also have become life-saving procedures for patients with renal failure. Statins and aspirin have been used to reduce thromboembolic risk factors. Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers have been used to treat proteinuria and hypertension.

Enzyme replacement therapy with recombinant alpha-galactosidase A (Replagal, TKT Corporation, Cambridge, Mass; Fabrazyme, Genzyme Corporation, Cambridge, Mass) is available. Fabrazyme is the only ERT for Fabry disease approved by the FDA 27). Data from clinical trials show a decrease in GL-3 levels following enzyme replacement therapy, reversal in lipid tissue storage, and stabilized or improved renal and cardiac function. Subjective reduction or relief from neuropathic pain has been documented, in addition to a decrease in the long-term use of neuropathic pain medication.

Oral migalastat is used to treat Fabry disease in some patients aged 16-18 years or older, depending on the specific gene mutation 28).

Recent advances in recombinant enzyme replacement, bone marrow transplantation, gene transfer, substrate reduction, and chaperone-mediated therapy provide great hope in potentially treating other lipid storage disorders.

Wolman disease

Dietary restriction has shown promise for disorders such as lysosomal acid lipase deficiency (Wolman disease), as has incorporation of lipid-lowering drugs in the regimen along with sebelipase alpha, a recombinant enzyme replacement therapy 29).

Diet

Nutritional therapies involving particularly specific subsets of macronutrients and/or micronutrients are used in the treatment of some lipid storage disorders. However, the variances in nutritional treatments and the limited population of affected individuals result in limited data with outcomes often based on case reports.

Neutral lipid storage disease with myopathy (NLSD-M): Patients may benefit from a diet that is particularly adequate in carbohydrates as a consistent source of energy production. This recommendation is believed to stem from a study in which patients who received intravenous glucose exhibited respiratory improvements 30).

Neutral lipid storage disease with ichthyosis (NLSD-I), also known as Chanarin-Dorman syndrome: Patients may benefit from high-carbohydrate, low-fat diets with supplemental medium-chain triacylglycerol (MCT). Other case reports have noted use of low-fat, long-chain fatty acid (LCFA)–restricted and carbohydrate-rich, protein-restricted diets with little therapeutic benefit. Finally, a case report has found that a gluten-free diet improved gastrointestinal symptoms and marginally enhanced muscle strength 31).

Primary carnitine deficiency (PCD): A case report described a patient with amelioration of cardiac symptoms after interventions including medium chain fatty acids (MCFAs) 32).

Multiple acyl-CoA dehydrogenation deficiency (MADD): Riboflavin supplementation in riboflavin-responsive (RR) MADD improves symptoms in adult-onset cases. Coenzyme Q10 (CoQ10) and vitamin B12 are also used in adult-onset cases to improve outcomes. In addition, dietary education may be warranted to prevent the potential dangers of carbohydrate restriction in this population 33).

Neurofibromatosis type 1 (NF1): Muscle lipid phenotypes may see improvements after a reduction in dietary long-chain fatty acid intake in addition to L-carnitine supplementation 34).

Inclusion body myositis (IBM): A phase 1 trial is scheduled to investigate whether triheptanoin oil can recover muscle performance in patients with inclusion body myositis 35).

Patients with sphingomyelinase deficiency (NPD) have elevated total cholesterol, although effects of dietary restriction of cholesterol have not been demonstrated in animal models of NPD type C 36).

Avoidance of prolonged fasting is recommended for all fatty acid disorders 37).

Activity

Gaucher disease and patients with sphingomyelinase deficiency (NPD types A and B) with organomegaly should avoid contact sports and seek immediate medical attention for trauma. If their platelet counts drop precipitously secondary to hypersplenism, they are at risk for both splenic rupture and intracranial bleeding.

Weight-bearing exercise has been recommended in patients with acid sphingomyelinase deficiency to prevent osteopenia 38).

Aerobic exercise lasting more than 30 minutes should be avoided in patients with fatty acid disorders 39).

Further outpatient care

Fabry disease

Baseline diagnostic studies (electrocardiography, echocardiogram, ophthalmologic examination, renal function tests, plasma and/or urine GL-3) should be obtained. Affected family members identified during screening should also undergo identical evaluations; adults should also undergo additional testing as recommended.

Infants with Fabry disease should be seen by a metabolic specialist at 6-month intervals and monitored for the onset of Fabry symptoms 40).

Gaucher disease

Evaluations for anemia/thrombocytopenia, hepatosplenomegaly, and bony involvement should be performed.

In patients who are predicted to have neuronopathic Gaucher disease and in patients whose genotype cannot accurately predict the phenotype, the degree of neurological impairment should also be assessed.

Gaucher biomarker and anti-GBA antibody levels should be measured before initiation of enzyme replacement therapy (ERT).

Infants should be monitored at regular intervals (at least quarterly) to assess response to treatment and development 41).

Niemann-Pick disease

Infants with Niemann-Pick disease should undergo dilated funduscopic examination performed by an ophthalmologist.

Plain chest radiography abdominal ultrasonography should be performed at regular intervals to document the extent of pulmonary involvement and hepatosplenomegaly.

The metabolic physician should evaluate the infant on a monthly basis, documenting weight gain, linear growth, pulse oximetry, and developmental progression.

Infants need evaluation and regular follow-up by a neurologist and pulmonologist as the disorder progresses. Because no curative treatment currently exists, only symptomatic and supportive care can be provided.

Lipid-lowering drugs (eg, statins) are ineffective 42).

Lipid storage disease prognosis

The prognosis for a lipid storage disorder is determined by the type of disease, the age of onset, and the severity of symptoms. Children treated for some forms of Gaucher disease may live well into adulthood, while children with Niemann-Pick disease often die at a young age from infection or progressive neurological loss. Children with Fabry disease often die prematurely of complications from heart disease, renal failure, or stroke. Most children with Farber’s disease die by age 2, usually from lung disease. Children with Tay-Sachs and Sandhoff diseases often die at an early age from recurring or respiratory infection.

References   [ + ]