Niemann-Pick Disease, Types A and B

Clinical Characteristics
Ocular Features: 

Affected infants usually develop prominent cherry red spots during the first 12 months of life and the entire retina has an ‘opaque’ appearance.  Intracellular lipid accumulation has been seen in retinal neurons, amacrine cells, retinal pigment epithelial cells, and receptors.  The cornea has stromal haziness.  The lens has a brownish coloration on the anterior surface with white spots on the posterior capsule.  Lens opacification seems to progress.

Vision in the first year of life is likely normal as infants have normal fixation, pupillary reactions, and following movements with no nystagmus.  However, by about 2 years of age visual responsiveness may be lost.

Systemic Features: 

Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age.  Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly.  Hepatosplenomegaly is usually the first physical sign.  Hypotonia and pulmonary infections are common.  These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.

The less severe form of Niemann-Pick disease, type B, has a later onset and slower course.  Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood.  Mutations in the same gene are involved, however.  

Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized.  The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.

Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration.  Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.


This is an autosomal recessive neurodegenerative disorder resulting from homozygous mutations in SMPD1 (11p15.4-p15.1) encoding sphingomyelin phosphodiesterase-1.  This recessive gene has an unusual biology.  Only the maternally inherited allele is active in the homozygous condition.  Such parent-specific gene activation is called gene imprinting.

Types A and B are allelic disorders.  

Niemann-Pick diseases designated types C1 and D (257220) are caused by mutations in the NPC1 gene (18q11-q12) and type C2 (607625)  from mutations in the NPC2 gene (14q24.3).

Treatment Options: 

Enzyme replacement therapy trials are underway.  Amniotic membrane, bone marrow, and stem cell transplantation have been tried with some improvement in visceral disease but the results are mixed and await further studies.

Article Title: 


Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. 2007 Oct;30(5):654-63. Review.

PubMedID: 17632693

McGovern MM, Aron A, Brodie SE, Desnick RJ, Wasserstein MP. Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. Neurology. 2006 Jan 24;66(2):228-32.

PubMedID: 16434659

Walton DS, Robb RM, Crocker AC. Ocular manifestations of group A Niemann-Pick disease. Am J Ophthalmol. 1978 Feb;85(2):174-80.

PubMedID: 623187