Niemann-Pick Disease (Type A)

Also known as: Acid sphingomyelinase deficiency; Sphingomyelin Lipidosis

Niemann-Pick disease type A (NPD type A) is a severe, autosomal recessive, sphingolipid disease that occurs in early childhood. NPD type A is characterised by failure to thrive, hepatosplenomegaly and a rapidly progressive neurodegenerative course leading to death by age 2-3 years.

Other forms of NPD have been described, depending on the speed of sphingolipid accumulation and the organs affected. NPD type B is a milder, attenuated but non-neuropathic form with a later onset and longer survival. NPD type C is a rarer form resulting from defects in the transport of cholesterol and related compounds in the brain.

Presentation

NPD type A presents in the first few months of life with:

  • Feeding difficulties and failure to thrive
  • Progressively increasing abdominal girth (hepatosplenomegaly)
  • Regression of early motor skills, progressive loss of tone and deep tendon reflexes. The neurological degeneration is relentless, leading to a spastic state.
  • Cherry-red macula (this is the only normal part of the retina. It is accentuated by the deposition of gangliosides in the surrounding retinal ganglion cells; the phenomenon also occurs in Tay-Sachs disease).
  • Progressive deterioration and death by the age of 2-3 years is the usual eventuality.
  • The condition is over-represented in the Ashkenazim but not exclusive to this community.

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  • NPD type A results from the deficient activity of acid sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene located on chromosome 11.
  • The enzymatic defect results in pathologic accumulation of sphingomyelin (a ceramide phospholipid) and other lipids in the monocyte-macrophage system (the primary site of pathology in patients with NPD).
  • Individuals with NPD type A typically have little or no residual acid sphingomyelinase enzyme activity, as shown in fibroblast cells from skin biopsies or in leukocytes prepared from peripheral blood.
  • Additional progressive deposition of sphingomyelin in the nervous system results in the neurodegenerative course observed in NPD type A.

  • Systemic involvement includes progressive lung disease, hepatosplenomegaly, short stature and pancytopenia.
  • Three common mutations account for approximately 90% of NPD type A alleles in the Ashkenazi Jewish population.
  • NPD is a very rare disorder with a disease incidence of approximately 1:10,000,000 in the general population.
  • NPD type A is more frequent in persons of Ashkenazi Jewish descent; with an estimated incidence of 1:40,000.
  • The diagnosis of NPD is confirmed with measurement of acid sphingomyelinase activity in peripheral white blood cells or in cultured fibroblasts.

Gene Specific:

  • Clinical diagnosis can be confirmed by targeted mutation analysis – normally sought for the 4 most frequent SMPD1 mutations in developed nations.
  • Three type A mutations predict the severe infantile form of the disease common in the Ashkenazi Jewish population.

Other supporting evidence:

  • Full blood count – pancytopenia may be present secondary to the enlarged spleen
  • Liver function tests – transaminase levels may be elevated.
  • Plasma cholesterol and lipoproteins – gross elevation of cholesterol due to raised HDL protein in the plasma of the blood
  • Chest X-ray – typical reticulonodular pattern of infiltration, even in patients with no obvious pulmonary symptoms.
  • The pathological hallmark but not absolutely pathognomonic NPD type A is the histochemical characteristic lipid-laden foam cell (the Niemann-Pick cell), on bone marrow examination.

There is no specific treatment, and management is symptomatic. For the extremely rare patients with milder disease, the enzyme therapy becoming available for Niemann-Pick type B (without neurological disease) may be indicated for the systemic complications in the lung, skeleton and viscera (liver and spleen enlargement).

Family members should be offered genetic counseling and testing. Carrier testing and pre-natal testing are available for this condition.

The clinical presentation and course of NPD type A is relatively uniform, characterised by normal appearance at birth, followed by progressive hepatosplenomegaly from 3 months of age and severe neurodegenerative course leading to death by approximately 2-3 years of age.

  • For children exhibiting features of Niemann-Pick Disease (NPD), initial referral would usually be to a paediatrician. For Jewish patients, it is important to note the child’s ancestry and higher prevalence of NPD in the Jewish population.
  • For patients that have received a positive NPD diagnosis:
    • On-going management is usually under the care of a paediatrician with other specialist input as appropriate.
    • Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.
  • Transition from paediatric to adult management should go through an appropriate adolescent unit where possible.
Niemann-Pick Disease Group UK

This UK-based group aims to make a positive difference to families affected by Niemann-Pick disease through the provision of a range of services covering care, information and research. The website presents information on all types of the disease, care and support services in the UK, research developments and links to other national and international resources.

Telephone: 0191 415 0693

National Niemann-Pick Foundation (USA)

This USA-based Foundation supports and promotes research to find treatments and a cure for all types of Niemann-Pick disease and aims to provide support services for affected individuals and families. It also has a Canadian chapter.

Niemann-Pick Disease Facebook Group

An open group on Facebook dedicated to spreading awareness of Niemann-Pick disease.

GeneReviews: www.ncbi.nlm.nih.gov/books/NBK1370

OMIM: #257200

Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by: Professor Tim Cox, Director of Research and Honorary Consultant Physician, University of Cambridge, Addenbrooke’s Hospital.
Last review: 03.05.2016

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