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Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot–Marie–Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Mitochondrial complex I deficiency is caused by pathogenic variants in mitochondrial and nuclear genes associated with complex I structure and assembly. We report the case of a patient with NDUFA8-related mitochondrial disease. The patient presented with developmental delay, microcephaly, and epilepsy. His fibroblasts showed apparent biochemical defects in mitochondrial complex I. Whole-exome sequencing revealed that the patient carried a homozygous variant in NDUFA8. His fibroblasts showed a reduction in the protein expression level of not only NDUFA8, but also the other complex I subunits, consistent with assembly defects. The enzyme activity of complex I and oxygen consumption rate were restored by reintroducing wild-typeNDUFA8 cDNA into patient fibroblasts. The functional properties of the variant in NDUFA8 were also investigated using NDUFA8 knockout cells expressing wild-type or mutated NDUFA8 cDNA. These experiments further supported the pathogenicity of the variant in complex I assembly. This is the first report describing that the loss of NDUFA8, which has not previously been associated with mitochondrial disease, causes severe defect in the assembly of mitochondrial complex I, leading to progressive neurological and developmental abnormalities.

Background Surgery to prevent aspiration has complications related to tracheostomy tube, such as the trachea-brachiocephalic artery fistula. Glottic closure procedure makes tracheostoma at a position higher than the first ring of the trachea and theoretically has a potential to prevent such complications owing to a longer distance between the tip of tracheostomy tube and the tracheal membrane adjacent to the brachiocephalic artery. Our aim is to evaluate the safety of glottic closure in neurologically impaired patients by comparing outcomes with laryngotracheal separation. Methods This study is a single-center retrospective study from 2004 to 2019, using data of 15 and 12 patients who underwent glottic closure (GC) and laryngotracheal separation (LTS). The primary outcome was the incidence of postoperative complications induced by tracheostomy tube placement and adjustment of the tracheostomy tube position to prevent these complications, such as by converting to a length-adjustable tube and/or placing gauze between the skin and tube flange. Additionally, we analyzed the anatomical relationship between the tracheostomy tube tip and brachiocephalic artery and measured the distance between them using postoperative CT images. Results No patients in either group had trachea-brachiocephalic artery fistula. Erosion or granuloma formation occurred in 1 patient (7%) and 4 patients (33%) in the GC and LTS groups, respectively. Adjustment of the tracheostomy tube was needed in 2 patients (13%) and 6 patients (50%) in the GC and LTS groups. CT revealed a higher proportion of patients with the tracheostomy tube tip superior to the brachiocephalic artery in GC than LTS group. The mean tracheostoma-brachiocephalic artery distance was 40.8 and 32.4 mm in the GC and LTS groups. Conclusions Glottic closure reduces the risk of postoperative complications related to a tracheostomy tube. This may be due to the higher position of the tracheostoma at the level of the cricoid cartilage, increasing the distance between the tracheostoma and brachiocephalic artery.

Variants in the type IV collagen gene (We examinedPathogenicPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and

SummaryObjective Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. Methods Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. Significance Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.

Compared to the classical ketogenic diet (KD), the modified Atkins diet (MAD) and the low glycemic index treatment (LGIT) are more liberal and less restrictive diet therapies for the treatment of medication-resistant epilepsy. The MAD was first reported by Kossoff et al. in 2003, and gained global popularity with sufficient evidence in its efficacy reported recently in a controlled study. The LGIT was first reported by Pfeifer et al. in 2005, and its use has also become widespread. We reviewed the efficacy of both diet therapies in the treatment of medication-resistant epilepsy based on the evidence from previous literatures and our own clinical experience. From our experience, the LGIT was more liberal, tolerable, and dietetically balanced than the MAD. To find out which of these diets is most appropriate in different epilepsies and different patients, future controlled comparative studies on the efficacy, tolerability, and dietetic advantages between the MAD and the LGIT are necessary.