Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome

PurposeTo investigate walking ability in Japanese patients with Rett syndrome (RTT).MethodsWalking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database.ResultsUnivariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X.ConclusionsMeaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.     

Exon skipping in Duchenne Muscle dystrophy due to a silent p.Ser443= mutation in the DMD gene

Duchenne Muscle dystrophy (DMD) is a X-linked inherited disease predominantly caused by severe mutations in DMD gene leading to absence of dystrophin protein. Here we report a 14-year-old Mongolian boy suffering from proximal muscle weakness, pseudohypertrophic deltoid and gastrocnemius muscles since early childhood. Lactate dehydrogenase (LDH) and creatine kinase (CK) levels were elevated. Mutation analysis including MLPA and sequencing of the DMD gene revealed a hemizygous silent variant, c.1329C>T (p.Ser443=) in exon 11. This silent mutation, listed in the SNP database (rs1060502631), was described as a variant of unknown significance (VUS) in ClinVar database. cDNA analysis demonstrated partial skipping of exon 11 due to this mutation. Although silent mutations are usually considered non-pathogenic, our case emphasizes that silent mutations can be potentially pathogenic. Hence, if silent variants are not annotated in database or not known to be benign, they should be analysed further at cDNA level.     

De novo truncating mutation in SCN1A as a cause of febrile seizures plus (FS+)

SCN1A is one of the most relevant epilepsy genes. In general, de novo severe mutations, such as truncating mutations, lead to a classic form of Dravet syndrome (DS), while missense mutations are associated with both DS and milder phenotypes within the GEFS+ spectrum, however, these phenotype‐genotype correlations are not entirely consistent. Case report. We report an 18‐year‐old woman with a history of recurrent febrile generalized tonic‐clonic seizures (GTCS) starting at age four months and afebrile asymmetric GTCS and episodes of arrest, suggestive of focal impaired awareness seizures, starting at nine months. Her psychomotor development was normal. Sequencing of SCN1A revealed a heterozygous de novo truncating mutation (c.5734C>T, p.Arg1912X) in exon 26. Conclusion. Truncating mutations in SCN1A may be associated with milder phenotypes within the GEFS+ spectrum. Accordingly, SCN1A gene testing should be performed as part of the assessment for sporadic patients with mild phenotypes that fit within the GEFS+ spectrum, since the finding of a mutation has diagnostic, therapeutic and genetic counselling implications.     

阻断NHE1抑制人胶质母细胞瘤细胞增殖和侵袭的研究

目的分析Na⁺/H⁺交换蛋白1（NHE1）抑制剂对癌基因BRAF野生型（BRAF^WT）和激活型BRAF^V600E突变的胶质母细胞瘤（GBM）细胞生长和侵袭能力的影响。 方法NHE1抑制剂Cariporide分别处理U251（BRAF^WT）和AM38（BRAF^V600E）GBM细胞系,乙酰甲酯化的2’,7’-双（2-羧乙基）-5（6）-羧荧光素荧光探针处理细胞并采用紫外分光光度计检测细胞在440 nm与490 nm的荧光强度,计算荧光强度比值以反映NHE1的活性,MTT法检测细胞增殖活性,基质胶-Transwell实验检测细胞侵袭能力。 结果AM38细胞的NHE1活性、增殖和侵袭能力均显著高于U251细胞,差异均有统计学意义（P=0.006、0.010、0.047）;Cariporide处理的U251和AM38细胞的NHE1活性、增殖和侵袭能力均显著低于溶剂二甲基亚砜处理的U251和AM38细胞,差异均有统计学意义（U251：P=0.012、0.023、0.044;AM38：P=0.006、0.001、0.038）。 结论采用Cariporide阻断NHE1活性可有效抑制BRAF^WT和BRAF^V600E突变型GBM细胞的增殖和侵袭。