Niemann-Pick disease type A

Alternate names

Sphingomyelin lipidosis; Sphingomyelinase deficiency

Definition

Niemann-Pick disease is an inherited condition involving lipid metabolism, which is the breakdown, transport, and use of fats and cholesterol in the body. In people with this condition, abnormal lipid metabolism causes harmful amounts of lipids to accumulate in the spleen, liver, lungs, bone marrow, and brain.

Summary

Niemann-Pick disease type A appears during infancy and is characterized by an enlarged liver and spleen (hepatosplenomegaly), failure to gain weight and grow at the expected rate (failure to thrive), and progressive deterioration of the nervous system. Due to the involvement of the nervous system, Niemann-Pick disease type A is also known as the neurological type.

Epidemiology

Niemann-Pick disease type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in the general population. The incidence within the Ashkenazi population is approximately 1 in 40,000 individuals.

Cause

• Niemann-Pick disease types A is caused by mutations in the SMPD1 gene.
• This gene provides instructions for producing an enzyme called acid sphingomyelinase.
• This enzyme is found in lysosomes, which are compartments within cells that break down and recycle different types of molecules.
• Acid sphingomyelinase is responsible for the conversion of a fat (lipid) called sphingomyelin into another type of lipid called ceramide.

Gene mutation

• Mutations in SMPD1 lead to a shortage of acid sphingomyelinase, which results in reduced break down of sphingomyelin, causing this fat to accumulate in cells.
• This fat buildup causes cells to malfunction and eventually die.
• Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

• Infants with Niemann-Pick disease type A usually develop an enlarged liver and spleen (hepatosplenomegaly) by age 3 months and fail to gain weight and grow at the expected rate (failure to thrive).
• The affected children develop normally until around age 1 year when they experience a progressive loss of mental abilities and movement (psychomotor regression).
• Children with Niemann-Pick disease type A also develop widespread lung damage (interstitial lung disease) that can cause recurrent lung infections and eventually lead to respiratory failure.
• All affected children have an eye abnormality called a cherry-red spot, which can be identified with an eye examination.
• Children with Niemann-Pick disease type A generally do not survive past early childhood.

Diagnosis

Niemann-Pick disease type A (NPD-A), characterized by a brief period of normal development followed by a severe neurodegenerative course and death in early childhood.<ref>Wasserstein MP, Schuchman EH. Acid Sphingomyelinase Deficiency. 2006 Dec 7 [Updated 2015 Jun 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1370/</ref>

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

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

The diagnosis of Niemann-Pick disease type A (NPD-A) is established by detection of either biallelic pathogenic variants in SMPD1 on molecular genetic testing or residual ASM enzyme activity that is less than 10% of controls (in peripheral blood lymphocytes or cultured skin fibroblasts).

Treatment

Severe neurodegenerative form (NPD-A) Progressive neurologic disease. <ref>Wasserstein MP, Schuchman EH. Acid Sphingomyelinase Deficiency. 2006 Dec 7 [Updated 2015 Jun 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1370/</ref>[1].

• Physical and occupational therapy to maximize function and to prevent contractures is appropriate.
• Aggressive therapy is not warranted and the plan for such treatment should be made in consultation with the neurologist, therapist(s), and family to establish realistic goals.

Nutrition Feeding difficulties can make provision of adequate calories a major challenge. Regular consultation with a dietician should be provided. The use of nasogastric tube feeding or surgical placement of a feeding tube should be discussed with the family. Sleep disorder Irritability and sleep disturbance are quality-of-life issues for the entire family that sometimes require the use of sedatives. Hematopoietic stem cell transplantation (HSCT)

Variable results have been reported with HSCT. Shah et al [2005] reported successful HSCT for NPD-A. 

References

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NIH genetic and rare disease info

• NIH info on Niemann-Pick disease type A

Niemann-Pick disease type A is a rare disease.

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