Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function

B Vitamins: Small molecules, big effects

In this themed issue of the Journal of Inherited Metabolic Disease, we review the roles of six of the B vitamins in human disease, focussing on treatable inborn errors of metabolism. The special issue starts with a review of thiamine metabolism. O'Callaghan et al provide a comprehensive review of the riboflavin transporter disorders, emphasising the role of mitochondrial dysfunction in the pathophysiology of these neuronopathic syndromes. Balasubramaniam et al then focus on disorders of riboflavin metabolism, in particular the recently discovered flavin adenine dinucleotide (FAD) synthase deficiency, and the rapidly growing list of riboflavin‐responsive disorders associated with mutations in the human flavoproteome (i.e., the >90 human proteins that use FAD or flavin mononucleotide [FMN] as cofactors). Two reviews focus on B6 dependent seizures. Crowther et al provide new insights into human lysine degradation pathways relevant for pyridoxine‐dependent epilepsy caused by antiquitin deficiency, whilst the second reviews all the known causes of B6‐dependent seizures, including the recently discovered disorder of an intracellular PLP‐binding protein (PLPBP deficiency). The roles of biotin in metabolism, gene expression and human disease are examined. Analytical methods for detecting cerebral folate deficiency and discuss the differential diagnosis of this condition, including disorders of folate transport and metabolism, secondary deficiencies related to other inborn errors and acquired causes. Finally, there is a comprehensive review of vitamin B12, folate and the methionine remethylation cycle, focussing on biochemical pathways and regulation, accompanied by a clinical review of the cobalamin‐related disorders

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management

Assessment of two complementary influenza surveillance systems : Sentinel primary care influenza-like illness versus severe hospitalized laboratory-confirmed influenza using the moving epidemic method

Monitoring seasonal influenza epidemics is the corner stone to epidemiological surveillance of acute respiratory virus infections worldwide. This work aims to compare two sentinel surveillance systems within the Daily Acute Respiratory Infection Information System of Catalonia (PIDIRAC), the primary care ILI and Influenza confirmed samples from primary care (PIDIRAC-ILI and PIDIRAC-FLU) and the severe hospitalized laboratory confirmed influenza system (SHLCI), in regard to how they behave in the forecasting of epidemic onset and severity allowing for healthcare preparedness. Epidemiological study carried out during seven influenza seasons (2010-2017) in Catalonia, with data from influenza sentinel surveillance of primary care physicians reporting ILI along with laboratory confirmation of influenza from systematic sampling of ILI cases and 12 hospitals that provided data on severe hospitalized cases with laboratory-confirmed influenza (SHLCI-FLU). Epidemic thresholds for ILI and SHLCI-FLU (overall) as well as influenza A (SHLCI-FLUA) and influenza B (SHLCI-FLUB) incidence rates were assessed by the Moving Epidemics Method. Epidemic thresholds for primary care sentinel surveillance influenza-like illness (PIDIRAC-ILI) incidence rates ranged from 83.65 to 503.92 per 100.000 h. Paired incidence rate curves for SHLCI-FLU/PIDIRAC-ILI and SHLCI-FLUA/PIDIRAC-FLUA showed best correlation index' (0.805 and 0.724 respectively). Assessing delay in reaching epidemic level, PIDIRAC-ILI source forecasts an average of 1.6 weeks before the rest of sources paired. Differences are higher when SHLCI cases are paired to PIDIRAC-ILI and PIDIRAC-FLUB although statistical significance was observed only for SHLCI-FLU/PIDIRAC-ILI (p-value Wilcoxon test = 0.039). The combined ILI and confirmed influenza from primary care along with the severe hospitalized laboratory confirmed influenza data from PIDIRAC sentinel surveillance system provides timely and accurate syndromic and virological surveillance of influenza from the community level to hospitalization of severe cases

Correction: Solving unsolved rare neurological diseases—a Solve-RD viewpoint (European Journal of Human Genetics, (2021), 29, 9, (1332-1336), 10.1038/s41431-021-00901-1)

In the original publication of the article, consortium author lists were missing in the article. The details are given below

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient’s data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases—a Solve-RD viewpoint

Abstract not availabl