Acid Sphingomyelinase Deficiency

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). Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type. As more affected individuals are treated with ERT for longer periods of time, the natural history of ASMD is likely to change. The most common presenting symptom in untreated NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Growth failure typically becomes evident by the second year of life. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. This feature may not be amenable to ERT. 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, although it is unclear if ERT will have an impact on this. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most untreated 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 in untreated individuals by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system 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 central nervous system manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B, even when untreated.

Diagnosis/testing.

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

Management.

Targeted therapies: Olipudase alfa (Xenpozyme^®) enzyme replacement therapy (ERT) helps to reduce the accumulation of sphingomyelin in the lung, liver, spleen, and other non-central nervous system organs. It does not impact the central nervous system and therefore does not impact the neurocognitive issues seen in individuals with NPD-A or NPD-A/B. 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, and it is likely to become obsolete now that enzyme replacement therapy is available.

Supportive care: 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 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.

Pregnancy management: For pregnant women with ASMD, prenatal care by a high-risk obstetrician is indicated to ensure appropriate monitoring of pulmonary function and hematologic status. Olipudase alfa ERT has not been studied in pregnant women, but animal studies have identified a potential impact on fetal development. Therefore, ERT is not recommended during pregnancy.

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 and prenatal/preimplantation genetic testing are possible. Biochemical prenatal diagnosis for a pregnancy at 25% risk is also possible by testing of acid sphingomyelinase enzyme activity.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of ASMD is established in a proband with biallelic pathogenic (or likely pathogenic) variants in SMPD1 identified by molecular genetic testing (see 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.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic SMPD1 variants of uncertain significance (or of one known SMPD1 pathogenic variant and one SMPD1 variant of uncertain significance) does not establish or rule out a diagnosis.

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 missense, nonsense, and splice site variants and small intragenic deletions/insertions. 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 7).

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 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

Clinical Description

Although the phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum, individuals with the severe early-onset infantile neurovisceral phenotype (Niemann-Pick disease type A, or NPD-A) can often be distinguished from those with the intermediate chronic neurovisceral phenotype (NPD-A/B) and chronic visceral ASMD (Niemann-Pick disease type B, or NPD-B) based on clinical presentation. Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type (see Management, Targeted Therapies). As more affected individuals are treated with ERT for longer periods of time, the natural history of ASMD is likely to change. ERT has been shown to improve many of the visceral and growth issues in affected individuals with NPD-A/B and NPD-B, but this therapy is not expected to have an impact on the central nervous system disease and neurocognitive issues.

Genotype-Phenotype Correlations

In the United States about two thirds of newly diagnosed affected individuals have a unique genotype. Although no firm genotype-phenotype correlations exist for this disease, there are some pathogenic variants for which enough data has been generated to make some conclusions. For example, the p.Arg610del pathogenic variant 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 chronic neurovisceral phenotype (NPD-A/B) [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 severe infantile neurovisceral phenotype. For example, any combination of the p.Arg498Leu, p.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 ASMD (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].

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

Treatment of Manifestations

There is no cure for ASMD.

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Olipudase alfa (Xenpozyme^®) enzyme replacement therapy (ERT) for ASMD has been approved by the FDA in the United States, the EMA in Europe, and other global regulatory authorities. This therapy helps to reduce the accumulation of sphingomyelin in the lung, liver, spleen, and other non-central nervous system organs. It does not impact the central nervous system and therefore does not impact the neurocognitive issues seen in individuals with NPD-A or NPD-A/B. It represents the first disease-specific treatment for the non-central nervous system manifestations of this disorder. See Table 4 for dosage information.

Hematopoietic stem cell transplantation (HSCT) has yielded variable results. 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. Similar to ERT, 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, and it is likely to become obsolete now that ERT is available.

Table 4.

Targeted Treatment of Acid Sphingomyelinase Deficiency

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

Supportive Treatment of Manifestations in Individuals with Acid Sphingomyelinase Deficiency

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 individuals with ASMD have been published [Wasserstein et al 2019]. These were published prior to the availability of ERT. However, such evaluations should still be considered, even for those on ERT, to assess for the individual's response to targeted and supportive care and the emergence of new manifestations.

Table 6.

Recommended Surveillance for Individuals with Acid Sphingomyelinase Deficiency

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 targeted treatment of ASMD. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, testing for the familial SMPD1 pathogenic variants or measurement of residual acid sphingomyelinase enzyme activity should be performed.

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

Pregnancy Management

For pregnant women with ASMD, prenatal care by a high-risk obstetrician is indicated to ensure appropriate monitoring of pulmonary function and hematologic status. Olipudase alfa ERT has not been studied in pregnant women, but animal studies have identified a potential impact on fetal development. Therefore, ERT is not recommended during pregnancy.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

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.

Mode of Inheritance

All forms of acid sphingomyelinase deficiency (ASMD), including infantile neurovisceral ASMD (Niemann-Pick disease type A, or NPD-A), chronic neurovisceral ASMD (NPD-A/B), and chronic visceral ASMD (Niemann-Pick disease type B, or 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:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Some heterozygotes have been found to have low high-density lipoprotein (HDL) associated with ASMD.

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 ASMD.

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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the SMPD1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

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 7), most individuals affected with infantile neurovisceral ASMD (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 chronic visceral ASMD (NPD-B) or chronic neurovisceral ASMD (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 7).

Table 7.

Notable SMPD1 Pathogenic Variants

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 and their families 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

• 27 April 2023 (ma) Comprehensive updated posted live
• 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

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 11-6-23.

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