Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

Abstract: Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability

TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms

Homozygous N-terminal missense variant in PLEKHG5 associated with intermediate CMT: A case report

Mutations in PLEKHG5, a pleckstrin homology domain containing member of the GEF family, are associated with distal spinal muscular atrophy and intermediate Charcot-Marie-Tooth disease. Here, we describe an isolated case with distal intermediate neuropathy with scapular winging. By whole exome sequencing, we identified the homozygous PLEKHG5 Arg97Gln missense mutation, located in the N-terminal region of the protein. This mutation resides between a zinc-finger motif and a RBD domain, involved in binding rnd3, a RhoA effector protein. We conclude that based on the characteristic phenotype presented by the patient and the supportive genetic findings, the PLEKHG5 mutation is the causative variant

COMPARISON OF SPEECH TASKS FOR AUTOMATIC CLASSIFICATION OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND HEALTHY SUBJECTS

In this work, we consider the task of acoustic and articulatory feature based automatic classification of Amyotrophic Lateral Sclerosis (ALS) patients and healthy subjects using speech tasks. In particular, we compare the roles of different types of speech tasks, namely rehearsed speech, spontaneous speech and repeated words for this purpose. Simultaneous articulatory and speech data were recorded from 8 healthy controls and 8 ALS patients using AG501 for the classification experiments. In addition to typical acoustic and articulatory features, new articulatory features are proposed for classification. As classifiers, both Deep Neural Networks (DNN) and Support Vector Machines (SVM) are examined. Classification experiments reveal that the proposed articulatory features outperform other acoustic and articulatory features using both DNN and SVM classifier. However, SVM performs better than DNN classifier using the proposed feature. Among three different speech tasks considered, the rehearsed speech was found to provide the highest F-score of 1, followed by an F-score of 0.92 when both repeated words and spontaneous speech are used for classification

Additional file 1: of MLPA identification of dystrophin mutations and in silico evaluation of the predicted protein in dystrophinopathy cases from India

Listing of mutations found in our samples. (XLSX 16 kb

Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor epsilon-subunit

WOS: 000423337400011PubMed ID: 29367459We identify 2 homozygous mutations in the epsilon-subunit of the muscle acetylcholine receptor ( AChR) in 3 patients with severe congenital myasthenia: epsilon R218W in the pre-M1 region in 2 patients and epsilon E184K in the beta 8-beta 9 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cysloop receptor superfamily, while Glu184 is conserved in the alpha-, delta-, and epsilon-subunits of AChRs from all species. epsilon R218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas epsilon E184K reduces channel gating efficiency 11-fold but does not alter AChR cell surface expression. Determinations of the effective channel gating rate constants, combined with mutant cycle analyses, demonstrate strong energetic coupling between epsilon R218 and epsilon E184, and between eR218 and epsilon E45 from the beta 1-beta 2 linker, as also observed for equivalent residues in the principal coupling pathway of the alpha-subunit. Thus, efficient and rapid gating of the AChR channel is achieved not only by coupling between conserved residues within the principal coupling pathway of the alpha-subunit, but also between corresponding residues in the epsilon-subunit.NIH grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS 6277, NS031744]This work was supported in part by NIH grants NS 6277 to AGE and NS031744 to SMS

Identification of a shared, common haplotype segregating with an SGCB c.544 T > G mutation in Indian patients affected with sarcoglycanopathy

Abstract Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the c.544 T > G mutation in the cases and related family members as well as 150 unrelated controls from Indian populations using PLINK1.9. We identified haplotype H1 = G, A, G, T, G, G, A, C, T, G, T at a significantly higher frequency in cases compared to related controls and unrelated control Indian population. Upon segregation analysis within the family pedigrees, H1 is observed to co-segregate with c.544 T > G in a homozygous state in all the pedigrees of cases except one indicating a probable event of founder effect. Furthermore, Identical-by-descent and inbreeding coefficient analysis revealed relatedness among 33 new pairs of seemingly unrelated individuals from sarcoglycanopathy cohort and a higher proportion of homozygous markers, thereby indicating common ancestry. Since all these patients are from the south Indian region, we suggest this region to be a primary target of mutation screening in patients diagnosed with sarcoglycanopathy