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Paroxysmal movement disorders encompass varied motor phenomena. Less recognized features and wide phenotypic and genotypic heterogeneity are impediments to straightforward molecular diagnosis. We describe a family with episodic ataxia type 1, initially mis‐characterized as paroxysmal dystonia to illustrate this diagnostic challenge. We summarize clinical features in affected individuals to highlight underappreciated aspects and provide comprehensive phenotypic description of the rare familial KCNA1 mutation. Delayed diagnosis in this family is emblematic of the broader challenge of diagnosing other paroxysmal motor disorders. We summarize genotypic and phenotypic overlap and provide a suggested diagnostic algorithm for approaching patients with these conditions.

Objective No drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low-dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment-1 (SAT-1) trial was a double-blind, placebo-controlled, translational pilot study to examine the safety and activity of low-dose suramin in children with ASD. Methods Ten male subjects with ASD, ages 5–14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS-2 comparison scores and Expressive One-Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire. Results Blood levels of suramin were 12 ± 1.5 μmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 μmol/L after 6 weeks. The terminal half-life was 14.7 ± 0.7 days. A self-limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS-2 comparison scores improved by −1.6 ± 0.55 points (n = 5; 95% CI = −2.3 to −0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors. Interpretation The safety and activity of low-dose suramin showed promise as a novel approach to treatment of ASD in this small study.

Continuous video electroencephalography (cEEG) monitoring is the recommended gold standard of care for at-risk neonates but is not available in many Neonatal Intensive Care Units (NICUs). To conduct a randomized treatment trial of levetiracetam for the first-line treatment of neonatal seizures (the NEOLEV2 trial), we developed a monitoring infrastructure at five NICUs, implementing recent technological advancements to provide continuous video EEG monitoring and real-time response to seizure detection. Here, we report on the feasibility of providing this level of care.Twenty-five key informant interviews were conducted with study neurologists, neonatologists, coordinators, and EEG technicians from the commercial EEG monitoring company Corticare. A general inductive approach was used to analyze these qualitative data.A robust infrastructure for continuous video EEG monitoring, remote review, and real-time seizure detection was established at all sites. At the time of this survey, 260 babies had been recruited and monitored for 2 to 6 days. The EEG technician review by the commercial EEG monitoring company was reassuring to families and neonatologists and led to earlier detection of seizures but did not reduce work load for neurologists. Neurologists found the automated neonatal seizure detector algorithm provided by the EEG software company Persyst useful, but the accuracy of the algorithm was not such that it could be used without review by human expert. Placement of EEG electrodes to initiate monitoring, especially after hours, remains problematic.Technological advancements have made it possible to provide at-risk neonates with continuous video EEG monitoring, real-time detection of and response to seizures. However, this standard of care remains unfeasible in usual clinical practice. Chief obstacles remain starting a recording and resourcing the real-time specialist review of suspect seizures.

To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).

Lesch-Nyhan disease (LND) is an inherited metabolic disorder characterized by the overproduction of uric acid and distinct behavioral, cognitive, and motor abnormalities. The most challenging clinical problem is self-injurious behavior (SIB), which includes self-biting, self-hitting, self-abrasion, and other features. Currently, these behaviors are managed by behavioral extinction, sedatives, physical restraints, and removal of teeth. More effective treatments are needed. Pre-clinical studies have led to the hypothesis that D1-dopamine receptor antagonists may provide useful treatments for SIB in LND. Ecopipam is one such selective D1-dopamine receptor antagonist. This report summarizes results of a dose-escalation study of the safety and tolerability of ecopipam in 5 subjects with LND. The results suggest that ecopipam is well tolerated, with sedation being the most common dose-limiting event. Several exploratory measures also suggest ecopipam might reduce SIB in this population. These results support the hypothesis that D1-dopamine receptor antagonists may be useful for suppressing SIB in LND, and encourage further studies of efficacy.

Genetic studies of Autism Spectrum Disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variation (SV) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping and de novo assembly to genome sequencing of 235 subjects, 71 cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different classes. We demonstrate a high diversity of de novo mutations, a majority of which were undetectable by previous methods. In addition, we observe complex mutation clusters where combinations of de novo SVs, nucleotide substitutions and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%). Genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs but not an elevated rate of genome rearrangement.

Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.