Screening of 25 Italian patients with Niemann-Pick a reveals fourteen new mutations, one common and thirteen private, inSMPD1

Ricci, Verena; Stroppiano, Marina; Corsolini, Fabio; Rocco, Maja Di; Parenti, Giancarlo; Regis, Stefano; Grossi, Serena; Biancheri, Roberta; Mazzotti, Raffaella; Filocamo, Mirella

doi:10.1002/humu.9258

Cited by 31 publications

(25 citation statements)

References 19 publications

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“…Patient 3 had missense mutation c.940G > A (p.V314M) and the previously reported deletion, 573delT, which resulted in early termination of the ASM polypeptide (10). The fact that the p.V314M mutant enzyme had significant residual activity when expressed provided sufficient neuroprotective activity For stability studies, 24 h after transfection cell extracts were prepared and incubated at 55°C, pH 7.0, for 30 min prior to enzyme assay.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease

Desnick

Kim

et al. 2010

Mol Med

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease

Desnick

Kim

et al. 2010

Mol Med

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“…Comparative studies of the SM degradation capacity in more cell types may shed further light on this problem. Absence of the Q292K mutation in a large cohort of published (Pittis et al 2004;Ricci et al 2004) and unpublished ASM-de¢cient patients (M.T.V.) suggests its prevalence in central Europe.…”

Section: The Molecular Basis Of the Phenotype Variabilitymentioning

confidence: 96%

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Pavlu-Pereira¹,

Asfaw²,

Poupčtová³

et al. 2005

J of Inher Metab Disea

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A multi-approach study in a series of 25 Czech and Slovak patients with acid sphingomyelinase deficiency revealed a broad phenotypic variability within Niemann-Pick disease types A and B. The clinical manifestation of only 9 patients fulfilled the historical classification: 5 with the rapidly progressive neurovisceral infantile type A and 4 with a slowly progressive visceral type B. Sixteen patients (64%) represented a hitherto scarcely documented 'intermediate type' (IT). Twelve patients showed a protracted neurovisceral course with overt or mild neurological symptoms, three a rapidly progressing fatal visceral affection with rudimentary neurological lesion. One patient died early from a severe visceral disease. The genotype in our patients was represented by 4 frameshift and 14 missense mutations. Six were novel (G166R, R228H, A241V, D251E, D278A, A595fsX601). The Q292K mutation (homoallelic, heteroallelic) was strongly associated with a protracted neurovisceral phenotype (10 of 12 cases). The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. In the IT group it ranged from 5% to 49% in a 24 h chase. The liver storage showed three patterns: diffuse, zonal (centrolobular), and discrete submicroscopic. Our series showed a notable variability in both the neurological and visceral lesions as well as in their proportionality and synchrony, and demonstrates a continuum between the historical 'A' and 'B' phenotypes of ASM deficiency. This points to a broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments. This report highlights the important position of the IT in the ASM deficiency phenotype classification. We define IT as a cluster of variants combining clinical features of both the classical types. The protracted neuronopathic variant with overt, borderline or subclinical neurology prevails and is important in view of future enzyme replacement therapy. It appears more common in central Europe. The visceral, rapidly progressing early fatal type has been recognized rarely so far.

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“…In contrast, it was observed in more than 85% of the mutant alleles from Northern-African NPD type B patients (Vanier, et al, 1993). Mutation spectra for specific populations have been published for only a few countries, such as Italy (Ricci, et al, 2004, Pittis, et al, 2004) or the Czech Republic and Slovakia (Pavlu-Pireira, et al, 2005). In some cases, expression studies have been performed (Dardis, et al, 2005, Pavlu-Pereira, et al, 2005, etc.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization ofSMPD1mutations causing Niemann-Pick types A and B in Spanish patients

et al. 2009

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Niemann-Pick disease (NPD) types A/B are both caused by a deficiency of lysosomal acid sphingomyelinase and display autosomal recessive inheritance. These two types of the disease were described according to the presence (type A) or absence (type B) of neurological symptoms. We present a molecular analysis of 19 Spanish NPD A/B patients and two from Maghreb. Eight of the patients had type A and 13 had type B NPD. All mutant SMPD1 alleles were identified, including 17 different mutations, 10 of which were novel. The only frequent mutations in the 21 NPD patients were c.1823_1825delGCC (p.R608del) (38%) and c.1445C>A (p.A482E) (9%). Genotype-phenotype correlations were established for most of the mutations and, in particular, the p.R608del-type B association was confirmed. This mutation accounts for 61.5% of the mutant alleles in the type B subgroup of patients. Expression studies performed on six of the identified mutations confirmed them to be disease-causing due to their low enzyme activity. An allele with a mutation affecting a non-canonical donor splice site produced only aberrant mRNAs corresponding to previously reported non-functional SMPD1 minor transcripts. This study is the first exhaustive mutational analysis of Spanish Niemann-Pick A/B disease patients.

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Screening of 25 Italian patients with Niemann-Pick a reveals fourteen new mutations, one common and thirteen private, inSMPD1

Cited by 31 publications

References 19 publications

Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease

Identification and Characterization of Eight Novel SMPD1 Mutations Causing Types A and B Niemann-Pick Disease

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Identification and characterization ofSMPD1mutations causing Niemann-Pick types A and B in Spanish patients

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