AUTHOR INFORMATION

Section 1 of 10

Authored by Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

Margaret McGovern, MD, PhD, is a member of the following medical societies: American Academy of Pediatrics, and American Society of Human Genetics

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Margaret McGovern, MD, PhD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, June 9 2006, VOLUME 7, Number 6

INTRODUCTION

Section 2 of 10

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. 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, GM2 gangliosidoses, Gaucher disease, Niemann-Pick disease (NPD), 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, for some disorders (eg, Gaucher disease) it is possible to make genotype-phenotype correlations that predict disease severity and allow more precise genetic counseling. 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 also may result in improved prognosis.

Pathophysiology: Since 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:

• In the US: Lipid storage disorders are rare disorders, although some have an ethnic predilection with more appreciable frequency.

• Internationally: 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 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.

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. Wide variability exists in clinical phenotypes for metachromatic leukodystrophy. 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 also exists 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

Section 3 of 10

History:

• Progressive lysosomal accumulation of glycosphingolipids results in clinical symptoms.



• Storage in central nervous system 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 are dependent on the underlying enzymatic deficiency and the particular substrate that is accumulated.

Physical:

• Neurologic findings


• • Accumulation of lipid substrates in central nervous system 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. Up to 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 central nervous system. 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.
  
  
  
  • 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 exists, 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.

    • Central nervous system 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.

  • 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 a-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 b-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; and 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 a-fucosidase and accumulation of fucose containing glycosphingolipids, glycoproteins, and oligosaccharides in lysosomes of the liver, brain, and other organs.

  • A-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).
  
  
  
• 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 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.

DIFFERENTIALS

Section 4 of 10

Gaucher Disease
Mucopolysaccharidosis Type IH

WORKUP

Section 5 of 10

Lab Studies:

• Diagnosis is dependent upon demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

Imaging Studies:

• Brain imaging


• • Brian imaging studies are frequently obtained during evaluation of infants and children with developmental delay or retrogression. However, they are not essential to diagnosis, which is dependent upon demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.
  
  
  
  • Findings vary with different disorders.
  
  
  
• Skeletal radiographs


• • 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 calvarium.
  
  
  
  • 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 radiograph


• • Patients with NPD typically have fine reticula-nodular infiltrates.
  
  
  
  • Findings are not associated with clinical pulmonary disease in young patients but can be accompanied by pulmonary dysfunction later in life.
  
  
  

Other Tests:

• Genetic testing


• • For most disorders, carrier identification and prenatal diagnosis are available. It is essential to make a specific diagnosis in an affected child 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.
  
  
  
  • In addition, some disorders (eg, Gaucher disease) are possible to make genotype-phenotype correlations that predict disease severity and allow more precise genetic counseling. Thus, determination of genotype is recommended when possible.
  
  
  

Gaucher disease has a pathologic hallmark, which is the Gaucher cell in the reticuloendothelial system, particularly in bone marrow. Cells, which are 20-100 m m in diameter, have a wrinkled-paper appearance resulting from presence of intracytoplasmic inclusions of substrate. Cytoplasm reacts strongly positive with periodic acid-Schiff stain. Presence in bone marrow and organ tissue specimens is highly suggestive of Gaucher disease, although it can be found in patients with granulocytic leukemia and myeloma.

NPD types A and B have a pathological hallmark, which is histochemically lipid-laden foam cells, often called Niemann-Pick cells. These cells can be readily distinguished from Gaucher cells by their histologic and histochemical characteristics. They are not pathognomonic for NPD, since histologically similar cells are found in patients with Wolman disease, cholesterol ester storage disease, lipoprotein lipase deficiency, and GM1 gangliosidosis type 2.

TREATMENT

Section 6 of 10

Medical Care:

• Except for Gaucher and Fabry disease, treatment options are limited. Primarily, treatment is directed at symptomatic relief. No specific treatment is available for either form of GM1 gangliosidosis, Tay-Sachs disease, Sandhoff disease, fucosidosis, Krabbe disease or Schindler disease. These disorders pursue a relentless course, leading to death.



• Enzyme replacement with recombinant acid a-glucosidase is available for the treatment of symptomatic patients with Gaucher disease type 1. Clinical trials have demonstrated that most extraskeletal symptoms are reversed within 12-36 months by an initial debulking dose of enzyme (60 IU/kg) administered by intravenous infusion every other week.
  • The effectiveness of enzyme replacement in reversing and preventing bone manifestations is still under study; however, data indicate that early treatment may be efficacious in normalizing linear growth and bone morphology in affected children.

  • Efforts are also underway to develop gene therapy for Gaucher disease type 1. Although enzyme replacement does not alter the neurologic progression of patients with Gaucher disease types 2 and 3, it has been used in selected patients as a palliative measure, particularly in patients with severe visceral involvement.

  • Alternative treatments also are being evaluated, including the use of agents designed to decrease the synthesis of glucosylceramide by chemical inhibition of glucosylceramide synthase.



• 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. More recently, clinical trials with recombinant a-galactosidase (Fabrazyme, Genzyme Corporation, Cambridge, MA; Replagal, TKT Corporation, Cambridge, MA) have revealed the safety and effectiveness of enzyme replacement therapy for Fabry disease at a dose of 1 mg/kg every other week. The enzyme replacement therapy is available in Europe and has been recently approved by the US Food and Drug Administration (FDA).



• At present, no specific treatment is available for NPD. Orthotopic liver transplantation in an infant with type A disease and amniotic cell transplantation in several type B patients has been attempted with little or no success. Bone marrow transplantation in one patient with NPD type B was successful in reducing spleen and liver volumes, sphingomyelin content in the liver, number of NPD cells in marrow, and radiologic infiltration of lungs. However, no long-term information is available because patient died 3 months after transplantation. To date, lung transplantation has not been performed in any severely compromised patient with type B NPD. Future prospects for therapy include enzyme replacement and gene therapy.

Consultations:

• Patients thought to have a lipidosis should have an evaluation with a clinical geneticist.



• Neurologic consultation also is indicated.



• Patients with Fabry disease should have a cardiac evaluation.



• Patients with Gaucher disease type 1 and NPD type B should have pulmonary consultations.

Diet:

• No specific dietary manipulations have an effect on the disease course. In particular, restriction of lipids is of no benefit.



• Patients with NPD have elevated total cholesterol, although effects of dietary restriction of cholesterol have not been demonstrated.

Activity:

• Gaucher disease and patients with NPD 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.

MEDICATION

Section 7 of 10

Drug Category: Enzyme replacement therapies -- Specific enzymes are available to treat Gaucher and Fabry Disease.

Drug Name	Imiglucerase (Cerezyme) -- A recombinant-derived analog of b-glucocerebrosidase. It is an enzyme used for replacement therapy in Gaucher disease. Catalyzes hydrolytic cleavage of glucocerebroside (a glycoprotein) to glucose and ceramide within the lysosomes of phagocytic cells in the reticuloendothelial system. This normally is a catabolic pathway of membrane lipids derived from hematologic cell turnover. A deficiency of this enzyme results in accumulation of glucocerebroside within tissue macrophages, which become engorged with the glycolipid. Treatment improves anemia and thrombocytopenia, reduces spleen and liver size, and decreases cachexia.
Adult Dose	60 U/kg IV q2wk, typically; dose must be individualized and varies widely; initial dose may be as little as 2.5 U/kg 3 times/wk or as much as 60 U/kg q1-4wk Dilute in 0.9% NaCl and infuse over 1-2 h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May develop IgG antibodies (15%) and hypersensitivity (6-7%); may cause nausea, abdominal pain, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia; may cause pruritus at site of injection

Drug Name	Agalsidase (Fabrazyme, Replagal) -- Recombinant form of the human enzyme a-Gal A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced. Agalsidase beta (Fabrazyme) is manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells. Agalsidase alfa (Replagal) is manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.
Adult Dose	Initial dose: Fabrazyme: 1 mg/kg IV infused over 4-6 h (initial infusion); subsequent infusions may be administered at a rate of 3-5 mg/min; repeat q2wk Replagal: 0.2 mg/kg IV infused over 40 min q2wk Maintenance dose: Not established
Pediatric Dose	Not established; appropriate time to initiate treatment in children has not been determined
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause IgG antibody production (55% with Replagal; 83% with Fabrazyme); may cause allergic reactions (10% Replagal, 59% Fabrazyme), which are prevented by premedication with hydrocortisone and/or antihistamines (standard for Fabrazyme) before IV infusion; infusion-related events (ie, fever, rigors, hypertension) may be reduced or eliminated by slower rate of administration or interruption of treatment

FOLLOW-UP

Section 8 of 10

Complications:

• Splenic rupture in Gaucher disease and NPD



• Aspiration that results in neurologic deficits possible in patients affected with infantile forms



• Renal failure in Fabry disease

Prognosis:

• Patients affected with infantile forms that include neurologic disease have an unrelenting course that leads to death, usually when patients are younger than 5 years.



• Most patients with GM1 gangliosidosis are blind and deaf when younger than 2 years. They also have severe neurologic impairment characterized by decerebrate rigidity. Death usually occurs by age 3-4 years.



• Infants with Tay-Sachs have a progressive course with death at age 4-5 years.



• Gaucher disease type 2, which is much less common than type 1 disease, is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life.



• Gaucher disease type 3 presents with clinical manifestations intermediate to those in types 1 and 2. Patients present in childhood and death occurs by age 10-15 years. Neurologic involvement is present, but occurs later and with decreased severity compared to type 2. Type 3 is further classified into type 3a and 3b based on extent of neurologic involvement and presence of progressive myotonia and dementia (type 3a) or isolated supranuclear gaze palsy (type 3b).



• For fucosidosis, Krabbe disease, and Schindler disease, the central nervous system storage results in a relentless neurodegenerative course with death in childhood.



• In metachromatic leukodystrophy, nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear. Disease progresses and the child dies within the first decade of life. The juvenile form has a more indolent course with onset as late as age 20 years.



• Clinical presentation and course of NPD type A is relatively uniform and characterized by normal appearance at birth with the occasional complication of prolonged jaundice. Hepatosplenomegaly, moderate lymphadenopathy, 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 their environment. Death occurs by age 5 years. In contrast to stereotyped type A phenotype, clinical presentation and course of patients with type B disease are more variable. Most patients are diagnosed in infancy or childhood when enlargement of liver and spleen is detected during a routine physical examination. Survival to adulthood is typical.



• Clinical manifestations of Gaucher disease type 1 have a variable age of onset from early childhood to late adulthood, with most symptomatic patients presenting by adolescence. Some patients may be discovered during evaluation for other conditions or as part of routine examinations who have a benign disease course. In patients who may experience developmental delays secondary to effects of chronic disease, with exception of children with severe growth retardation, final development and intelligence are normal. Patients typically survive until adulthood.



• Patients with Fabry disease have major morbid symptoms resulting from progressive involvement of vascular system. Gradual deterioration of renal function and development of azotemia occur in the second through fourth decades of life, and cardiovascular findings may include hypertension, left ventricular hypertrophy, anginal chest pain, myocardial ischemia or infarction, and congestive heart failure. Death most 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.

Patient Education:

• Genetic evaluation is essential to identify additional carriers and offer prenatal diagnosis for future pregnancies.

TEST QUESTIONS

Section 9 of 10

CME Question 1: The mother of a 9-month-old boy reports that her child no longer makes eye contact with her. He startles very easily when there is a loud noise in the house. On physical examination, you note the boy no longer sits independently as he did on his prior visit. Of the following, which laboratory test would be most appropriate?

A: Leukocyte hexosaminidase activity
B: Urine organic acids
C: Plasma amino acids
D: Urine reducing substances
E: Thyroid function tests

The correct answer is A: This infant presents with loss of skills and exaggerated startle. Any child with a loss of milestones should have a workup for a storage disorder. Hyperacusis is suggestive of Tay-Sachs disease. Diagnosis can be confirmed by measurement of hexosaminidase.

CME Question 2: A 4-year-old child on a routine health maintenance examination presents with hepatosplenomegaly. Laboratory studies reveal normal liver function, slight anemia, and thrombocytopenia. What is the most appropriate consultation to obtain?

A: Gastroenterology, to obtain a liver biopsy
B: Infectious diseases, to rule out viral infection
C: Genetics, to initiate a storage disease workup
D: Hematology, to obtain a bone marrow examination
E: Surgery, to schedule a splenectomy

The correct answer is C: Hepatosplenomegaly with normal liver function should prompt an evaluation for presence of a storage disorder.

Pearl Question 1 (T/F): A child of Ashkenazi Jewish heritage is found to have neurodegeneration. The most likely diagnosis is Fabry disease.

The correct answer is False: The most likely diagnosis is Tay-Sachs disease.

Pearl Question 2 (T/F): Angiokeratoma is associated with Gaucher disease.

The correct answer is False: Angiokeratoma is associated with Fabry disease, which is a lysosomal storage disease.

Pearl Question 3 (T/F): The size of the liver is helpful in differentiating Tay-Sachs disease from Sandhoff disease.

The correct answer is True: Hepatomegaly may be evident on physical examination of a child with Sandhoff disease, but it is not a feature of Tay-Sachs disease.

Pearl Question 4 (T/F): Parents of a 6-year-old child who was just diagnosed with Gaucher disease are concerned about prognosis. Diagnosis was achieved by demonstration of the enzymatic deficiency in peripheral leukocytes. Genotyping of the child could be offered to assist in determining prognosis.

The correct answer is True: Genotyping of the child to identify the specific mutations in the acid glucosidase gene may be helpful in providing information about prognosis. In particular, the N370S mutation is associated with mild disease.

BIBLIOGRAPHY

Section 10 of 10

• Arora P, Tullu MS, Muranjan MN, et al: Congenital and inherited ophthalmologic abnormalities. Indian J Pediatr 2003 Jul; 70(7): 549-52[Medline].
• Burton BK: Inborn errors of metabolism: the clinical diagnosis in early infancy. Pediatrics 1987 Mar; DA - 19870331(3): 359-69[Medline].
• Mistry PK, Smith SJ, Ali M: Genetic diagnosis of Gaucher's disease. Lancet 1992 Apr 11; 339(8798): 889-92[Medline].
• Scriver CR, Beaudet AL, Sly WS: The Metabolic Basis of Inherited Disease. 1995.
• Watts W, Gibbs D: Lysosomal storage diseases: Biochemical and clinical aspects. 1986.

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