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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic [Niemann-Pick disease type A (NPD-A)], with death in early childhood, or non-neuronopathic [Niemann-Pick disease type B (NPD-B)]. While forms intermediate to these two extremes occur, all ASM deficiency that is not NPD-A is designated in this review as NPD-B, despite its wide range of manifestations and severity. The first symptom in NPD-A is hepatosplenomegaly, usually noted by age three months; over time the liver and spleen become massive. Although neurologic findings are almost normal in the first few months of life, psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. A classic cherry-red spot of the macula of the retina, often not observed early in the disease course, is eventually present in all affected individuals. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year. NPD type B, later in onset and milder in manifestations than NPD type A, is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations can occur. Survival to adulthood is common.
Diagnosis/testing. The diagnosis of ASM deficiency is established when residual ASM enzyme activity in peripheral blood lymphocytes or cultured skin fibroblasts is less than 10% of controls. SMPD1 is the only gene known to be associated with ASM deficiency. Sequence analysis of SMPD1 detects mutations in 99% of individuals with enzymatically confirmed ASM deficiency. Targeted mutation analysis for common population-specific mutations is available for individuals of Ashkenazi Jewish background with NPD-A and individuals of North African descent with NPD-B.
Management. Treatment of manifestations: NPD-A: physical and occupational therapy; feeding tube for nutrition and sedatives for irritability and sleep disturbance as indicated. NPD-B: transfusion of blood products for life-threatening bleeding; supplemental oxygen for symptomatic pulmonary disease; treatment of hyperlipidemia in adults; adequate calorie intake. Surveillance: NPD-A: periodic assessments of nutritional status and gross and fine motor skills. NPD-A: assessment at least every 6-12 months of: growth in children and weight in all ages; changes in activity level; bleeding; shortness of breath; abdominal pain; neurologic function; liver enzymes, platelet count, and fasting lipid profile; pulmonary function testing and chest radiograph; dual-energy x-ray absorptiometry (DEXA). Circumstances to avoid: contact sports in those who have splenomegaly.
Genetic counseling. Acid sphingomyelinase (ASM) deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at 25% risk is possible either by biochemical testing of ASM enzyme activity and/or by molecular genetic testing if both disease-causing alleles of an affected family member have been identified.
Acid sphingomyelinase (ASM) deficiency has traditionally been categorized as either neuropathic or non-neuronopathic:
Neuronopathic: Niemann-Pick disease type A (NPD-A), characterized by a brief period of normal development followed by a severe neurodegenerative course and death in early childhood
Non-neuronopathic: Niemann-Pick disease type B (NPD-B)
However, forms intermediate to these two extremes occur as a continuum of neurologic findings in those who survive early childhood. In this review, all forms of ASM deficiency that are not NPD-A are designated NPD-B, recognizing that NPD-B encompasses a broad range of somatic and neurologic features of varying severity.
The diagnosis of NPD-A should be suspected in infants with the following:
Hepatosplenomegaly
Developmental delay
Evidence of interstitial lung disease on chest radiograph
Cherry-red maculae
The diagnosis of NPD-B, as defined in this review, should be suspected in individuals with the following:
Hepatosplenomegaly
Interstitial lung disease
Hyperlipidemia
Thrombocytopenia
Acid sphingomyelinase deficiency cannot be diagnosed solely on clinical grounds.
Acid sphingomyelinase (ASM) enzyme activity. The diagnosis of acid sphingomyelinase deficiency requires measurement of acid sphingomyelinase (ASM) enzyme activity in peripheral blood lymphocytes or cultured skin fibroblasts. Compared to controls, affected individuals typically have less than 10% residual enzyme activity [van Diggelen et al 2005].
Note: (1) Individuals with the SMPD1 mutation p.Q292K may have apparently normal enzymatic activity when artificial substrate is used [Harzer et al 2003]. (2) The level of residual enzyme activity is not a reliable predictor of phenotype. (3) As the diagnosis of acid sphingomyelinase deficiency can be confirmed through assay of enzyme activity performed on peripheral blood leukocytes, bone marrow examination or liver biopsy is not necessary to establish the diagnosis.
For laboratories offering biochemical testing, see
.
Bone marrow examination reveals lipid-laden macrophages.
Note: Although thrombocytopenia sometimes prompts bone marrow examination, this procedure is not necessary for diagnosis and should not be performed unless specific clinical indications are present.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. SMPD1 is the only gene known to be associated with acid sphingomyelinase deficiency.
Molecular genetic testing: Clinical uses
Prognostication
Molecular genetic testing: Clinical methods
NPD type A. Three mutations (p.R496L, p.L302P, p.P330SfsX382(NM_000543.2:c.990delC) (also known as fsP330) account for approximately 90% of NPD type A disease-causing alleles in the Ashkenazi Jewish population.
NPD type B. The mutation p.R608del (also known as DeltaR608) may account for:
Almost 90% of NPD type B mutant alleles in individuals from the Maghreb region of North Africa (i.e., Tunisia, Algeria, and Morocco);
100% of NPD type B mutant alleles in Grand Canaria Island [Fernandez-Burriel et al 2003];
About 20%-30% of the NPD type B mutant alleles in persons of North African descent in the United States.
Sequence analysis. Sequence analysis of the SMPD1 coding region may detect mutations in 99% of individuals with enzymatically confirmed acid sphingomyelinase deficiency.
Table 1 summarizes molecular genetic testing for this disorder.
| Test Methods | Mutations Detected | Mutation Detection Rate | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | Four common SMPD1 mutations 1 | 90% 2 | Clinical
|
| Sequence analysis | SMPD1 sequence variants | 99% |
1. p.R496L, p.L302P, p.P330SfsX382(NM_000543.2:c.990delC) (also known as fsP330), p.R608del
2. In NPD type A
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To establish the diagnosis of ASM deficiency in a proband:
Assay of ASM enzyme activity in leukocytes or cultured fibroblasts is performed.
Molecular genetic testing can confirm the diagnosis of ASM deficiency if both disease-causing alleles are identified, but should not be used in place of biochemical testing.
For individuals of Ashkenazi Jewish background with a severe neurodegenerative form of the disease suggestive of NPD-A and individuals of North African descent with NPD-B, targeted mutation analysis is the molecular genetic testing method of choice.
If targeted mutation analysis does not identify both mutations in individuals with enzymatically confirmed acid sphingomyelinase deficiency, sequence analysis of SMPD1 is appropriate.
No other phenotypes have been associated with mutations in the SMPD1 gene.
Although the phenotype of acid sphingomyelinase (ASM) deficiency occurs along a continuum, individuals with a severe early-onset form, which has historically been called Niemann-Pick disease type A (NPD-A), can be distinguished from individuals with later onset and milder forms of the disease, which in this review are called Niemann-Pick disease type B (NPD-B).
Hepatosplenomegaly. The first symptom in most individuals with NPD-A is hepatosplenomegaly, which typically is noted by age three months [McGovern et al 2006]. Non-neurologic findings include feeding problems, failure to thrive, gastrointestinal complaints (e.g., constipation, diarrhea, and vomiting), recurrent respiratory infections, and irritability. Frequent vomiting can contribute to insufficient caloric intake.
The hepatosplenomegaly worsens with time; eventually, the liver and spleen become massive.
Pulmonary disease. Affected infants have evidence of interstitial lung disease on chest radiograph caused by storage of sphingomyelin in the pulmonary macrophages. Low pO2 on arterial blood gas determination is usually found later in the disease course. Frequent respiratory infections are common and respiratory failure can be a cause of death.
Ophthalmologic findings. Fundus examination reveals retinal changes at the time of diagnosis in most children. The accumulation of lipid in the retinal ganglion cells results in a white ring of lipid-laden neurons encircling the red, ganglion cell-free fovea and appears as either a macular halo or a cherry-red macula, depending on the degree of opacity and diameter of the white annulus surrounding the fovea. Although a classic cherry-red spot is often not observed early in the disease course, all children with NPD-A develop one with time.
Neurologic findings. The neurologic examination at the time of presentation can be normal except for slight hypotonia. Hypotonia is progressive and deep tendon reflexes are lost with time. Cranial nerve function remains intact.
Psychomotor development does not progress beyond the 12-month level for any domain and skills are lost with disease progression [McGovern et al 2006]. Developmental age usually does not progress beyond age ten months for adaptive behavior, 12 months for expressive language, nine months for gross motor skills, and ten months for fine motor skills.
Neurologic deterioration is relentless and most children succumb before the third year.
Growth. Linear growth is within the normal range whereas weight attainment declines in the first year of life.
In this review, all forms of ASM deficiency that are not NPD-A are designated NPD-B, recognizing that NPD-B encompasses a broad range of somatic and neurologic features of varying severity.
NPD-B, later in onset and milder in manifeststions than NPD-A, is characterized by hepatosplenomegaly with progressive hypersplenism, worsening atherogenic lipid profile, gradual deterioration in pulmonary function, and stable liver dysfunction [Wasserstein et al 2004]. Individuals with acid sphingomyelinase deficiency who survive early childhood can have progressive and/or clinically significant neurologic manifestations.
Survival to adulthood is common.
Hepatosplenomegaly. The degree of hepatosplenomegaly ranges from mild to massive. Those with significant organomegaly have hypersplenism with secondary thrombocytopenia. Infarction of the spleen can cause acute abdominal pain.
Liver enlargement is common, although cirrhosis and hepatic failure are rare.
Pulmonary involvement. Pulmonary involvement is common in affected individuals of all ages [Minai et al 2000, Mendelson et al 2006]. Clinical impairment ranges from none to oxygen dependence and severe limitations of activity. Most affected individuals have evidence of interstitial lung disease on chest radiographs and thin-section CT. Although most individuals have progressive gas exchange abnormalities, the extent of the radiographic findings may not correlate with impairment of pulmonary function.
Calcified pulmonary nodules can also be seen.
Ophthalmologic manifestations. Up to one-third of individuals with NPD-B have a macular halo or a cherry-red macula. Most have no evidence of progressive neurologic disease; the presence of a macular halo or a cherry-red macula is not an absolute predictor of neurodegeneration [McGovern, Wasserstein et al 2004].
Neurologic signs. The neurologic findings can include cerebellar signs and nystagmas [Obenberger et al 1999], extrapyramidal involvement [Elleder et al 1983], mental retardation [Sogawa et al 1978], and psychiatric disorders [DuBois et al 1990]. In a review of 64 persons with NPD-B, Wasserstein et al (2006) determined that 19 (30%) had neurologic abnormalities. Of the 19, 14 (22%) had minor and non-progressive findings and five (8%) had global and progressive findings (peripheral neuropathy, retinal abnormalities) with onset between age two and seven years. The five with progressive findings had the p.Q292K mutation.
Growth. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents and can result in significant short stature in adulthood. In one study, the mean Z scores for height and weight were -1.24 (29th centile) and -0.75 (34th centile) respectively, and skeletal age in children under age 18 years was delayed by an average of 2.5 years [Wasserstein et al 2003]. Short stature and low weight are correlated with large organ volumes, delayed bone age, and low serum IGF-1 concentrations.
Hyperlipidemia. Low serum concentration of high density lipoprotein-cholesterol (HDL-C) is common in NPD-B [McGovern, Pohl et al 2004]. In most individuals the low serum concentration of HDL-C is accompanied by hyperlipidemia characterized by hypertriglyceridemia and elevated serum concentration of low density lipoprotein-cholesterol (LDL-C). Lipid abnormalities are evident from the earliest age studied.
Early coronary artery disease, identified in some adults with NPD-B, is presumably related to the dyslipidemia.
Other. Calcifications in organs other than the lungs have been described.
Pregnancy and childbirth. Pregnancy in a mildly affected woman has been reported [Porter et al 1997] and 14 pregnancies monitored in women with a wide spectrum of somatic manifestations have been successful [McGovern, personal communication]. Most affected women, even those with significant pulmonary disease, can have normal pregnancies and childbirth. Hepatosplenomegaly does not usually pose a threat to fetal growth.
The most consistent phenotype-genotype correlation in ASM deficiency is a milder clinical course than average in individuals homozygous for the p.R608del mutation [Wasserstein et al 2004]. In contrast to individuals with other mutations, individuals homozygous for the p.R608del mutation usually have normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal serum concentration of IGF-1.
Lipid abnormalities occur with all genotypes, including homozygosity for the p.R608del mutation.
Some evidence suggests that the p.L137P, p.A196P, and p.R474W mutations result in a less severe form of NPD-B.
The p.H421Y and p.K576N mutations, found most commonly in Saudi Arabia, lead to an early-onset severe form of the disease [Simonaro et al 2002].
The p.Q292K mutation, associated with intermediate phenotypes with later-onset neuronopathic disease, appears to be relatively common in individuals of Czech and Slovak heritage [Pavlu-Pereira 2005].
Homozygosity or compound heterozygosity for some combination of the common SMPD1 mutations observed in individuals with NPD-A predicts the type A phenotype.
The estimated prevalence of acid sphingomyelinase deficiency is 1:250,000 [Meikle et al 1999].
Mutations causing the severe neurodegenerative form of the disease (NPD-A) are more prevalent in the Ashkenazi Jewish population where the combined carrier frequency for the three common SMPD1 mutations, p.R496L, p.L302P, and p.P330SfsX382(NM_000543.2:c.990delC) (also known as fsP330) is between 1:80 and 1:100 [Li et al 1997]. Carrier screening programs and the availability of prenatal diagnosis have resulted in a low birth incidence in this population.
The later-onset and mild forms of acid sphingomyelinase deficiency (i.e., NPD-B) are pan ethnic. Genotype information has been reported on individuals with NPD-B from 29 different countries [Simonaro et al 2002].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Lysosomal storage diseases (LSD). The clinical features of acid sphingomyelinase deficiency may overlap with other lysosomal storage diseases such as Gaucher disease; however, the availability of biochemical testing in clinical laboratories permits precise diagnosis. In addition, the pulmonary infiltration and the low serum concentration of HDL cholesterol are distinctive features that are present very early in the NPD disease course.
Hepatosplenomegaly also occurs in Gaucher disease, hexosaminidase A deficiency, Sandhoff disease, Niemann-Pick disease type C (NPD type C), Wolman disease, the mucopolysaccharidoses, and the oligosaccharidoses. However, these disorders should be distinguishable from acid sphingomyelinase deficiency based on other associated features such as coarse facial features and dysostosis multiplex in the mucopolysaccharide disorders, specific neurologic findings in NPD type C, and enzymatic studies in Gaucher disease and Sandhoff disease.
Hepatosplenomegaly can also accompany some infectious diseases and other genetic disorders, including familial hemophagocytic lymphohistiocytosis and glycogen storage diseases (see Glycogen Storage Disease Type I). The diagnosis in infants with NPD-A is sometimes delayed during evaluation for an infectious etiology.
Interstitial lung disease can result from many causes including environmental exposures, connective tissue diseases, and infections. However, the presence of hepatosplenomegaly in acid sphingomyelinase deficiency helps distinguish it from these other causes of interstitial lung disease.
Infants with NPD-A
Ophthalmologic examination, if not yet performed
Comprehensive neurologic evaluation
Compete blood count
Serum chemistries including liver function tests
Dietary consultation
Occupational and physical therapy evaluations
NPD-B
Chest radiograph to assess the extent of interstitial lung disease
Pulmonary function testing, including assessment of diffusing capacity, in individuals old enough to cooperate
Bone age in children under age18 years
Ophthalmologic examination
Neurologic examination
Baseline laboratory studies including complete blood count, fasting lipid profile, serum chemistries, liver function tests
Liver biopsy in individuals with evidence of deteriorating liver function
Severe neurodegenerative form (NPD-A)
Progressive neurologic disease. Physical and occupational therapy to maximize function and to prevent contractures. Aggressive therapy is not warranted and the plan for such treatment should be made in consultation with the neurologist, therapist(s), and family to establish realistic goals.
Nutrition. Feeding difficulties can make provision of adequate calories a major challenge. Regular consultation with a dietician should be provided. The use of nasogastric tube feeding or surgical placement of a feeding tube should be discussed with the family.
Sleep disorder. Irritability and sleep disturbance are quality-of-life issues for the entire family that sometimes require the use of sedatives.
NPD-B
Bleeding. Most affected individuals have thrombocytopenia. When bleeding is life-threatening, transfusion of blood products is indicated. Partial or total splenectomy is a last resort since removal of the spleen exacerbates the pulmonary disease.
Pulmonary disease. Individuals with symptomic pulmonary disease may require supplemental oxygen. Other measures to treat interstitial lung disease, such as steroids, have not been well studied. Several individuals have undergone bronchopulmonary lavage with variable results [Nicholson et al 2002].
Hyperlipidemia. Adults with hyperlipidemia should be treated to bring the serum concentration of total cholesterol into the normal range.
Growth retardation. Dietary assessment is indicated in all cases to assure that calories provided are adequate for growth.
Bone marrow transplantation (BMT). Variable results have been reported with BMT. Successful engraftment can correct the metabolic defect, improve blood counts, and reduce increased liver and spleen volumes. However, stabilization of the neurologic component following BMT has not been reported; therefore, any attempts to perform BMT in individuals with clinically evident neurologic disease should be considered experimental. The morbidity and mortality associated with BMT limits its use.
Liver function needs to be monitored in individuals receiving medications with known hepatotoxicity (e.g., statins for treatment of hypercholesterolemia).
Individuals with NPD-A should receive routine care from a pediatrician and a neurologist including evaluation of the following:
Nutrition status
Occupational and physical therapy needs
Individuals with NPD-B should be evaluated at least yearly for the following:
History (at least every 6-12 months): growth and weight gain in children; fatigue; any change in social, domestic, or school- or work-related activities; bleeding, shortness of breath; abdominal pain; headaches; extremity pain
Physical examination including assessment of neurologic function
Blood tests including liver enzymes, platelet count, and fasting lipid profile
Pulmonary function testing and chest radiograph
Skeletal assessment by dual-energy x-ray absorptiometry (DEXA)
Nutrition assessment
In pregnant women with NPD-B, prenatal care by a high-risk obstetrician is indicated to ensure appropriate monitoring of pulmonary function and hematologic status.
Individuals who have splenomegaly should avoid contact sports.
Hematopoietic cell transplantation for NPD-A [Shah et al 2005]
Enzyme replacement therapy (ERT) trials for NPD-B (to begin in the near future)
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Orthotopic liver transplantation in an infant with NPD-A and amniotic cell transplantation in several individuals with NPD-B have been attempted with little or no success [Kayler et al 2002].
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Acid sphingomyelinase (ASM) deficiency is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Some heterozygotes have been found to have the lipid abnormalities associated with acid sphingomyelinase deficiency.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Some heterozygotes have been found to have the lipid abnormalities associated with acid sphingomyelinase deficiency.
Offspring of a proband
Individuals with Niemann-Pick disease type A (NPD-A) do not reproduce.
The offspring of an individual with Niemann-Pick disease type B (NPD-B) are obligate heterozygotes (carriers) for a disease-causing mutation in the SMPD1 gene.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the proband.
Carrier identification by determination of enzymatic activity is not reliable.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Molecular genetic testing. Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Biochemical genetic testing. Prenatal diagnosis for pregnancies at 25% risk is also possible using biochemical testing of ASM enzyme activity in cultured amniocytes obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) has been successfully utilized for NPD-B [Hellani et al 2004] and may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| SMPD1 | 11p15.4-p15.1 | Sphingomyelin phosphodiesterase |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 257200 | NIEMANN-PICK DISEASE, TYPE A |
| 607608 | SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1 |
| 607616 | NIEMANN-PICK DISEASE, TYPE B |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| SMPD1 | 6609 (MIM No. 607608) | SMPD1 |
For a description of the genomic databases listed, click here.
Acid sphingomyelinase (ASM) deficiency is an inborn error of metabolism that results from a deficiency of acid sphingomyelinase (ASM) (sphingomyelin phosphodiesterase; EC 3.1.4.12) and the subsequent accumulation of sphingomyelin in cells and tissues.
Normal allelic variants: The SMPD1 gene is about 5 kb long and the coding sequence is divided among six exons. Exon 2 is unusually large, encoding 258 amino acids, or about 44% the mature ASM polypeptide. The regulatory region upstream of the SMPD1 coding sequence is GC rich and contains putative promoter elements, including SP1, TATA, CAAT, NF1, and AP1 binding sites.
Two common polymorphisms lead to amino acid substitutions at codons 322 and 506. The common alleles are p.T322(ACA) and p.G506(GGG) with frequencies of 0.6 and 0.8, respectively, while the less common alleles are p.I322(ATA) and p.R506(AGG). In addition to these polymorphisms, the number of alanine/leucine repeats within the ASM signal peptide region is polymorphic.
Pathologic allelic variants: Over 100 mutations causing acid sphingomyelinase deficiency have been published [Simonaro et al 2002] including missense, nonsense, and frameshift mutations and one in-frame three-nucleotide deletion that results in the removal of a single amino acid from the ASM polypeptide. One splice site alteration has also been described.
Three common mutations account for over 90% of the mutant alleles in individuals of Ashkenazi Jewish ancestry with NPD-A. Two are missense mutations, p.R496L and p.L302P, and the third, p.P330SfsX382(NM_000543.2:c.990delC) (also known as fsP330), is a single-nucleotide deletion in codon 330 resulting in a frameshift and the introduction of a premature stop at codon 382 within the ASM open reading frame. In contrast to the Ashkenazi Jewish population, each individual affected with NPD-A studied in other populations has a unique SMPD1 mutation.
In individuals with NPD-B, the only common mutation is a p.R608del, which is frequently found in individuals with NPD-B originating from the Maghreb region of North Africa (i.e., Tunisia, Algeria, and Morocco), in whom it may account for almost 90% of mutant alleles. In the United States, p.R608del accounts for about 20%-30% of the mutant alleles found in individuals with NPD-B of North African background.
Normal gene product: Acid sphingomyelinase (sphingomyelin phosphodiesterase) is a lysosomal enzyme responsible for hydrolyzing sphingomyelin to ceramide and phosphorylcholine.
Abnormal gene product: SMPD1 mutations result in an enzyme with altered activity that leads to decreased hydrolysis of the substrate and its subsequent accumulation in cells, particularly in the monocyte macrophage system.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Niemann-Pick Disease Foundation
PO Box 49
415 Madison Ave Suite B
Fort Atkinson WI 53538
Phone: 877-CURE-NPC (877-287-3672); 920-563-0930
Fax: 920-563-0931
Email: nnpdf@idcnet.com
www.nnpdf.org
Chicago Center for Jewish Genetic Disorders
Ben Gurion Way
One South Franklin Street Fourth Floor
Chicago IL 60606
Phone: 312-357-4718
Fax: 312-855-3295
Email: jewishgeneticsctr@juf.org
www.jewishgeneticscenter.org
Children Living with Inherited Metabolic Diseases (CLIMB)
Climb Building
176 Nantwich Road
Crewe CW2 6BG
United Kingdom
Phone: (+44) 0870 7700 326
Fax: (+44) 0870 7700 327
Email: steve@climb.org.uk
www.climb.org.uk
National Tay-Sachs and Allied Diseases Association, Inc
2001 Beacon Street Suite 204
Brighton MA 02135
Phone: 800-906-8723; 617-277-4463
Fax: 617-277-0134
Email: info@ntsad.org
www.ntsad.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
7 December 2006 (me) Review posted to live Web site
8 May 2006 (mm) Original submission
