title: Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral Gypsy mutation.
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.
authors.affiliation: Department of Neurology, Medical University, Sofia, Bulgaria.
authors.forename: Violeta
authors.initials: V
authors.lastname: Mihaylova
authors.forename: Janina
authors.initials: J
authors.lastname: Hantke
authors.forename: Ivanka
authors.initials: I
authors.lastname: Sinigerska
authors.forename: Silvia
authors.initials: S
authors.lastname: Cherninkova
authors.forename: Margarita
authors.initials: M
authors.lastname: Raicheva
authors.forename: Sonja
authors.initials: S
authors.lastname: Bouwer
authors.forename: Radka
authors.initials: R
authors.lastname: Tincheva
authors.forename: Djako
authors.initials: D
authors.lastname: Khuyomdziev
authors.forename: Jaume
authors.initials: J
authors.lastname: Bertranpetit
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Dora
authors.initials: D
authors.lastname: Angelicheva
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D002493:Central Nervous System Diseases / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000150:complications / Q000208:ethnology / Q000235:genetics; D004569:Electroencephalography / Q000379:methods; D005192:Family Health; D005260:Female; D005451:Fluorescein Angiography / Q000379:methods; D005838:Genotype; D006801:Humans; D007223:Infant; D008266:Macula Lutea / Q000473:pathology; D008297:Male; D001523:Mental Disorders / Q000150:complications / Q000208:ethnology / Q000235:genetics; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000208:ethnology / Q000235:genetics; D010641:Phenotype; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency* / Q000235:genetics
chemical_list: D013108:Sphingomyelin Phosphodiesterase