eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Lipid Storage Disorders

Author: Margaret M McGovern, MD, PhD, Professor and Chair of Pediatrics, Stony Brook University, New York
Contributor Information and Disclosures

Updated: May 28, 2009

Introduction

Background

Lipid storage disorders are a family of diverse diseases related by their molecular pathology. In each disorder, a deficiency of a lysosomal hydrolase is inherited, which leads to lysosomal accumulation of the enzyme's specific sphingolipid substrate.^1,2 Lipid substrates share a common structure, including a ceramide backbone (2-N -acyl-sphingosine), in which various sphingolipids are derived by substitution of hexoses, phosphorylcholine, or one or more sialic acid residues on terminal hydroxyl groups of the ceramide molecule.

Pathways of glycosphingolipid metabolism in both nervous tissue and visceral organs are elucidated, and for each catabolic step, a genetically determined metabolic derangement is identified. Disorders include GM1 gangliosidoses,³ GM2 gangliosidoses,³ Gaucher disease, Niemann-Pick disease (NPD),⁴ Fabry disease, fucosidosis, Schindler disease, metachromatic leukodystrophy (MLD), Krabbe disease, multiple sulfatase deficiency, Farber disease, and Wolman disease.

The biochemical basis of lipid storage disorders is well characterized and includes determining properties of enzymatic activities and various storage products. Research has led to development of diagnostic assays for identification of affected individuals, which usually rely on measurement of specific enzymatic activity in isolated leukocytes or cultured fibroblasts. For most disorders, carrier identification and prenatal diagnosis are available as well. Making a specific diagnosis in an affected individual is essential in order to provide accurate genetic counseling.

More recently, investigators have focused efforts on determining molecular basis. These studies have resulted in identifying specific disease-causing mutations and have led to improved diagnosis, prenatal diagnosis, and carrier identification. In addition, in some disorders (eg, Gaucher disease), making genotype-phenotype correlations that predict disease severity and allow more precise genetic counseling is possible. Advances in understanding molecular basis include cloning and characterization of most genes that encode specific enzymes required for sphingolipid metabolism. These investigations permit development of improved therapeutic options, such as recombinant enzyme replacement therapy. Future gene therapy for selected lipidoses may also result in improved prognosis.

Pathophysiology

Because glycosphingolipids are essential components of all cell membranes, inability to degrade these substances and their subsequent accumulation results in physiologic and morphologic alterations that lead to characteristic clinical manifestations. In particular, progressive lysosomal accumulation of glycosphingolipids in the central nervous system can lead to a neurodegenerative course; whereas, storage in visceral cells can lead to organomegaly, skeletal abnormalities, pulmonary infiltration, and other manifestations. In general, storage of any particular substrate in a specific tissue is dependent on normal distribution of compound. Thus, various disorders are characteristic patterns of organ involvement, depending on particular substrate that is stored.

Frequency

United States

Lipid storage disorders are rare disorders, although some have an ethnic predilection with more appreciable frequency.

International

Frequency is similar to that in the United States.

Mortality/Morbidity

Infantile forms are usually fatal. Juvenile-onset and adult-onset disorders have variable survival rates that depend on particular manifestations.

Race

Most lipid storage disorders are panethnic; however, an ethnic predilection has been noted for Tay-Sachs disease, type 1 Gaucher disease, and NPD type A, which all occur at increased frequency in Ashkenazi Jews. Guidelines for carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent have been established.⁵

Sex

Each disorder is an autosomal recessive trait, except Fabry disease, which is X-linked.

Age

• Presentation in infancy
  • GM1 gangliosidosis type 1 and NPD type A usually appear in early infancy. GM2 gangliosidoses, which include Tay-Sachs disease and Sandhoff disease, have infantile forms. 
  • The clinical phenotypes for MLD widely vary. Patients who are severely affected usually present in the first year of life with developmental delay and somatic features, similar to those of mucopolysaccharidoses. Late infantile forms of MLD, which is most common, usually present in infants aged 12-18 months with irritability, inability to walk, and hyperextension of the knee, causing genu-recurvatum.
  • Infantile forms of Krabbe disease are rapidly progressive and present early in infancy with irritability, seizures, and hypertonia. Optic atrophy is evident in the first year of life and mental development is severely impaired. A second, late infantile form of Krabbe disease is also observed and presents in children older than 2 years. Affected individuals have a disease course similar to early infantile form.
  • Wolman disease is a fatal disorder of infancy. Clinical features become apparent in the first week of life and include failure to thrive, relentless vomiting, abdominal distention, and hepatosplenomegaly.
• Presentation in childhood: GM1 and GM2 gangliosidoses type 2 are juvenile-onset forms. NPD type B has a variable age of presentation but frequently appears early in childhood, when hepatosplenomegaly is detected. Angiokeratomas that appear in Fabry disease usually occur in childhood and can lead to early diagnosis. Juvenile forms of MLD have more indolent courses and onset can occur in persons as old as 20 years. This form presents with gait disturbances, mental deterioration, urinary incontinence, and emotional difficulties.
• Presentation in adulthood: Adult forms of MLD, which present after the second decade of life, are similar to juvenile forms in clinical manifestations, although emotional difficulties and psychosis are more prominent features.

Clinical

History

• 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, 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.

Physical

• 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 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.
  • Niemann-Pick disease (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.
  • 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).
  • 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.
  • 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. Affected children develop opisthotonos and usually die when younger than 3 years.
• 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 infantile form of GM1 gangliosidosis, Sandhoff disease, but not Tay-Sachs disease, Gaucher disease, NPD, 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.
• 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 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.
• 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 α -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.
• 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, 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.
• Neurologic examination: Neurologic examination documents presence and extent of neuropathology.

Causes

Each 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 β -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 a subunit and causes Tay-Sachs disease; mutations in 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. To date, more than 50 mutations have been identified, most associated with infantile forms of 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 subacute or chronic forms have been demonstrated to result in higher residual enzymatic activity levels, which correlate with severity.
• Gaucher disease
  • Three clinical subtypes are delineated by the presence and progression of neurologic manifestations. All 3 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 b -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 b -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.
• 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.
• 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).
  • Enzymatic defects lead to systemic accumulation of neutral glycosphingolipids, primarily globotriaosylceramide, 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 a-galactosidase A.
  • Both cDNA and genomic sequences, encoding a-galactosidase A, are isolated and characterized. Molecular studies have identified a variety of different mutations in a-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 α -fucosidase and accumulation of fucose containing glycosphingolipids, glycoproteins, and oligosaccharides in lysosomes of the liver, brain, and other organs.
  • α -fucosidase gene is localized to chromosome 1 (band 1p24), and specific mutations have been identified.
• Schindler disease
  • This autosomal recessive neurodegenerative disorder results from deficient activity of a -N -acetylgalactosaminidase, and accumulation of sialylated, asialia-glycopeptides, and oligosaccharides.
  • Genes for the enzyme have been cloned and mapped to chromosome 22 (bands 22q13.1-13.2).
• 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 deficiency of 3 enzymatic activities: arylsulfatases A, B, and C. Underlying etiology remains unknown.
  • 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.
  • It has not been cloned or localized to a chromosome.

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