NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Acid Sphingomyelinase Deficiency

, MD, PhD and , PhD.

Author Information
, MD, PhD
Professor and Chair of Pediatrics
Stony Brook University School of Medicine
Stony Brook, New York
, PhD
Genetic Disease Foundation
Francis Crick Professor & Vice Chairman for Research of Genetics & Genomic Sciences
Mount Sinai School of Medicine
New York, New York

Initial Posting: ; Last Update: June 25, 2009.

Summary

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. 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, which may not be present in the first few months, is eventually present in all affected children. 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 occur infrequently. Survival to adulthood can occur.

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 more than 95% of individuals with enzymatically confirmed ASM deficiency. Targeted mutation analysis identifies common population-specific mutations in individuals of Ashkenazi Jewish background with NPD-A, individuals of North African descent with NPD-B, and certain other populations.

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-B. Assessment at least annually 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; and dual-energy x-ray absorptiometry (DEXA) as indicated in those with osteoporosis.

Circumstances to avoid: NPD-B: 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. Carrier testing for at-risk relatives is possible if both disease-causing alleles in the family are known. Prenatal diagnosis for pregnancies at 25% risk is possible by biochemical testing of ASM enzyme activity and/or by molecular genetic testing if both disease-causing alleles in the family are known.

GeneReview Scope

Acid Sphingomyelinase Deficiency: Included Disorders
  • Niemann-Pick disease type A
  • Niemann-Pick disease type B

Diagnosis

Clinical Diagnosis

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.

Testing

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.Gln294Lys 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.

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.

Molecular Genetic Testing

Gene. SMPD1 is the only gene known to be associated with acid sphingomyelinase deficiency.

Clinical testing

  • Targeted mutation analysis

    NPD type A. Three mutations (p.Arg498Leu, p.Leu304Pro, p.Phe333SerfsTer52) account for approximately 90% of NPD type A disease-causing alleles in the Ashkenazi Jewish population.

    NPD type B. The mutation p.Arg610del 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];
    • Approximately 20%-30% of 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 95% of individuals with enzymatically confirmed acid sphingomyelinase deficiency.
  • Deletion/duplication analysis. The usefulness of deletion/duplication testing has not been demonstrated, as no deletions or duplications involving SMPD1 have been reported to cause acid sphingomyelinase deficiency. While new deletion/duplication testing methods may define such mutations in affected individuals (or obligate carriers) who tested negative by sequence analysis, the detection rate is unknown and may be very low.

Table 1. Summary of Molecular Genetic Testing Used in Acid Sphingomyelinase Deficiency


Gene 1
Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SMPD1Targeted mutation analysisFour common mutations 490% 5
Sequence analysis 6Sequence variants>95%
Deletion/duplication analysis 7Partial- and whole-gene deletions or duplicationsUnknown 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. p.Arg498Leu, p.Leu304Pro, p.Phe333SerfsTer52, p.Arg610del (see Table 2)

5. In NPD type A

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that detects exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. No deletions or duplications involving SMPD1 have been reported to cause acid sphingomyelinase deficiency. New deletion/duplication testing methods may define such mutations in affected individuals (obligate carriers) who tested negative by sequence analysis. However, the detection rate is unknown and may be very low.

Testing Strategy

Confirming the diagnosis of ASM deficiency in a proband

  • Assay of ASM enzyme activity in leukocytes or cultured fibroblasts
  • Molecular genetic testing to 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.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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, referred to as Niemann-Pick disease type B (NPD-B) in this review.

Severe Early-Onset Form (NPD-A)

Hepatosplenomegaly. The first symptom in most children 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 may not be present 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.

NPD-B

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 manifestations 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, McGovern et al 2008]. Individuals with acid sphingomyelinase deficiency who survive early childhood can have progressive and/or clinically significant neurologic manifestations.

Survival to adulthood can occur.

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 hepatic failure is 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 et al 2004b].

Neurologic signs. The neurologic findings can include cerebellar signs and nystagmus [Obenberger et al 1999], extrapyramidal involvement, intellectual disability, and psychiatric disorders. 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.Gln294Lys 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 et al 2004a]. 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 and 17 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.

Genotype-Phenotype Correlations

The most consistent phenotype-genotype correlation in ASM deficiency is a milder clinical course than average in individuals homozygous for the p.Arg610del mutation [Wasserstein et al 2004]. In contrast to individuals with other mutations, individuals homozygous for the p.Arg610del 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.Arg610del mutation.

Some evidence suggests that the p.Leu139Pro, p.Ala198Pro, and p.Arg476Trp mutations result in a less severe form of NPD-B.

The p.His423Tyr and p.Lys578Asn mutations, found most commonly in Saudi Arabia, lead to an early-onset severe form of the disease [Simonaro et al 2002].

The p.Gln294Lys mutation, associated with intermediate phenotypes with later-onset neuronopathic disease, appears to be relatively common in individuals of Czech and Slovak heritage [Pavlu-Pereira et al 2005].

Homozygosity or compound heterozygosity for some combination of the common SMPD1 mutations observed in individuals with NPD-A predicts the type A phenotype.

Prevalence

The estimated prevalence of acid sphingomyelinase deficiency is 1:250,000 [Meikle et al 1999]. However, population wide screening has not been performed, and this and other estimates are based on the number of clinically diagnosed cases referred for biochemical confirmation.

Mutations causing the severe neurodegenerative form of the disease (NPD-A) are more prevalent in the Ashkenazi Jewish population in which the combined carrier frequency for the three common SMPD1 mutations, p.Arg498Leu, p.Leu304Pro, and p.Phe333SerfsTer52 is between 1:80 and 1:100. 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].

Differential Diagnosis

Lysosomal storage diseases (LSD). The clinical features of acid sphingomyelinase deficiency may overlap with other lysosomal storage diseases such as Gaucher disease; however, biochemical testing 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 (see Mucolipidosis II, Mucolipidosis III Alpha/Beta, and Mucolipidosis IV). 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with acid sphingomyelinase (ASM) deficiency, the following evaluations are recommended:

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 age 18 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

Treatment of Manifestations

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 because removal of the spleen exacerbates the pulmonary disease.
  • Pulmonary disease. Individuals with symptomatic 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 calorie intake is adequate for growth.

Prevention of Primary Manifestations

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 limit its use.

Prevention of Secondary Complications

Liver function needs to be monitored in individuals receiving medications with known hepatotoxicity (e.g., statins for treatment of hypercholesterolemia).

Surveillance

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.

Agents/Circumstances to Avoid

Individuals who have splenomegaly should avoid contact sports.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Successful hematopoietic cell transplantation for NPD-A has been reported [Shah et al 2005].

A Phase I enzyme replacement therapy (ERT) trial in adults with NPD-B is underway and expected to be completed soon.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

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].

Genetic Counseling

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. —ED.

Mode of Inheritance

Acid sphingomyelinase (ASM) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

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 SMPD1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations in the family are known.

Carrier identification by determination of enzymatic activity is not reliable.

Related Genetic Counseling Issues

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.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 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 an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • National Niemann-Pick Disease Foundation (NNPDF)
    401 Madison Avenue
    Suite B
    PO Box 49
    Fort Atkinson WI 53538
    Phone: 877-287-3672 (toll-free); 920-563-0930
    Fax: 920-563-0931
    Email: nnpdf@nnpdf.org
  • Chicago Center for Jewish Genetic Disorders
    Ben Gurion Way
    30 South Wells Street
    Chicago IL 60606
    Phone: 312-357-4718
    Email: jewishgeneticsctr@juf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    2001 Beacon Street
    Suite 204
    Boston MA 02135
    Phone: 800-906-8723 (toll-free)
    Fax: 617-277-0134
    Email: info@ntsad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Acid Sphingomyelinase Deficiency: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SMPD111p15​.4Sphingomyelin phosphodiesteraseSMPD1 databaseSMPD1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Acid Sphingomyelinase Deficiency (View All in OMIM)

257200NIEMANN-PICK DISEASE, TYPE A
607608SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1
607616NIEMANN-PICK DISEASE, TYPE B

Molecular Genetic Pathogenesis

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.

Gene structure. SMPD1 is approximately 5 kb long and the coding sequence is divided among six exons. Exon 2 is unusually large, encoding 258 amino acids, or approximately 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Two common polymorphisms lead to amino acid substitutions at codons 322 and 506. The common alleles are p.Thr322 and p.Gly506 with frequencies of 0.6 and 0.8, respectively, while the less common alleles are p.Ile322 and p.Arg506. In addition to these polymorphisms, the number of alanine/leucine repeats within the ASM signal peptide region is polymorphic.

Pathogenic allelic variants. More than 100 mutations causing acid sphingomyelinase deficiency have been published [Simonaro et al 2002, Schuchman 2007] 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 more than 90% of the mutant alleles in individuals of Ashkenazi Jewish ancestry with NPD-A (Table 2). Two are missense mutations, p.Arg498Leu and p.Leu304Pro, and the third, p.Phe333SerfsTer52, is a single-nucleotide deletion resulting in a frameshift and the introduction of a premature stop at codon 385 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 p.Arg610del, 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.Arg610del accounts for approximately 20%-30% of the mutant alleles found in individuals with NPD-B of North African background.

Table 2. Selected SMPD1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.971C>Tp.Thr324Ile
(p.Thr322Ile)
NM_000543​.3
NP_000534​.3
c.1522G>Cp.Gly508Arg
(p.Gly506Arg)
c.416T>Cp.Leu139Pro
(p.Leu137Pro)
c.592G>Cp.Ala198Pro
(p.Ala196Pro)
c.874C>Ap.Gln294Lys
(p.Gln292Lys)
c.911T>Cp.Leu304Pro
(p.Leu302Pro)
c.996delC
(c.990delC)
p.Phe333SerfsTer52
(p.Pro330SerfsTer382, or fsP330)
c.1267C>Tp.His423Tyr
(p.His421Tyr)
c.1426C>Tp.Arg476Trp
(p.Arg474Trp)
c.1493G>Tp.Arg498Leu
(p.Arg496Leu)
c.1734G>Cp.Lys578Asn
(p.Lys576Asn)
c.1828_1830delp.Arg610del
(p.Arg608del or DeltaR608)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

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.

Note: Paternal imprinting of SMPD1 has been described [Simonaro et al 2006]. The influence of imprinting on the NPD phenotype has not been studied in detail.

References

Published Guidelines/Consensus Statements

  1. ACOG Committee on Genetics; ACOG committee opinion. Number 298, August 2004. Prenatal and preconceptional carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2004;104:425–8. [PubMed: 15292027]

Literature Cited

  1. Fernandez-Burriel M, Pena L, Ramos JC, Cabrera JC, Marti M, Rodriguez-Quinones F, Chabas A. The R608del mutation in the acid sphingomyelinase gene (SMPD1) is the most prevalent among patients from Gran Canaria Island with Niemann-Pick disease type B. Clin Genet. 2003;63:235–6. [PubMed: 12694237]
  2. Harzer K, Rolfs A, Bauer P, Zschiesche M, Mengel E, Backes J, Kustermann-Kuhn B, Bruchelt G, van Diggelen OP, Mayrhofer H, Krageloh-Mann I. Niemann-Pick disease type A and B are clinically but also enzymatically heterogeneous: pitfall in the laboratory diagnosis of sphingomyelinase deficiency associated with the mutation Q292 K. Neuropediatrics. 2003;34:301–6. [PubMed: 14681755]
  3. Hellani A, Schuchman EH, Al-Odaib A, Al Aqueel A, Jaroudi K, Ozand P, Coskun S. Preimplantation genetic diagnosis for Niemann-Pick disease type B. Prenat Diagn. 2004;24:943–8. [PubMed: 15612058]
  4. Kayler LK, Merion RM, Lee S, Sung RS, Punch JD, Rudich SM, Turcotte JG, Campbell DA, Holmes R, Magee JC. Long-term survival after liver transplantation in children with metabolic disorders. Pediatr Transplant. 2002;6:295–300. [PubMed: 12234269]
  5. McGovern MM, Wasserstein MP, Giugliani R, Bembi B, Vanier MT, Mengel E, Brodie SE, Mendelson D, Skloot G, Desnic RJ, Kuriyama N, Cox GF. A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. Pediatrics. 2008;122:e341–9. [PMC free article: PMC2692309] [PubMed: 18625664]
  6. McGovern MM, Aron A, Brodie SE, Desnick RJ, Wasserstein MP. Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. Neurology. 2006;66:228–32. [PubMed: 16434659]
  7. McGovern MM, Pohl-Worgall T, Deckelbaum RJ, Simpson W, Mendelson D, Desnick RJ, Schuchman EH, Wasserstein MP. Lipid abnormalities in children with types A and B Niemann Pick disease. J Pediatr. 2004a;145:77–81. [PubMed: 15238911]
  8. McGovern MM, Wasserstein MP, Aron A, Desnick RJ, Schuchman EH, Brodie SE. Ocular manifestations of Niemann-Pick disease type B. Ophthalmology. 2004b;111:1424–7. [PubMed: 15234149]
  9. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54. [PubMed: 9918480]
  10. Mendelson DS, Wasserstein MP, Desnick RJ, Glass R, Simpson W, Skloot G, Vanier M, Bembi B, Giugliani R, Mengel E, Cox GF, McGovern MM. Type B Niemann-Pick disease: findings at chest radiography, thin-section CT, and pulmonary function testing. Radiology. 2006;238:339–45. [PubMed: 16304086]
  11. Minai OA, Sullivan EJ, Stoller JK. Pulmonary involvement in Niemann-Pick disease: case report and literature review. Respir Med. 2000;94:1241–51. [PubMed: 11192962]
  12. Nicholson AG, Wells AU, Hooper J, Hansell DM, Kelleher A, Morgan C. Successful treatment of endogenous lipoid pneumonia due to Niemann-Pick Type B disease with whole-lung lavage. Am J Respir Crit Care Med. 2002;165:128–31. [PubMed: 11779742]
  13. Obenberger J, Seidl Z, Pavlu H, Elleder M. MRI in an unusually protracted neuronopathic variant of acid sphingomyelinase deficiency. Neuroradiology. 1999;41:182–4. [PubMed: 10206162]
  14. Pavlu-Pereira H, Asfaw B, Poupctova H, Ledvinova J, Sikora J, Vanier MT, Sandhoff K, Zeman J, Novotna Z, Chudoba D, Elleder M. Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study. J Inherit Metab Dis. 2005;28:203–27. [PubMed: 15877209]
  15. Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase deficient Niemann-Pick disease. J Inherit Metab Dis. 2007;30:654–63. [PubMed: 17632693]
  16. Shah AJ, Kapoor N, Crooks GM, Parkman R, Weinberg KI, Wilson K, Kohn DB. Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B. Pediatrics. 2005;116:1022–5. [PubMed: 16199719]
  17. Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman EH. The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet. 2002;71:1413–9. [PMC free article: PMC378582] [PubMed: 12369017]
  18. Simonaro CM, Park JH, Eliyahu E, Shtraizent N, McGovern MM, Schuchman EH. Imprinting at the SMPD1 locus: implications for acid sphingomyelinase-deficient Niemann-Pick disease. Am J Hum Genet. 2006;78:865–70. [PMC free article: PMC1474038] [PubMed: 16642440]
  19. van Diggelen OP, Voznyi YV, Keulemans JL, Schoonderwoerd K, Ledvinova J, Mengel E, Zschiesche M, Santer R, Harzer K. A new fluorimetric enzyme assay for the diagnosis of Niemann-Pick A/B, with specificity of natural sphingomyelinase substrate. J Inherit Metab Dis. 2005;28:733–41. [PubMed: 16151905]
  20. Wasserstein MP, Aron A, Brodie SE, Simonaro C, Desnick RJ, McGovern MM. Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. J Pediatr. 2006;149:554–9. [PubMed: 17011332]
  21. Wasserstein MP, Desnick RJ, Schuchman EH, Hossain S, Wallenstein S, Lamm C, McGovern MM. The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. Pediatrics. 2004;114:e672–7. [PubMed: 15545621]
  22. Wasserstein MP, Larkin AE, Glass RB, Schuchman EH, Desnick RJ, McGovern MM. Growth restriction in children with type B Niemann-Pick disease. J Pediatr. 2003;142:424–8. [PubMed: 12712061]

Suggested Reading

  1. Schuchman EH, Desnick RJ. Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 144. Available online. 2013. Accessed 4-30-14.

Chapter Notes

Revision History

  • 25 June 2009 (me) Comprehensive update posted live
  • 7 December 2006 (me) Review posted to live Web site
  • 8 May 2006 (mm) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1370PMID: 20301544
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...