Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral Gypsy mutation
| Autor: | Sonja Bouwer, Djako Khuyomdziev, Pavel Seeman, Margarita Raicheva, Silvia Cherninkova, Radka Tincheva, Ivailo Tournev, Jaume Bertranpetit, Luba Kalaydjieva, Ivanka Sinigerska, David Chandler, Janina Hantke, Ivo Kremensky, V. Mihaylova, Dora Angelicheva |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Ataxia Adolescent Genotype Population Biology medicine.disease_cause Central Nervous System Diseases medicine Humans Macula Lutea Age of Onset Fluorescein Angiography Child education Family Health Niemann-Pick Diseases Genetics Mutation education.field_of_study Base Sequence Mental Disorders Infant Peripheral Nervous System Diseases Electroencephalography Enzyme replacement therapy medicine.disease Phenotype Sphingomyelin Phosphodiesterase Child Preschool Female Sphingomyelin phosphodiesterase 1 Allelic heterogeneity Neurology (clinical) medicine.symptom Acid sphingomyelinase Cognition Disorders Niemann–Pick disease medicine.drug |
| Zdroj: | Brain. 130:1050-1061 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awm026 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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