PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.

BACKGROUND AND OBJECTIVES: Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. METHODS: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. RESULTS: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. DISCUSSION: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by adrenergically driven ventricular arrhythmia predominantly caused by pathogenic variants in the cardiac ryanodine receptor (RyR2). We describe a novel variant associated with cardiac arrest in a mother and daughter. METHODS: Initial sequencing of the RYR2 gene identified a novel variant (c.527G > T, p.R176L) in the index case (the mother), and her daughter. Structural analysis demonstrated the variant was located within the N-terminal domain of RyR2, likely leading to a gain-of-function effect facilitating enhanced calcium ion release. Four generation cascade genetic and clinical screening was carried out. RESULTS: Thirty-eight p.R176L variant carriers were identified of 94 family members with genetic testing, and 108 family members had clinical evaluations. Twelve carriers were symptomatic with previous syncope and 2 additional survivors of cardiac arrest were identified. Thirty-two had clinical features suggestive of CPVT. Of 52 noncarriers, 11 had experienced previous syncope with none exhibiting any clinical features of CPVT. A documented arrhythmic event rate of 2.89/1000 person-years across all carriers was calculated. CONCLUSION: The substantial variability in phenotype and the lower than previously reported penetrance is illustrative of the importance of exploring family variants beyond first-degree relatives.

Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy.

COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency.

On the persistence and detectability of ancient Beothuk mitochondrial DNA genomes in living First Nations peoples.

Claims have long been made as to the survival to the present day of descendants of the Newfoundland Beothuk, a group generally accepted to have become extinct with the death of the last known member, Shanawdithit, in 1829. Interest has recently been revived by the availability of commercial genetic testing, which some claim can assign living individuals to specific Native American groups. We compare complete mitogenome sequences (16569 bp) from aDNA of eight distinct Beothuk lineages, including Shanawdithit's uncle Nonosabasut and his wife Demasduit, with three Newfoundland Mi'kmaq lineages and 21 other living Native Americans drawn from GenBank. A Newfoundland Mi'kmaq lineage in Haplogroup A is more similar to three Native Americans (1-3 SNPs) than to the most closely related Beothuk (24 SNPs). Nonosabasut in Haplogroup X is identical to a non-Beothuk Native American. Demasduit in Haplogroup C differs from three other Native Americans by 1-4 substitutions. Within a 2168 bp region of the HVS sequences available from living Mi'kmaq of the Miawpukek First Nation in Newfoundland, lineages in Haplogroups C, X, and A differ by 1, 4, and 8 substitutions, from the most similar Beothuk, and are more similar to other Native Americans. MtDNA genome sequences in living persons identical or similar to those of Beothuk do not necessarily indicate Beothuk ancestry. Mi'kmaq lineages cannot at this time be associated with any Beothuk lineages more closely than those of other Native Americans.

Learning preferences of surgery residents: a multi-institutional study.

BACKGROUND: The VARK model categorizes learners by preferences for 4 modalities: visual, aural, read/write, and kinesthetic. Previous single-institution studies found that VARK preferences are associated with academic performance. This multi-institutional study was conducted to test the hypothesis that the VARK learning preferences of residents differ from the general population and that they are associated with performance on the American Board of Surgery In-Training Examination (ABSITE). METHODS: The VARK inventory was administered to residents at 5 general surgery programs. The distribution of the VARK preferences of residents was compared with the general population. ABSITE results were analyzed for associations with VARK preferences. χ2, Analysis of variance, and multiple linear regression were used for statistical analysis. RESULTS: A total of 132 residents completed the VARK inventory. The distribution of the VARK preferences of residents was different than the general population (P < .001). The number of aural responses on the VARK inventory was an independent predictor of ABSITE percentile rank (P = .03), percent of questions correct (P = .01), and standard score (P = .01). CONCLUSION: This study represents the first multi-institutional study to examine VARK preferences among surgery residents. The distribution of preferences among residents was different than that of the general population. Residents with a greater number of aural responses on VARK had greater ABSITE scores. The VARK model may have potential to improve learning efficiency among residents.

The Learning Preferences of Applicants Who Interview for General Surgery Residency: A Multiinstitutional Study.

BACKGROUND: Learning styles theory posits that learners have distinct preferences for how they assimilate new information. The VARK model categorizes learners based on combinations of 4 learning preferences: visual (V), aural (A), read/write (R), and kinesthetic (K). A previous single institution study demonstrated that the VARK preferences of applicants who interview for general surgery residency are different from that of the general population and that learning preferences were associated with performance on standardized tests. This multiinstitutional study was conducted to determine the distribution of VARK preferences among interviewees for general surgery residency and the effect of those preferences on United States Medical Licensing Examination (USMLE) scores. METHODS: The VARK learning inventory was administered to applicants who interviewed at 3 general surgery programs during the 2014 to 2015 academic year. The distribution of VARK learning preferences among interviewees was compared with that of the general population of VARK respondents. Performance on USMLE Step 1 and Step 2 Clinical Knowledge was analyzed for associations with VARK learning preferences. Chi-square, analysis of variance, and Dunnett's test were used for statistical analysis, with p < 0.05 considered statistically significant. RESULTS: The VARK inventory was completed by a total of 140 residency interviewees. Sixty-four percent of participants were male, and 41% were unimodal, having a preference for a single learning modality. The distribution of VARK preferences of interviewees was different than that of the general population (p = 0.02). By analysis of variance, there were no overall differences in USMLE Step 1 and Step 2 Clinical Knowledge scores by VARK preference (p = 0.06 and 0.21, respectively). However, multiple comparison analysis using Dunnett's test revealed that interviewees with R preferences had significantly higher scores than those with multimodal preferences on USMLE Step 1 (239 vs. 222, p = 0.02). CONCLUSION: Applicants who interview for general surgery residency have a different pattern of VARK preferences than that of the general population. Interviewees with preferences for read/write learning modalities have higher scores on the USMLE Step 1 than those with multimodal preferences. Learning preferences may have impact on residency applicant selection and represents a topic that warrants further investigation.

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy.

BACKGROUND: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. METHODS AND RESULTS: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. CONCLUSIONS: ICD therapy is indicated for PP in postpubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.