Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Epilepsia/diagnóstico , Taquicardia/etiologia , Esclerose Tuberosa/diagnóstico , Encéfalo/diagnóstico por imagem , Pré-Escolar , Eletrocardiografia , Eletroencefalografia , Epilepsia/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Esclerose Tuberosa/complicaçõesRESUMO
OBJECTIVE: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. METHODS: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. RESULTS: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. CONCLUSIONS: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.
Assuntos
Hemiplegia/genética , Transtornos das Habilidades Motoras/genética , Paralisia Respiratória/genética , ATPase Trocadora de Sódio-Potássio/genética , Estado Epiléptico/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Hemiplegia/complicações , Hemiplegia/fisiopatologia , Heterozigoto , Humanos , Lactente , Masculino , Transtornos das Habilidades Motoras/etiologia , Transtornos das Habilidades Motoras/fisiopatologia , Mutação de Sentido Incorreto/genética , Paralisia Respiratória/etiologia , Paralisia Respiratória/fisiopatologia , Índice de Gravidade de Doença , Estado Epiléptico/etiologia , Estado Epiléptico/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either of two genes, TSC1 and TSC2. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. TSC2 lies immediately adjacent to PKD1 and large heterozygous deletions can result in the TSC2/PKD1 contiguous gene syndrome (PKDTS). PKDTS has been identified in patients with TSC and early-onset severe ADPKD. However, genetic diagnosis with conventional methods proved to be difficult because its genetic aberrations are large monoallelic mutations. METHODS: In the study presented here, we used both multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array-CGH) for four PKDTS patients. RESULTS: We were able to detect large heterozygous deletions including TSC2 and PKD1 by both of MLPA and array-CGH in all four patients. And in two patients, array-CGH identified relatively large genomic aberrations (RAB26, NTHL1, etc.), that extended outside of TSC2 or PKD1. CONCLUSION: The identical results obtained with these two completely different methods show that both constitute highly reliable strategies. Only a few studies have determined the breakpoints of large deletions in this disease and ours is the first to have identified the breakpoints by using array-CGH. We suggest that these methods are not only useful for the diagnosis of PKDTS but also for elucidation of its molecular mechanism.