Clinical 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, osteopenia, 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 by detection of either biallelic pathogenic variants in SMPD1 or residual ASM enzyme activity that is less than 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts).

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. Annual (or more frequent) assessments: 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 and chest radiograph; 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.

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 and prenatal diagnosis for pregnancies at increased risk are possible if both SMPD1 pathogenic variants in the family are known. Prenatal diagnosis for pregnancies at 25% risk is also possible by testing of ASM enzyme activity.

Suggestive Findings

NPD-A should be suspected in infants with the following clinical findings or results on newborn screening:

Clinical findings

• Hepatosplenomegaly
• Developmental delay
• Evidence of interstitial lung disease on chest radiograph
• Cherry-red maculae

NPD-B, as defined in this review, should be suspected in individuals with the following:

• Hepatosplenomegaly
• Interstitial lung disease
• Hyperlipidemia
• Thrombocytopenia

Results on newborn screening. At present, New York state is conducting a pilot newborn screening program for four lysosomal storage disorders, including NPD-A and NPD-B. Acid sphingomyelinase activity is measured in newborn dried blood spots using a high throughput multiplex tandem MS assay. Other states are considering implementation of newborn screening for NPD-A and B.

Acid sphingomyelinase deficiency cannot be diagnosed solely on clinical grounds.

Establishing the Diagnosis

The diagnosis of ASM deficiency is established by detection of either biallelic pathogenic variants in SMPD1 on molecular genetic testing (Table 1) or residual ASM enzyme activity that is less than 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts).

Molecular testing approaches include single-gene testing and use of a multigene panel.

Single-gene testing. For individuals from populations in which common SMPD1 pathogenic variants occur (e.g., individuals of Ashkenazi Jewish background with a severe neurodegenerative form of the disease suggestive of NPD-A, individuals of North African descent with NPD-B, or individuals from Chile, Saudi Arabia, and Turkey):

1.

Perform targeted analysis for pathogenic variants.

2.

If targeted analysis does not identify both pathogenic variants in individuals from these populations, sequence analysis of SMPD1 is appropriate.

For individuals who are not in the populations discussed above:

1.

Perform sequence analysis.

2.

If no or only one pathogenic variant is identified, consider gene-targeted deletion/duplication analysis.

A multigene panel that includes SMPD1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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 pathogenic variant 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. Because of the bone marrow involvement in ASM deficiency, in many cases other specialists have performed bone marrow examination (and identified lipid-laden macrophages) prior to the suspicion of Niemann-Pick disease. Note that bone marrow examination is not necessary for diagnosis and should not be performed unless specific clinical indications are present.

Clinical Description

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.

Genotype-Phenotype Correlations

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

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

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

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

Homozygosity or compound heterozygosity for some combination of the common SMPD1 pathogenic variants 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. More recently in Chile, screening of 1691 healthy individuals for a common SMPD1 pathogenic variant, p.Ala359Asp, found a heterozygote frequency of 1:105.7, predicting a disease incidence of 1:44,960 [Acuña et al 2016].

Pathogenic variants 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 pathogenic variants (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 on individuals with NPD-B from 29 different countries has been reported [Simonaro et al 2002].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
• Consultation with a clinical geneticist and/or genetic counselor

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
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Severe neurodegenerative form (NPD-A)

• Progressive neurologic disease. Physical and occupational therapy to maximize function and to prevent contractures is appropriate. 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. While partial splenectomy may be considered for individuals with severe hypersplenism, total splenectomy should be avoided 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.

Note: 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].

Prevention of Primary Manifestations

Hematopoietic stem cell transplantation (HSCT). Variable results have been reported with HSCT. Shah et al [2005] reported successful HSCT for NPD-A. Successful engraftment can correct the metabolic defect, improve blood counts, and reduce increased liver and spleen volumes. However, stabilization of the neurologic component following HSCT has not been reported; therefore, any attempts to perform HSCT in individuals with clinically evident neurologic disease should be considered experimental. The morbidity and mortality associated with HSCT limit its use.

Enzyme replacement therapy. See Therapies Under Investigation.

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

Agents/Circumstances to Avoid

Individuals who have splenomegaly should avoid contact sports.

Evaluation of Relatives at Risk

If the SMPD1 pathogenic variants in the family are known it is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early identification and treatment.

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

Pregnancy Management

For pregnant women with NPD-B, prenatal care by a high-risk obstetrician is indicated to ensure appropriate monitoring of pulmonary function and hematologic status.

Therapies Under Investigation

Enzyme replacement therapy. A Phase I study of recombinant human acid sphingomyelinase in five adults with NPD-B using an intra-patient dose-escalation scheme was recently completed. This regimen was generally well tolerated with study subjects showing a reduced liver and spleen volumes and improved lung-diffusing capacity [Wasserstein et al 2015]. A Phase II study is currently underway in children with NPD-B, and a Phase II/III study is planned in adults with NPD-B.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 (i.e., carriers of one SMPD1 pathogenic variant).
• 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 a heterozygote, and a 25% chance of being unaffected and not a carrier.
• 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 pathogenic variant in SMPD1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SMPD1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SMPD1 pathogenic variants in the family.

Carrier identification by determination of ASM enzymatic activity is not reliable.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the SMPD1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Biochemical genetic testing. Prenatal diagnosis for pregnancies at 25% risk is also possible using biochemical testing of acid sphingomyelinase (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.

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 ~5 kb in length 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.

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

Pathogenic variants. More than 100 pathogenic variants causing acid sphingomyelinase deficiency have been published [Simonaro et al 2002, Schuchman 2007] including missense, nonsense, and frameshift variants 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 pathogenic variants account for more than 90% of the mutated alleles in individuals of Ashkenazi Jewish ancestry with NPD-A (Table 2). Two are missense variants, 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 pathogenic variant.

In individuals with NPD-B, one of the most common pathogenic variants 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 mutated alleles. In the United States, p.Arg610del accounts for approximately 20%-30% of the mutated alleles found in individuals with NPD-B.

Normal gene product. Acid sphingomyelinase (sphingomyelin phosphodiesterase) is a lysosomal enzyme responsible for hydrolyzing sphingomyelin to ceramide and phosphorylcholine.

Abnormal gene product. SMPD1 pathogenic variants 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.

Published Guidelines / Consensus Statements

• 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

• Acuña M, Martínez P, Moraga C, He X, Moraga M, Hunter B, Nuernberg P, Gutiérrez RA, González M, Schuchman EH, Luis Santos J, Miquel JF, Mabe P, Zanlungo S. Epidemiological, clinical and biochemical characterization of the p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B. Eur J Hum Genet. 2016;24:208–13. [PMC free article: PMC4717211] [PubMed: 25920558]
• Fernández-Burriel M, Peña L, Ramos JC, Cabrera JC, Marti M, Rodríguez-Quiñones F, Chabás 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]
• 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]
• Kayler LK, Merion RM, Lee S, Sung RS, Punch JD, Rudich SM, Turcotte JG, Campbell DA Jr, Holmes R, Magee JC. Long-term survival after liver transplantation in children with metabolic disorders. Pediatr Transplant. 2002;6:295–300. [PubMed: 12234269]
• McGovern MM, Lippa N, Bagiella E, Schuchman EH, Desnick RJ, Wasserstein MP. Morbidity and Mortality in type B Niemann Pick Disease. Genet Med. 2013;15:618–23. [PubMed: 23412609]
• 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]
• 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]
• 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]
• 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]
• Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–54. [PubMed: 9918480]
• 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]
• 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]
• 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]
• 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]
• Pavlů-Pereira H, Asfaw B, Poupctová H, Ledvinová J, Sikora J, Vanier MT, Sandhoff K, Zeman J, Novotná 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]
• Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase deficient Niemann-Pick disease. J Inherit Metab Dis. 2007;30:654–63. [PubMed: 17632693]
• 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]
• 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]
• 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]
• Thurberg BL, Wasserstein MP, Schiano T, O'Brien F, Richards S, Cox GF, McGovern MM. Liver and Skin Histopathology in Adults With Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type B). Am J Surg Pathol. 2012;36:1234–46. [PMC free article: PMC3396757] [PubMed: 22613999]
• 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]
• 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]
• 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]
• 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]
• Wasserstein MP, Jones SA, Soran H, Diaz GA, Lippa N, Thurberg BL, Culm-Merdek K, Shamiyeh E, Inguilizian H, Cox GF. Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. Mol Genet Metab. 2015;116:88–97. [PMC free article: PMC4561589] [PubMed: 26049896]
• Wasserstein M, Godbold J, McGovern MM. Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. J Inherit Metab Dis. 2013;36:123–7. [PubMed: 22718274]

Suggested Reading

• Schuchman EH, Desnick RJ. Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 144.

Author History

Margaret M McGovern, MD, PhD; Stony Brook University School of Medicine (2006-2015)
Edward H Schuchman, PhD (2006-present)
Melissa P Wasserstein, MD (2015-present)

Revision History

• 18 June 2015 (me) Comprehensive update posted live
• 25 June 2009 (me) Comprehensive update posted live
• 7 December 2006 (me) Review posted to live Web site
• 8 May 2006 (mm) Original submission