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Niemann-Pick disease type A - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

Niemann-Pick disease type A

MONDO:0009756

Also known as:Niemann-PICK disease, type ANiemann-Pick disease, Intermediate, protracted neurovisceralsphingomyelin lipidosis

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Overview

Niemann-Pick disease type A is a very severe subtype of Niemann-Pick disease, an autosomal recessive lysosomal disease, and is characterized clinically by onset in infancy or early childhood with failure to thrive, hepatosplenomegaly, and rapidly progressive neurodegenerative disorders.

GeneticsAutosomal recessive · SMPD1 (chr 11)

OnsetINFANTILE

Clinical Trials6 registered · 2 recruiting

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Inability to walk, Delayed CNS myelination, Cherry red spot of the macula, and Enlarged liver (hepatomegaly) and others; and sometimes findings: Macrocephaly, Prolonged neonatal jaundice, and Ascites. 36 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	8	Inability to walk, Muscle stiffness (rigidity), Irritability

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

SMPD1 function has not been fully characterized.

Niemann-Pick disease type A is associated with mutations in the SMPD1 gene on chromosome 11.

GeneReviews

Clinical Guidance

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 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 . In contrast to individuals with other pathogenic variants, individuals homozygous for the p.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

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

Suggestive Findings

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 United States Recommended Uniform Screening Panel and is performed in a limited number of states within the US. Several pilot studies have also 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.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for Niemann-Pick disease type A. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with acid sphingomyelinase deficiency (ASMD), the evaluations summarized (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

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Recommendations for clinical monitoring of individuals with ASMD have been published . 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

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

6 clinical trials registered, 2 recruiting. Interventions under study include other interventions and drug therapy. Research is sponsored by a mix of industry and academic institutions.

NCT ID	Title	Phase	Sponsor	Status
[NCT03655223](https://clinicaltrials.gov/study/NCT03655223)

Data assembled from 8 of 12 sources · Last updated Sep 19, 2026, 2:41 AM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:257200

Orphanet

European rare disease database

Orphanet:77292

GARD

Genetic and Rare Diseases Info Center

GARD:7206

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are any of the 6 active clinical trials a good fit for my situation?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

GeneReviews

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. Recent studies of individuals with hepatosplenomegaly whose testing for Gaucher disease was normal were subsequently found to have ASMD [Author, personal communication]. Pulmonary infiltration and the low serum concentration of high-density lipoprotein cholesterol are distinctive features that are present very early in individuals with ASMD but not in those with Gaucher disease. Hepatosplenomegaly. Other hereditary disorders associated with hepatosplenomegaly are summarized in . Table 2. Disorders with Hepatosplenomegaly in the Differential Diagnosis of Acid Sphingomyelinase Deficiency

Gene(s)	Differential Diagnosis Disorder	MOI	Distinguishing Features
ASAH1	Farber disease (See ASAH1-Related Disorders.)	AR	Joint nodules hoarseness in Farber disease G6PC
SLC37A4	Glycogen storage diseases (e.g., GSD1)	AR	Hypoglycemia in glycogen storage diseases GALNS GNS HGSNAT IDS IDUA NAGLU
SGSH	Mucopolysaccharidoses (e.g., MPS I, MPS II, MPS III, MPS IVA)	ARXL	Coarse facial features dysostosis multiplex in mucopolysaccharidoses GBA1 (GBA)
Gaucher disease	AR	Interstitial 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)	AR	Coarse features dermatologic ophthalmologic abnormalities may be present in oligosaccharidoses.	—
HEXA	Tay-Sachs disease (See HEXA Disorders.)	AR	Hepatosplenomegaly lung disease are not common in Tay-Sachs disease. HEXB
Sandhoff disease	AR	Hepatosplenomegaly lung disease are not common in Sandhoff disease.	—
LIPA	Wolman disease (See Lysosomal Acid Lipase [LAL] Deficiency.)	AR	Interstitial lung disease is not common in LAL deficiency; splenomegaly is less pronounced than in ASMD. NPC1
NPC2	Niemann-Pick disease type C (NPD-C)	AR	Specific neurologic findings in NPD-C PRF1 STX11 STXBP2
UNC13D	Familial hemophagocytic lymphohistiocytosis (HLH)	AR	Familial HLH may present w/fever inflammation may have involvement of organs not typically affected in ASMD. Hepatosplenomegaly can also accompany some infectious diseases (e.g., Epstein-Barr virus, cytomegalovirus).

Source: GeneReviews — "Acid Sphingomyelinase Deficiency"

Research Type	Count	% of Total
New treatment approaches	4	29%
Research summaries	3	21%
Patient case studies	3	21%
Disease patterns and progression	3	21%
Laboratory research	1	7%

Kisho

Niemann-Pick disease type A

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Scenario 1 – Abnormal Newborn Screening (NBS) Result

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Differential Diagnosis

Growth/Nutrition

Liver function

Hepatosplenomegaly

Hematologic

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Recent Publications

Niemann-Pick disease type A

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Scenario 1 – Abnormal Newborn Screening (NBS) Result

Treatment

Management Guidelines

Evaluations Following Initial Diagnosis

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Differential Diagnosis

Growth/Nutrition

Liver function

Hepatosplenomegaly

Hematologic

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Recent Publications