Objective Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband. Methods Three modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel de novo mutation; 2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds. Results A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden. Interpretation This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.

Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.Genet Med 19 2, 160-168.

Chromist algae include diverse photosynthetic organisms of great ecological and social importance. Despite vigorous research efforts, a clear understanding of how various chromists acquired photosynthetic organelles has been complicated by conflicting phylogenetic results, along with an undetermined number and pattern of endosymbioses, and the horizontal movement of genes that accompany them. We apply novel statistical approaches to assess impacts of endosymbiotic gene transfer on three principal chromist groups at the heart of long-standing controversies. Our results provide robust support for acquisitions of photosynthesis through serial endosymbioses, beginning with the adoption of a red alga by cryptophytes, then a cryptophyte by the ancestor of ochrophytes, and finally an ochrophyte by the ancestor of haptophytes. Resolution of how chromist algae are related through endosymbioses provides a framework for unravelling the further reticulate history of red algal-derived plastids, and for clarifying evolutionary processes that gave rise to eukaryotic photosynthetic diversity.

On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care.

Electrographic seizures are common in pediatric patients with acute encephalopathy. This study supports the practice of cVEEG monitoring for at least 24 h in pediatric patients with acute encephalopathy, particularly if they are less then 24 months of age and/or if a clinical event suspicious for seizure precedes the encephalopathy.

Objective: Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism characterized by elevated levels of GABA and gammahydroxybutyric acid. Clinical findings include intellectual impairment, hypotonia, hyporeflexia, hallucinations, autistic behaviors, and seizures. Autoradiographic labeling and slice electrophysiology studies in the murine model demonstrate use-dependent downregulation of GABA(A) receptors. We studied GABA(A) receptor activity in human SSADH deficiency utiliz- Succinic semialdehyde dehydrogenase (SSADH) deficiency, also called 4-hydroxybutyric aciduria (McKusick 279180) and aldehyde dehydrogenase 5a1 (Aldh5a1), is an autosomal recessive disorder. About 350 patients are known, with about 85% under 18, making this the most prevalent pediatric neurotransmitter disorder. 1 In the absence of SSADH, transamination of GABA to succinic semialdehyde is followed by its conversion to 4-hydroxybutryic acid (gamma-hydroxybutyric acid, or GHB), leading to CNS GABA and ␥-hydroxy butyrate (GHB) accumulation.2 Major clinical manifestations include developmental delay, hypotonia, ataxia, and seizures. Hyperkinetic behavior, aggression, self-injurious behaviors, and hallucinations have also been described; EEG abnormalities include generalized and focal epileptiform discharges, photosensitivity, and background slowing.

Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.

Background and Objectives Inherited disorders of GABA metabolism include SSADH and GABA-transaminase deficiencies. The clinical features, pathophysiology, diagnosis, and management of both are discussed, including an updated list of ALDH5A1 mutations causing SSADH deficiency. Methods Our SSADH patient database was analyzed and murine and translational studies leading to clinical trials are reviewed. Results The database containing 112 SSADH-deficient patients (71 pediatric and adolescent subjects, 41 adults) indicates that developmental delay and hypotonia are the most common presenting symptoms. Epilepsy is present in 2/3 of patients by adulthood. Murine genetic model, and human studies using flumazenil-PET and transcranial magnetic stimulation, have led to therapeutic trials and identified additional metabolic disruptions. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy with enhanced activation of the mTor pathway. A total of 45 pathogenic mutations have been reported in SSADH deficiency including the discovery of three previously unreported. Conclusions Investigations into the disorders of GABA metabolism provide fundamental insights into mechanisms underlying epilepsy and support the development of biomarkers and clinical trials. Comprehensive definition of the phenotypes of both SSADH and GABA-T deficiencies may increase our knowledge of the neurophysiological consequences of a hyperGABAergic state.