RESUMO
Congenital muscular dystrophies due to defects in genes encoding proteins involved in α-dystroglycan (α-DG) glycosylation are a heterogeneous group of muscle disorders variably associated with central nervous system and eye abnormalities. One of the more severe is muscle-eye-brain disease (MEB). Mutations in genes coding for proven or putative glycosyltransferases (POMT1, POMT2, POMGnT1, fukutin, FKRP, and LARGE), the DPM3 gene encoding a DOL-P-Man synthase subunit, and the DAG1 gene encoding α-dystroglycan, have been associated with altered α-DG glycosylation. We report new POMGnT1 mutations and evaluate protein expression in 3 patients and 2 foetuses with variably severe MEB features. We identify two new point mutations (c.643C>T, c.1863delC), one new intragenic rearrangement (deletion of exons 2-8), and a new intron retention (between exons 21 and 22) resulting from a known point mutation c.1895+1G>T. Our study provides further evidence that rearrangements of the POMGnT1 gene are relatively common. Importantly, if heterozygous, they can be missed on standard genomic DNA sequencing. POMGNT1 protein analysis in 3 patients showed that the severity of the phenotype does not correlate with protein expression. Cerebral MRI is important for identifying MEB and α-dystroglycanopathy phenotypes in children and foetuses, and hence for directing the genetic analysis.
Assuntos
Predisposição Genética para Doença/genética , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Síndrome de Walker-Warburg/enzimologia , Síndrome de Walker-Warburg/genética , Adolescente , Criança , Pré-Escolar , Evolução Fatal , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/enzimologia , Doenças Fetais/genética , Rearranjo Gênico/genética , Humanos , Masculino , Fenótipo , Mutação Puntual/genética , Gravidez , Índice de Gravidade de Doença , Síndrome de Walker-Warburg/diagnósticoRESUMO
BACKGROUND: Cognitive impairment has been reported in a significant proportion of patients with congenital muscular dystrophies (CMD), generally associated with brain changes. OBJECTIVES: The aim of this study was to establish 1) the overall prevalence of CMD and cognitive impairment in the Italian population; 2) the frequency of individual genetically defined forms; and 3) the presence of distinct phenotypes not associated with mutations in the known genes. METHODS: We included all patients with CMD and cognitive impairment followed in all the Italian tertiary neuromuscular centers. Clinical, brain MRI, and morphologic data were collected. Genetic screening of the known genes was performed according to clinical and muscle biopsy findings. RESULTS: Ninety-two of the 160 (58%) patients with CMD followed in our centers had cognitive impairment. alpha-Dystroglycan (alpha-DG) reduction on muscle biopsy was found in 73/92 (79%), with 42/73 carrying mutations in the known genes. Another 6/92 (7%) showed a laminin alpha2 deficiency on muscle biopsy and 5 of the 6 carried mutations in LAMA2. The remaining 13/92 (14%) patients had normal alpha-DG and laminin alpha2 expression on muscle. CONCLUSIONS: This is the first population study establishing the prevalence of CMD and cognitive impairment and providing a classification on the basis of clinical, MRI, and genetic findings. We also showed that cognitive impairment was not always associated with alpha-DG or laminin alpha2 reduction or with structural brain changes.
Assuntos
Encéfalo/patologia , Transtornos Cognitivos/epidemiologia , Distrofias Musculares/congênito , Distrofias Musculares/epidemiologia , Mapeamento Encefálico , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Comorbidade , Distroglicanas/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Itália/epidemiologia , Laminina/genética , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Mutação , Fenótipo , PrevalênciaRESUMO
BACKGROUND: Congenital muscular dystrophies (CMD) with reduced glycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of conditions associated with mutations in six genes encoding proven or putative glycosyltransferases. OBJECTIVES: The aim of the study was to establish the prevalence of mutations in the six genes in the Italian population and the spectrum of clinical and brain MRI findings. METHODS: As part of a multicentric study involving all the tertiary neuromuscular centers in Italy, FKRP, POMT1, POMT2, POMGnT1, fukutin, and LARGE were screened in 81 patients with CMD and alpha-DG reduction on muscle biopsy (n = 76) or with a phenotype suggestive of alpha-dystroglycanopathy but in whom a muscle biopsy was not available for alpha-DG immunostaining (n = 5). RESULTS: Homozygous and compound heterozygous mutations were detected in a total of 43/81 patients (53%), and included seven novel variants. Mutations in POMT1 were the most prevalent in our cohort (21%), followed by POMT2 (11%), POMGnT1 (10%), and FKRP (9%). One patient carried two heterozygous mutations in fukutin and one case harbored a new homozygous variant in LARGE. No clear-cut genotype-phenotype correlation could be observed with each gene, resulting in a wide spectrum of clinical phenotypes. The more severe phenotypes, however, appeared to be consistently associated with mutations predicted to result in a severe disruption of the respective genes. CONCLUSIONS: Our data broaden the clinical spectrum associated with mutations in glycosyltransferases and provide data on their prevalence in the Italian population.
