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Acid Sphingomyelinase Deficiency

, MD and , PhD.

Author Information

Initial Posting: ; Last Update: February 25, 2021.

Estimated reading time: 27 minutes

Summary

Clinical characteristics.

The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). The most common presenting symptom in NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. Failure to thrive typically becomes evident by the second year of life. 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 of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system (CNS) manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some CNS manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B.

Diagnosis/testing.

The diagnosis of ASMD is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity that is less than 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts).

Management.

Treatment of manifestations: Feeding therapy and/or feeding tube as needed for nutritional support; supportive management of coagulopathy and end-stage liver disease manifestations; transfusion of blood products for life-threatening bleeding; partial splenectomy may be considered for individuals with severe hypersplenism; supplemental oxygen for symptomatic pulmonary disease; physical and occupational therapy to maximize function and to prevent contractures; early intervention and developmental support for those with developmental issues; treatment of hyperlipidemia in adults; calcium and vitamin D for osteopenia/osteoporosis; sedatives for irritability and sleep disturbance as indicated.

Prevention of primary manifestations: Hematopoietic stem cell transplantation (HSCT) can correct the metabolic defect, improve blood counts, and reduce increased liver and spleen volumes but does not stabilize neurologic disease. The morbidity and mortality associated with HSCT limit its use.

Prevention of secondary complications: Monitor liver function in individuals receiving hepatotoxic medications (e.g., statins for hypercholesterolemia).

Surveillance: Periodic assessments of nutritional status; annual EKG; echocardiogram every two to four years; liver transaminases (ALT, AST), albumin, clotting factors, and platelet count at least annually; assess for fatigue, abdominal pain, and/or increased bleeding at least annually; radiologic measurements of liver and spleen size as needed; assess for shortness of breath at each visit; annual pulmonary function testing; chest radiograph every two to four years; assess neurologic function and frequency of headaches at least annually; monitor developmental progress, educational needs, and occupational and physical therapy needs at each visit; fasting lipid profile at least annually; assess for extremity pain at each visit; bone density assessment every two to four years; assess need for family support and resources at each visit.

Agents/circumstances to avoid: Contact sports in those who have splenomegaly.

Genetic counseling.

All forms of ASMD (NPD-A, NPD-A/B, and NPD-B) are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SMPD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the SMPD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. Biochemical prenatal diagnosis for a pregnancy at 25% risk is also possible by testing of acid sphingomyelinase enzyme activity.

GeneReview Scope

Acid Sphingomyelinase Deficiency: Included Phenotypes
  • Infantile neurovisceral ASMD (Niemann-Pick disease type A; NPD-A)
  • Chronic neurovisceral ASMD (intermediate form; NPD-A/B)
  • Chronic visceral ASMD (Niemann-Pick disease type B; NPD-B)

ASMD = acid sphingomyelinase deficiency, which includes NPD-A, NPD-A/B, and NPD-B

Diagnosis

Acid sphingomyelinase deficiency (ASMD) cannot be diagnosed solely on clinical grounds.

Scenarios

Scenario 1 – Abnormal Newborn Screening (NBS) Result

NBS for ASMD is primarily based on quantification of acid sphingomyelinase activity on dried blood spots. At the time of writing, ASMD is not included on the US Recommended Uniform Screening Panel and is performed in a limited number of states within the US. Several pilot studies also have been performed in Europe.

Acid sphingomyelinase activity values below the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical and/or molecular genetic testing for confirmation.

  • Follow-up biochemical testing can include quantification of lipid biomarkers such as lyso-sphingomyelin and/or or lyso-sphingomyelin-509, although the validity of these biomarkers in asymptomatic newborns with ASMD remains to be determined.
  • Molecular genetic testing involves sequence analysis of SMPD1.

Referral to a metabolic or genetic disease specialist should be made immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish the diagnosis of ASMD.

Scenario 2 – Symptomatic Individual

A symptomatic individual who has findings associated with later-onset ASMD (NPD-A/B or NPD-B) or infantile-onset ASMD (NPD-A) may present because of any of the following: NBS not performed, false negative NBS result, and/or caregivers not compliant with recommended treatment.

In these cases supportive – but nonspecific – clinical, radiographic, and laboratory findings can include the following (by phenotype).

Infantile neurovisceral ASMD (NPD-A)

  • Hepatosplenomegaly
  • Developmental delay
  • Evidence of interstitial lung disease on chest radiograph
  • Cherry-red maculae
  • Failure to thrive
  • Presentation before age three years

Chronic neurovisceral ASMD (intermediate form; NPD-A/B)

  • Hepatosplenomegaly
  • Interstitial lung disease
  • Dyslipidemia
  • CNS manifestations such as learning difficulties, ataxia, or developmental delay
  • Thrombocytopenia
  • Coarse facial features (present in a subset of individuals with NPD-A/B)

Chronic visceral ASMD (NPD-B)

  • Hepatosplenomegaly
  • Interstitial lung disease
  • Dyslipidemia
  • Thrombocytopenia
  • Growth restriction in children

Establishing the Diagnosis

The diagnosis of ASMD is established in a proband by identification of biallelic pathogenic variants in SMPD1 on molecular genetic testing (Table 1) and residual acid sphingomyelinase enzyme activity that is less than 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts). SMPD1 molecular genetic testing is increasingly the preferred test for ASMD, but demonstration of low acid sphingomyelinase enzyme activity is required to confirm the diagnosis in individuals with variants of uncertain significance.

Molecular Genetic Testing

Approaches include single-gene testing, use of multigene panels, and genomic testing (exome sequencing, genome sequencing).

Scenario 1 – abnormal NBS result. When NBS results and/or clinical, radiographic, and laboratory findings suggest the diagnosis of ASMD, single-gene testing can be considered.

  • Sequence analysis of SMPD1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
  • Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.

Note: Targeted analysis for specific pathogenic variants can be performed first in individuals of Ashkenazi Jewish, North African, Chilean, Saudi Arabian, and Turkish ancestry (see Table 6).

Scenario 2 – symptomatic individual. When a symptomatic individual presents with typical or atypical findings associated with later-onset ASMD or untreated infantile-onset ASMD (resulting from NBS not performed or false negative NBS result), a multigene panel or genomic testing can be considered:

  • A multigene panel that includes SMPD1 and other genes of interest (see Differential Diagnosis) 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. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (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.
  • When the phenotype is indistinguishable from many other inherited biochemical disorders, comprehensive genomic testing (which does not require the clinician to determine which gene is likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Acid Sphingomyelinase Deficiency

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
SMPD1Targeted analysis for pathogenic variants 390% 4, 5
Sequence analysis 6>95% 7
Gene-targeted deletion/duplication analysis 8Unknown 9
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Pathogenic variants included in a panel may vary by laboratory.

4.

In NPD-A, three variants (p.Arg498Leu, p.Leu304Pro, p.Phe333SerfsTer52) account for approximately 90% of pathogenic alleles in the Ashkenazi Jewish population. Note: Two numbering systems are currently in use to describe SMPD1 variants that differ by two amino acids due to a polymorphism in the length of SMPD1. For example, p.Arg498Leu is also described as p.Arg496Leu; p.Leu304Pro is also described as p.Leu302Pro; and p.Arg610del is also described as p.Arg608del (see Molecular Genetics).

5.

In NPD-B, the variant p.Arg610del may account for almost 90% of pathogenic alleles in individuals from the Maghreb region of North Africa (i.e., Tunisia, Algeria, and Morocco); 100% of pathogenic alleles in Gran Canaria Island [Fernández-Burriel et al 2003]; and about 20%-30% of pathogenic variants in the US.

6.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

8.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

9.

No deletions or duplications involving SMPD1 have been reported to cause acid sphingomyelinase deficiency. While new deletion/duplication testing methods may identify such pathogenic variants in individuals who did not have a pathogenic variant identified by sequence analysis, the detection rate is unknown and may be very low.

Other Testing

Measurement of acid sphingomyelinase 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) The level of residual enzyme activity is not a reliable predictor of phenotype. (2) As the diagnosis of ASMD 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 ASMD, in some instances specialists have performed bone marrow examination to identify lipid-laden macrophages as part of the diagnosis. Note that bone marrow examination is not necessary for diagnosis and should not be performed unless specific clinical indications are present.

Clinical Characteristics

Clinical Description

Although the phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum, individuals with the severe early-onset infantile neurovisceral phenotype (NPD-A) can be distinguished from those with the intermediate chronic neurovisceral phenotype (NPD-A/B) and chronic visceral ASMD (NPD-B) based on clinical presentation.

Infantile Neurovisceral ASMD (NPD-A)

Feeding problems / growth. Feeding problems are severe, resulting in failure to thrive. Initially, feeding issues appear to result from early satiety because of gastric compression due to hepatosplenomegaly, but as the neurologic decline progresses, infants lose the ability to coordinate sucking and swallowing. Frequent vomiting can contribute to insufficient caloric intake. Linear growth is within the normal range during the first year, whereas weight attainment declines in the first year of life.

Gastrointestinal manifestations (in addition to vomiting) include constipation and diarrhea. Some infants have abdominal discomfort and gassiness which may result in irritability and sleep disturbance.

Liver manifestations. The first symptom in most children with NPD-A is hepatomegaly, which typically is noted by age three months [McGovern et al 2006]. Transaminases are persistently elevated. The hepatomegaly worsens with time; eventually, the liver becomes massive. Over time, infants with NPD-A can exhibit evidence of liver failure such as coagulopathy and ascites.

Splenic manifestations. Enlargement of the spleen is often noted by age three months. Blood counts can be abnormal, reflective of hypersplenism.

Pulmonary disease. On chest radiograph, affected infants have evidence of interstitial lung disease 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 manifests 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. The most common immediate cause of death is respiratory infection [Author, personal observation].

Chronic Neurovisceral ASMD (NPD-A/B)

Individuals with ASMD who survive early childhood but have progressive and/or clinically significant neurologic manifestations have chronic neurovisceral ASMD (NPD-A/B). Most individuals with NPD-A/B survive into adulthood. The extent of visceral organ involvement is variable, similar to NPD-B.

Liver dysfunction. The degree of hepatosplenomegaly ranges from mild to massive. Transaminases are often elevated, and some individuals have histologic abnormalities ranging from hepatic fibrosis to frank cirrhosis [Thurberg et al 2012]. Similar to NPD-B disease, liver failure may require liver transplantation [McGovern et al 2013].

Splenic involvement. Hypersplenism leads to secondary thrombocytopenia and can cause acute abdominal pain.

Pulmonary involvement. Interstitial lung disease may result in oxygen dependence and severe limitations of activity.

Neurologic signs. In individuals with NPD-A/B, 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 initially classified as having 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 ages two and seven years. The five with progressive findings had the p.Gln294Lys pathogenic variant.

Growth. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with ASMD 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 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 and contribute to cardiac disease.

Coarse facial features are present in a subset of individuals with NPD-A/B.

Osteopenia or osteoporosis may lead to an increase in fractures.

Chronic Visceral ASMD (NPD-B)

NPD-B, later in onset and milder in manifestations, is characterized by hepatosplenomegaly, liver dysfunction, progressive hypersplenism, worsening atherogenic lipid profile, and gradual deterioration in pulmonary function [Wasserstein et al 2004, McGovern et al 2008]. Most individuals with NPD-B survive into adulthood.

Liver dysfunction. Liver enlargement is common. The degree of hepatosplenomegaly ranges from mild to massive. Many individuals with NPD-B have elevated transaminases and some have histologic abnormalities ranging from hepatic fibrosis to frank cirrhosis [Thurberg et al 2012]. In rare instances, liver failure has required liver transplantation [McGovern et al 2013].

Splenic involvement. Those with significant organomegaly have hypersplenism with secondary thrombocytopenia. Infarction of the spleen can cause acute abdominal pain.

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. While 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] and there do not appear to be any clinical consequences with respect to visual function.

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 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 LDL-C. Lipid abnormalities are evident from the earliest age studied.

Cardiac disease. Early coronary artery disease, identified in some adults with NPD-B, is presumably related to the dyslipidemia. Some individuals have valvular heart disease due to sphingomyelin deposition.

Osteopenia. Skeletal involvement is common in individuals with NPD-B. In one study, lumbar spine Z scores for children ranged from 0.061 to −4.879. Most adults with NPD-B had osteopenia or osteoporosis at one or more sites according to the WHO classification of bone marrow density [Wasserstein et al 2013]. Pathologic fractures have been reported.

Other. Calcifications in organs other than the lungs have been described, such as the adrenal glands. There are no known clinical consequences of these findings.

Pregnancy and childbirth. Pregnancy in a mildly affected woman has been reported, and 17 pregnancies monitored in women with a wide spectrum of clinical 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

p.Arg610del appears to be neuroprotective; individuals with at least one copy of p.Arg610del will not develop neurologic manifestations and will have NPD-B disease. Individuals homozygous for p.Arg610del will have less severe disease than those with one copy in combination with a more severe 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 also result in a less severe form of NPD-B.

The p.His423Tyr and p.Lys578Asn pathogenic variants, found most commonly in individuals from Saudi Arabia, lead to an early-onset severe form of the disease that is most consistent with the intermediate phenotype (NPD-A/B; chronic neurovisceral form) [Simonaro et al 2002].

The p.Gln294Lys pathogenic variant, associated with intermediate phenotypes with later-onset neuronopathic disease (NPD-A/B), 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. For example, any combination of the Arg498Leu, Leu304Pro, or p.Phe333SerfsTer52 variants results in NPD-A.

Prevalence

The estimated prevalence of ASMD 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 individuals referred for biochemical and/or molecular confirmation. In Chile, screening of 1,691 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 testing have resulted in a low birth incidence in this population.

All forms of ASMD are pan ethnic. Genotype information on individuals with NPD-B from 29 different countries has been reported [Simonaro et al 2002].

Differential Diagnosis

Lysosomal storage diseases (LSD). The clinical features of acid sphingomyelinase deficiency (ASMD) may overlap with other lysosomal storage diseases such as Gaucher disease; however, biochemical and/or molecular genetic testing permits clear distinction between these disorders. In addition, the pulmonary infiltration and the low serum concentration of high-density lipoprotein cholesterol are distinctive features that are present very early in ASMD, but not in Gaucher disease.

Hepatosplenomegaly. Other hereditary disorders associated with hepatosplenomegaly are summarized in Table 2.

Table 2.

Disorders with Hepatosplenomegaly in the Differential Diagnosis of Acid Sphingomyelinase Deficiency

Gene(s)DiffDx DisorderMOIDiffDx Disorder & ASMD: Distinguishing Features
ASAH1Farber disease (See ASAH1-Related Disorders.)ARJoint nodules & hoarseness in Farber disease
G6PC
SLC37A4
Glycogen storage diseases (e.g., GSD1)ARHypoglycemia in GSD
GALNS
GNS
HGSNAT
IDS
IDUA
NAGLU
SGSH
Mucopolysaccharidoses (e.g., MPS I, MPS II, MPS III, MPS IVA)AR
XL
Coarse facial features & dysostosis multiplex in MPS
GBAGaucher diseaseARInterstitial lung disease in ASMD, more prominent skeletal disease in Gaucher disease
GNPTAB
GNPTG
MCOLN1
Oligosaccharidoses (e.g., GNPTAB-related disorders, mucolipidosis III gamma, mucolipidosis IV)ARCoarse features & dermatologic & ophthalmologic abnormalities may be present in oligosaccharidosis.
HEXATay-Sachs disease (See HEXA Disorders.)ARHepatosplenomegaly & lung disease are not common in Tay-Sachs disease.
HEXBSandhoff disease (OMIM 268800)ARHepatosplenomegaly & lung disease are not common in Sandhoff disease.
LIPAWolman disease (See Lysosomal Acid Lipase Deficiency.)ARInterstitial lung disease is not common in LAL deficiency; splenomegaly is less pronounced than in ASMD.
NPC1
NPC2
Niemann-Pick disease type CARSpecific neurologic findings in NPD-C
PRF1
RC3H1
STX11
STXBP2
UNC13D
Familial hemophagocytic lymphohistiocytosis (OMIM PS267700)ARFamilial HLH may present w/fever & inflammation & may have involvement of organs not typically affected in ASMD.

ASMD = acid sphingomyelinase deficiency; DiffDx = differential diagnosis; GSD = glycogen storage disease; HLH = hemophagocytic lymphohistiocytosis; LAL = lysosomal acid lipase; MPS = mucopolysaccharidoses; NPD = Niemann-Pick disease

Hepatosplenomegaly can also accompany some infectious diseases (e.g., Epstein-Barr virus, cytomegalovirus). The diagnosis in infants with NPD-A is sometimes delayed during evaluation for an infectious etiology.

Hematologic malignancies such as leukemia may present with hepatosplenomegaly and pancytopenia. The presence of interstitial lung disease and dyslipidemia may help distinguish ASMD from acute presentation of a hematologic malignancy.

Interstitial lung disease can result from many causes including environmental exposures, connective tissue diseases, and infections. However, the presence of hepatosplenomegaly in ASMD helps distinguish it from these other causes of interstitial lung disease.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with acid sphingomyelinase deficiency (ASMD), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Acid Sphingomyelinase Deficiency

System/ConcernEvaluationComment
Growth/Nutrition
  • Growth assessment
  • Gastroenterology / nutrition / feeding team eval
In persons w/NPD-A:
  • Incl eval of aspiration risk & nutritional status.
  • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
In persons w/NPD-B:
  • Assess nutritional status incl appropriate caloric, calcium, & vitamin D intake.
Bone age in children age <18 yrs
  • Skeletal age, often delayed, is useful for interpreting DEXA scans.
  • Knowledge about additional potential growth yrs can be reassuring to families concerned about child's stature.
Liver functionSerum chemistries incl liver transaminases (ALT, AST), albumin, & clotting factorsTo evaluate for progression of hepatic dysfunction
Liver elastography or FibroScanTo evaluate for hepatic fibrosis & cirrhosis
Liver biopsy in persons w/evidence of deteriorating liver function may be indicated if noninvasive means to ascertain fibrosis are not available.
HepatosplenomegalyRadiologic exam w/measurement of liver & spleen size
HematologicCompete blood countTo evaluate for thrombocytopenia, leukopenia, & anemia
PulmonaryChest radiograph
  • To assess extent of interstitial lung disease
  • Should be done at time of diagnosis regardless of age
Pulmonary function testing, incl assessment of diffusing capacityIn persons old enough to cooperate
OphthalmologicOphthalmologic exam
  • Optional
  • No visual consequences of cherry-red spots are known; their presence does not imply neuronopathic disease, as they are found in many adults w/NPD-B.
NeurologicComprehensive neurologic evalEspecially important in infants when type A disease is under consideration
HyperlipidemiaFasting lipid profileIn those w/NPD-B & NPD-A/B
CardiacCT exam of coronary artery status
MusculoskeletalAssess for frequent fractures &/or extremity pain.
DevelopmentalDevelopmental assessment
  • To incl motor, adaptive, cognitive, & speech/language eval
  • Eval for early intervention / special education
Genetic counselingBy genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of ASMD to facilitate medical & personal decision making
Family support/
resources
Assess need for:

ALT = alanine aminotransaminase; ASMD = acid sphingomyelinase deficiency; AST = aspartate aminotransferase; DEXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); NPD-A/B = chronic neurovisceral ASMD (intermediate form); NPD-B = chronic visceral ASMD (Niemann-Pick disease type B)

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with Acid Sphingomyelinase Deficiency

Manifestation/ConcernTreatmentConsiderations/Other
Growth/Nutrition
  • Regular consultation w/dietician to assure that calorie intake is adequate for growth
  • Feeding therapy
  • Nasogastric tube feeding or surgical placement of feeding tube should be discussed.
Feeding difficulties can make provision of adequate calories a major challenge.
Liver dysfunction
  • Supportive mgmt may be indicated (e.g., diuretics for ascites, vitamin K for coagulopathy).
  • Liver transplantation has been used successfully in liver failure due to ASMD.
Bleeding disorderTransfusion of blood products when bleeding is life threatening
SplenomegalyPartial splenectomy may be considered for persons w/severe hypersplenism, although surgical risks are significant due to multisystemic disease & bleeding risks.Total splenectomy should be avoided because removal of spleen exacerbates pulmonary disease.
Pulmonary diseaseSupplemental oxygen for those w/symptomatic pulmonary diseaseOther treatments for interstitial lung disease (e.g., steroids) have not been well studied. Several persons have undergone bronchopulmonary lavage w/variable results [Nicholson et al 2002, Uyan et al 2005].
Progressive
neurologic disease /
Neurodevelopmental
issues
  • PT & OT to maximize function & prevent contractures
  • Early intervention & developmental support for those w/developmental issues
Aggressive therapy for infants w/NPD-A is not warranted & the plan for such treatment should be made in consultation w/neurologist, therapist(s), & family to establish realistic goals.
HyperlipidemiaAdults w/hyperlipidemia may be treated to bring serum concentration of total cholesterol into normal range.Although not studied specifically in ASMD, statins have been used in adults w/ASMD [Author, personal observation].
OsteopeniaCalcium & vitamin D for osteopenia/osteoporosis
Sleep disorderConsider sedatives as needed.Irritability & sleep disturbance are quality-of-life issues for entire family.

ASMD = acid sphingomyelinase deficiency; NPD-A = infantile neurovisceral ASMD (Niemann-Pick disease type A); OT = occupational therapy; PT = physical therapy

Prevention of Primary Manifestations

Hematopoietic stem cell transplantation (HSCT). Variable results have been reported with HSCT. Shah et al [2005] reported successful HSCT for infantile neurovisceral ASMD (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.

Note: Orthotopic liver transplantation in an infant with NPD-A and amniotic cell transplantation in several individuals with chronic visceral ASMD (NPD-B) have been attempted with little or no success [Kayler et al 2002]. Liver transplantation in individuals with NPD-B can be therapeutic and may be associated with systemic improvement, presumably through secreted acid sphingomyelinase from the transplanted liver, although this observation requires further study [Author, personal communication].

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

Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency have been published [Wasserstein et al 2019].

Table 5.

Recommended Surveillance for Individuals with Acid Sphingomyelinase Deficiency

System/ConcernEvaluationFrequency
Growth/Nutrition
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
CardiacEKGAnnually
EchocardiogramEvery 2-4 yrs
Liver functionSerum chemistries incl liver transaminases (ALT, AST), albumin, & clotting factorsAt least annually
Hematologic
  • Assess for fatigue, abdominal pain, &/or ↑ bleeding.
  • Platelet count
HepatosplenomegalyRadiologic measurements of liver & spleen sizeAt baseline & as needed
PulmonaryAssess for shortness of breath.At each visit
Pulmonary function testingAnnually
Chest radiographEvery 2-4 yrs
NeurologicAssess neurologic function & frequency of headaches.At least annually
Developmental
  • Monitor developmental progress & educational needs.
  • Evaluate OT & PT needs.
At each visit
HyperlipidemiaFasting lipid profileAt least annually
MusculoskeletalAssess for extremity pain.At each visit
Bone density assessment (DEXA)Every 2-4 yrs
Family support/
resources
Assess for any change in social, domestic, or school- or work-related activities.At each visit

ALT = alanine aminotransaminase; AST = aspartate aminotransferase; DEXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

Individuals who have splenomegaly should avoid contact sports.

Evaluation of Relatives at Risk

Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of ASMD. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, either test for the familial SMPD1 pathogenic variants or measure residual acid sphingomyelinase enzyme activity.

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

Pregnancy Management

For pregnant women with NPD, 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 (olipudase alfa) in five adults with NPD-B using an intra-patient dose-escalation scheme was completed. This regimen was generally well tolerated, with study subjects showing reduced liver and spleen volumes and improved lung-diffusing capacity [Wasserstein et al 2015]. These individuals have been treated for more than 45 months in an extension study and their clinical status has continued to improve without any adverse events. An open-label Phase II study has also been completed in 20 children with NPD-B, and a placebo controlled, double-blind Phase II/III study has been completed in 36 adults with NPD-B. Top-line data from these studies has been released and positive clinical findings have been reported, including reduction in liver/spleen volumes, improved lung-diffusing capacities, and improvement in dyslipidemia [Wasserstein et al 2018]. The primary efficacy endpoint in the placebo-controlled adult Phase II/III study was met with high significance. No serious adverse events occurred in either trial. Submission of the data to international regulatory authorities is expected in the near future.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All forms of acid sphingomyelinase deficiency (Niemann-Pick disease type A [NPD-A], NPD-A/B, and NPD-B) are 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., presumed to be carriers of one SMPD1 pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SMPD1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • Some heterozygotes have been found to have low high-density lipoprotein (HDL) associated with acid sphingomyelinase deficiency.

Sibs of a proband

  • If both parents are known to be heterozygous for an SMPD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being a carrier (heterozygous), and a 25% chance of inheriting neither of the familial pathogenic variants and being unaffected and not a carrier.
  • Phenotypic severity is similar, overall, among sibs with the same biallelic pathogenic variants, although some intrafamilial clinical variability may be observed.
  • Some heterozygotes have been found to have low HDL associated with acid sphingomyelinase deficiency.

Offspring of a proband

  • Individuals with NPD-A do not reproduce.
  • The offspring of an individual with NPD-B or NPD-A/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 Detection

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

Note: Carrier identification by determination of acid sphingomyelinase enzyme 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 and discussion of the availability of prenatal/preimplantation genetic 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 Testing

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 testing are possible.

Biochemical genetic testing. Prenatal testing for pregnancies at 25% risk is also possible using biochemical testing of acid sphingomyelinase enzyme activity in cultured amniocytes obtained by amniocentesis or chorionic villus sampling.

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.

  • MedlinePlus
  • 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
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
    Email: contact@metabolicsupportuk.org
  • 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
  • Norton & Elaine Sarnoff Center for Jewish Genetics
    IL
  • International Niemann–Pick Disease Alliance
    Email: info@inpda.org
  • International Niemann-Pick Disease Registry (INPDR)

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SMPD111p15​.4Sphingomyelin phosphodiesteraseSMPD1 databaseSMPD1SMPD1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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 Pathogenesis

SMPD1 encodes acid sphingomyelinase (sphingomyelin phosphodiesterase; EC 3.1.4.12), a lysosomal enzyme responsible for hydrolyzing sphingomyelin to ceramide and phosphorylcholine. Acid sphingomyelinase deficiency (ASMD) is an inborn error of metabolism that results in the accumulation of sphingomyelin in cells and tissues. More than 150 pathogenic variants causing ASMD have been published [Simonaro et al 2002, Schuchman 2007, Zampieri et al 2016] 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 [Zampieri et al 2016]. Splice site alterations have also been described. In contrast to the Ashkenazi Jewish population (see Table 6), most individuals affected with NPD-A studied in other populations have a unique SMPD1 pathogenic variant. There are also a small number of SMPD1 pathogenic variants that can predict NPD-B or NPD-A/B in specific populations, but as with NPD-A, most individuals will have unique variants.

Mechanism of disease causation. 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. Secondary to the primary substrate (sphingomyelin) accumulation, other lipids also accumulate, including cholesterol, lyso-sphingomyelin, and lyso-sphingomyelin-509. These accumulating lipids can also contribute to the pathogenesis of ASMD.

SMPD1-specific laboratory technical considerations

  • Paternal imprinting of SMPD1 has been described [Simonaro et al 2006]. The influence of imprinting on the ASMD phenotype has not been studied in detail.
  • Two numbering systems to describe SMPD1 variants that differ by two amino acids (due to a polymorphism in the length of SMPD1) are currently in use (see Table 6).

Table 6.

Notable SMPD1 Pathogenic Variants

Reference SequencesDNA Nucleotide
Change
(Alias 1)
Predicted
Protein Change
(Alias 1)
Comment [Reference]
NM_000543​.3
NP_000534​.3
c.416T>Cp.Leu139Pro
(Leu137Pro)
Some evidence suggests that these pathogenic variants are assoc w/a less severe form of NPD-B [Simonaro et al 2002].
c.592G>Cp.Ala198Pro
(Ala196Pro)
c.874C>Ap.Gln294Lys
(Gln292Lys)
  • Assoc w/intermediate phenotypes w/later-onset neuronopathic disease
  • Appears to be relatively common in persons of Czech & Slovak heritage [Pavlů-Pereira et al 2005]
c.911T>Cp.Leu304Pro
(Leu302Pro)
1 of 3 common variants that accounts for >90% of pathogenic variants in persons of Ashkenazi Jewish ancestry w/NPD-A [Levran et al 1992]
c.996delC
(990delC)
p.Phe333SerfsTer52
(Pro330SerfsTer382 or fsP330)
1 of 3 common variants that accounts for >90% of pathogenic variants in persons of Ashkenazi Jewish ancestry w/NPD-A [Levran et al 1993]
c.1076C>Ap.Ala359AspIn Chile, screening of 1,691 healthy persons for this common SMPD1 pathogenic variant found a heterozygote frequency of 1:105.7, predicting a disease incidence of 1:44,960 [Acuña et al 2016].
c.1267C>Tp.His423Tyr
(His421Tyr)
  • Found most commonly in persons from Saudi Arabia
  • Leads to early-onset severe form of NPD-A [Simonaro et al 2002]
c.1426C>Tp.Arg476Trp
(Arg474Trp)
Some evidence suggests that this pathogenic variant is assoc w/a less severe form of NPD-B [Simonaro et al 2002].
c.1493G>Tp.Arg498Leu
(Arg496Leu)
1 of 3 common variants that accounts for >90% of pathogenic variants in persons of Ashkenazi Jewish ancestry w/NPD-A
c.1734G>Cp.Lys578Asn
(Lys576Asn)
  • Found most commonly in persons from Saudi Arabia
  • Leads to early-onset severe form of NPD-A [Simonaro et al 2002]
c.1828_1830delp.Arg610del
(Arg608del or DeltaR608)
  • Homozygotes have milder clinical course [Wasserstein et al 2004].
  • One of the most common pathogenic variants in persons w/NPD-B.
  • In persons w/NPD-B originating from Maghreb region of North Africa (i.e., Tunisia, Algeria, Morocco), accounts for almost 90% of mutated alleles
  • On Gran Canaria Island, accounts for 100% of pathogenic alleles [Fernández-Burriel et al 2003]
  • Accounts for ~20%-30% of pathogenic variants in those w/NPD-B in the US.

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

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

1.

Variant designation that does not conform to current naming conventions

Chapter Notes

Acknowledgments

The authors wish to acknowledge the many students and staff members who have worked with them over the years, as well as all the individuals with ASMD who have contributed to these studies.

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

  • 25 February 2021 (sw) Comprehensive update posted live
  • 18 June 2015 (me) Comprehensive update posted live
  • 25 June 2009 (me) Comprehensive update posted live
  • 7 December 2006 (me) Review posted live
  • 8 May 2006 (mm) Original submission

References

Published Guidelines / Consensus Statements

  • Wasserstein M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z, Mengel E, Mistry PK, Schuchman EH, McGovern M. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Available online. 2019. Accessed 2-23-21.

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]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • 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]
  • Levran O, Desnick RJ, Schuchman EH. Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients. Blood. 1992;80:2081–7. [PubMed: 1391960]
  • Levran O, Desnick RJ, Schuchman EH, Type A. Niemann-Pick disease: a frameshift mutation in the acid sphingomyelinase gene (fsP330) occurs in Ashkenazi Jewish patients. Hum Mutat. 1993;2:317–9. [PubMed: 8401540]
  • 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, 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, 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]
  • 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]
  • 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]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • 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]
  • Uyan ZS, Karadağ B, Ersu R, Kiyan G, Kotiloğlu E, Sirvanci S, Ercan F, Dağli T, Karakoç F, Dağli E. Early pulmonary involvement in Niemann-Pick type B disease: lung lavage is not useful. Pediatr Pulmonol. 2005;40:169–72. [PubMed: 15965955]
  • 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 M, Dionisi-Vici C, Giugliani R, Hwu WL, Lidove O, Lukacs Z, Mengel E, Mistry PK, Schuchman EH, McGovern M. Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD). Mol Genet Metab. 2019;126:98–105. [PMC free article: PMC7249497] [PubMed: 30514648]
  • 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]
  • 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, Diaz GA, Lachmann RH, Jouvin MH, Nandy I, Ji AJ, Puga AC. Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months. J Inherit Metab Dis. 2018;41:829–38. [PMC free article: PMC6133173] [PubMed: 29305734]
  • 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 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]
  • Zampieri S, Filocamo M, Pianta A, Lualdi S, Gort L, Coll MJ, Sinnott R, Geberhiwot T, Bembi B, Dardis A. SMPD1 mutation update: database and comprehensive analysis of published and novel variants. Hum Mutat. 2016;37:139–47. [PubMed: 26499107]
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