Handbook of Genetic Counseling/Niemann-Pick Disease-2

Niemann-Pick Disease

(Type A)

Background

• Niemann-Pick disease is a neurodegenerative disease caused by a lysosomal storage disorder. A deficiency in acid sphingomyelinase (ASM) activity results in the accumulation of sphingomyelin.

Genetics

• Caused by mutation in ASM gene
• Chromosomal location 11p15.1-p15.4
• 18 causal mutations mapped
• 3 mutations account for 92% of Ashkenazi Jewish (R496L, L302P, and fsP330)

Incidence

• Within Ashkenazi Jewish population:
• Incidence: 1 in 40,000
• Carrier frequency: 1 in 90

Diagnosis

• Clinical-
• Hepatosplenomegaly
• Developmental delay and loss of milestones
• Presence of "Niemann-Pick" foam cells in bone marrow aspirates
• Enzymatic-
• ASM activity below 5% or normal
• Molecular-
• Mutation found in ASM gene

Natural History

• Perinatal:
• Generally unremarkable:
• Prolonged jaundice in neonatal period occasionally
• Early infancy:
• Around 3 Months:
• Hepatosplenomegaly noted by physical exam
• "Niemann-pick" foam cells present in bone marrow aspirates
• Moderate anemia may be present
• Hypotonia and muscular weakness, feeding difficulties
• By 6 months:
• Psychomotor retardation evident
• Loss of developmental milestones
• Cherry-red maculae noted in ophthalmologic exam (50%)
• Loss of deep tendon reflexes
• Progression:
• Continued loss of motor function
• Deterioration of intellectual capabilities
• Emaciation, spasticity, and rigidity
• Death occurs by 2-3 years of age

Inheritance

• Autosomal recessive

Testing

• Ashkenazi Jewish panel is available clinically:
• Carrier and prenatal also available for known family mutations

Management & Treatment

• There is currently no treatment for Niemann-Pick disease
• Differential Diagnosis
• Niemann-Pick disease Type C and D
• Gaucher Disease
• Other storage disorders

Psychosocial Issues

• Early death of child
• Loss of developmental milestones

Patient Resources

• National Niemann-Pick Disease Foundation

PO Box 49

415 Madison Ave

Ft. Atkinson, WI 53538

(877)-287-3672

(920)-563-0930

Email: nnpdf @idcnet.com

References

• Molecular Basis of Metabolic Disease
• Web:
• Genzyme: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/niemann-pick-disease-type-a-testing.aspx
• Baylor: http://www.bcmgeneticlabs.org/tests/dna/niemannpick.html

Notes

• The information in this outline was last updated in Feb 2003.