Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral Gypsy mutation

Brain. 2007 Apr;130(Pt 4):1050-61. doi: 10.1093/brain/awm026. Epub 2007 Mar 14.

Abstract

Niemann-Pick disease (NPD), an autosomal recessive disorder resulting from mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, is subdivided into the acute, lethal neuronopathic type A, and the chronic visceral type B, explained by the different residual activity levels of acid sphingomyelinase (ASMase). An increasing number of reports on intermediate forms, challenging this traditional clinical classification, have described a broad range of neurological manifestations; however genotype-phenotype correlations have been compromised by relatively small sample sizes and/or allelic heterogeneity. Here we present a genetically homogeneous group of 20 Gypsy patients with intermediate NPD, where we observed a surprising diversity of neurological features. All affected subjects were homozygous for the same ancestral mutation, W391G in SMPD1, yet displayed the entire spectrum of phenotypic variation observed previously in unrelated affected subjects of diverse ethnicity and disease-causing mutations, ranging from subclinical retinal involvement to severe ataxia, cognitive deficits and psychiatric disorders. The clinical heterogeneity of W391G homozygotes points to additional factors, beyond SMPD1 and residual ASMase, which determine the localization, extent and severity of neural involvement. The phenotype similarity of affected relatives suggests a possible role of genetic modifying factors. In practical terms, W391 is common in the Gypsy population and the diagnosis of NPD should be borne in mind despite the atypical course of the disease. Generally, our findings indicate that mutation analysis is of limited value in predicting brain damage, and the option of enzyme replacement therapy should be considered in intermediate NPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Base Sequence
  • Central Nervous System Diseases / complications
  • Central Nervous System Diseases / ethnology
  • Central Nervous System Diseases / genetics*
  • Child
  • Child, Preschool
  • Cognition Disorders / complications
  • Cognition Disorders / ethnology
  • Cognition Disorders / genetics
  • Electroencephalography / methods
  • Family Health
  • Female
  • Fluorescein Angiography / methods
  • Genotype
  • Humans
  • Infant
  • Macula Lutea / pathology
  • Male
  • Mental Disorders / complications
  • Mental Disorders / ethnology
  • Mental Disorders / genetics
  • Mutation
  • Niemann-Pick Diseases / complications
  • Niemann-Pick Diseases / ethnology
  • Niemann-Pick Diseases / genetics*
  • Peripheral Nervous System Diseases / complications
  • Peripheral Nervous System Diseases / ethnology
  • Peripheral Nervous System Diseases / genetics
  • Phenotype
  • Sphingomyelin Phosphodiesterase / deficiency*
  • Sphingomyelin Phosphodiesterase / genetics

Substances

  • Sphingomyelin Phosphodiesterase