Juvenile amyotrophic lateral sclerosis (JALS) occurs at an age of onset below 25 years with a heterogeneous disease onset location, variable progression and survival time. To investigate whether an ALS gene profile could resolve any aspects of clinical symptom heterogeneity, we have used targeted sequencing technology in a cohort of 12 JALS patients of Chinese descent. We detected 5 likely pathogenic mutations, 2 in familial probands and 3 in sporadic patients. One was a known TARDBP mutation (p.G348V) and 4 were FUS frameshift mutations including a known p.Gln519Ilefs*9 mutation and 3 novel mutations, p.Gly515Valfs*14, p.Gly486Profs*30, and p.Arg498Alafs*32. Of the 4 FUS mutations, 2 were able to be confirmed as de novo mutations. The TARDBP mutation carrier showed a classic ALS phenotype. All patients with FUS mutations experienced limb weakness at an early age and developed bulbar symptoms during the disease course. FUS mutations have previously been associated with increased JALS disease progression, however, we found a large range 12 to 84 months in disease survival (mean 58.2 months). Our results justify future screening for variants in FUS as it remains the most frequent genetic determinant of early onset, JALS (found in 30% of our patients).
The Bruno et al. 1 criteria are commonly used to diagnose paroxysmal kinesigenic dyskinesia (PKD), listed as follows:• Identified kinesigenic trigger for the attacks • Short duration of attacks (1 minute) • No loss of consciousness or pain during attacks • Exclusion of other organic diseases and normal neurologic examination • Control of attacks with phenytoin or carbamazepine, if tried • Age at onset between 1 and 20 years, if no family history of PKD Our previous study has identified PRRT2 as a causative gene for PKD, 2 which was supported by several independent groups. 3-5 To date, many PRRT2 mutations in PKD have been reported, but the genotype-phenotype relationship of PKD has not been well-studied. Our objective was to investigate correlations of PRRT2 mutations with phenotypes of PKD and responses to carbamazepine in a cohort of patients with PKD.Classification of evidence. This study provides Class IV evidence of a correlation between phenotype and genotype in patients with PKD, the PRRT2 mutation, and response to carbamazepine. Methods.We recruited 81 patients with PKD, including 44 familial cases from 14 pedigrees and 37 possibly sporadic cases, from Huashan Hospital and First Affiliated Hospital during 2 periods, December 2005 to March 2011 (stage 1) and April 2011 to April 2012 (stage 2), prior to or after the discovery of PRRT2 mutations, respectively. All cases met Bruno et al. criteria. The study followed standard protocol approvals, registrations, and patient consents.Clinical evaluations were performed and patients were followed up. Sanger sequencing was performed to identify PRRT2 mutations. Differences in clinical characteristics between patients with PKD with and without PRRT2 mutations were tested using the 2-sample t test or the x 2 test. A generalized estimating equation (GEE) model was used to account for familial correlation. SAS version 9.2 (SAS Inc., Cary, NC) was used for statistical analyses.Results. Phenotypes of patients with PKD in this study were classified into 2 subtypes, choreoathetosis or dystonia, according to their main symptoms (detailed classifications seen in appendix e-1 on the Neurology ® Web site at www.neurology.org). Three cases had a positive history of infantile convulsions, and one had viral encephalitis before onset of PKD attacks. All others had no significant medical history. Available EEG and brain MRI showed unremarkable results.Four documented PRRT2 mutations, 2,6 including c.649dupC, c.514_517delTCTG, c.972delA, and c.649delC, were detected in 100% of familial cases and 11% of possibly sporadic cases (table e-1 and table e-2). The c.649dupC mutation was also detected in the asymptomatic parents of family 34 and 47, suggesting the incomplete penetrance of this mutation. Interestingly, we found a de novo mutation of c.649dupC in the patient with PKD of Mongolian ancestry. 7 Associations between PRRT2 mutations and the clinical presentation of PKD are shown in table 1. The mean age at onset in PRRT2 mutation carriers was significantly lower than that in non-P...
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