We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.

Exome sequencing has recently identified mutations in the gene TANGO2 (transport and Golgi organization 2) as a cause of developmental delay associated with recurrent crises involving rhabdomyolysis, cardiac arrhythmias, and metabolic derangements. The disease is not well understood, in part as the cellular function and subcellular localization of the TANGO2 protein remain unknown. Furthermore, the clinical syndrome with its heterogeneity of symptoms, signs, and laboratory findings is still being defined. Here, we describe 11 new cases of TANGO2‐related disease, confirming and further expanding the previously described clinical phenotype. Patients were homozygous or compound heterozygous for previously described exonic deletions or new frameshift, splice site, and missense mutations. All patients showed developmental delay with ataxia, dysarthria, intellectual disability, or signs of spastic diplegia. Of importance, we identify two subjects (aged 12 and 17 years) who have never experienced any overt episode of the catabolism‐induced metabolic crises typical for the disease. Mitochondrial complex II activity was mildly reduced in patients investigated in association with crises but normal in other patients. In one deceased patient, post‐mortem autopsy revealed heterotopic neurons in the cerebral white matter, indicating a possible role for TANGO2 in neuronal migration. Furthermore, we have addressed the subcellular localization of several alternative isoforms of TANGO2, none of which were mitochondrial but instead appeared to have a primarily cytoplasmic localization. Previously described aberrations in Golgi morphology were not observed in cultured skin fibroblasts.

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Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy.

Introduction:The phenotypic variability of NARS2 associated disease is vast, yet not thoroughly explored. We present the phenotypic and genetic features of 2 siblings with early-onset mitochondrial encephalopathy due to pathogenic variant in NARS2, along with the results from a systematic literature review. Aims: To better delineate the phenotypic variability and natural history of NARS2 associated disease. Methods: The clinical and radiological phenotype, along with the results from the morphological and biochemical investigations from the muscle biopsy as well as the postmortem investigations, where applicable, are presented. Genetic analysis was performed with next-generation sequencing.Results: Together with these 2 patients, we have diagnosed and followed 3 Scandinavian patients with the same homozygous p. Pro214Leu variant in NARS2 who presented with phenotypic features of earlyonset mitochondrial encephalopathy and variable disease course. Another 14 patients with pathogenic variants in NARS2 were identified in the literature. We found that sensorineural hearing impairment is a cardinal feature of early-onset NARS2 associated disease, either isolated or in combination with central nervous system disease. Early-onset mitochondrial encephalopathy due to NARS2 variants shared phenotypic features of Alpers or Leigh syndrome and was characterized by more severe disease course and poorer survival compared to the other NARS2 associated phenotypes. Conclusion: NARS2 variants present with a spectrum of clinical severity from a severe, infantile-onset, progressive disease to a mild, non-progressive disease, without strong association between the genotype and the disease outcome.