Brain Advance Access published online on March 14, 2007
Brain, doi:10.1093/brain/awm026
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Highly variable neural involvement in sphingomyelinase-deficient Niemann–Pick disease caused by an ancestral Gypsy mutation
1Department of Neurology, 2National Genetic Laboratory, and, 3Department of Pediatrics, Medical University, Sofia, Bulgaria, 4Centre for Medical Research and Western Australian Institute for Medical Research, The University of Western Australia, Perth, Australia, 5Department of Pediatrics, Regional Hospital Pazardjik, Bulgaria, 6Biologia Evolutiva CEXS, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain and 7Department of Child Neurology, 2nd School of Medicine, Charles University, Prague, Czech Republic
Correspondence to:
Luba Kalaydjieva, Laboratory of Molecular Genetics, Western Australian Institute for Medical Research, "B" Block, QE II Medical Centre, Perth, WA 6009, Australia E-mail: luba{at}cyllene.uwa.edu.au
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.
Key Words: intermediate Niemann–Pick disease; neurological manifestations; Gypsy founder mutation
Abbreviations: ASMase, acid sphingomyelinase; NPD, Niemann–Pick disease; SMPD1 gene, sphingomyelin phosphodiesterase 1 gene
Received October 28, 2006. Revised January 18, 2007. Accepted January 29, 2007.
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