BACKGROUND The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders.We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. OBJECTIVE To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. METHODS We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to evaluate mitochondrial and peroxisome dynamics. RESULTS We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. CONCLUSIONS The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts.

Paraneoplastic neuropathy, including pruritis, remains a vexing problem as it often does not resolve even with successful treatment of cancer. Scrambler Therapy is a superficial form of neuromodulation that replaces the pain signal with “non-pain information” that is approved for chronic and neuropathic pain, with few side effects. We report here two cases of paraneoplastic neuropathy, one with additional pruritis, that both responded satisfactorily to Scrambler Therapy with no side effects.

Increases in blood concentrations of glucose induced by epinephrine, of lactate induced by epinephrine and isoproterenol, and of glycerol and insulin induced by isoproterenol in rats showed graded responses dependent on the dose of the catecholamines and were blocked also progressively by increasing doses of 5-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol), a new beta-adrenergic blocking agent. The ed50 estimated for these metabolic parameters, other than blood insulin, was 100–200 μg/kg of body wt for epinephrine and 10–20 μg/kg for isoproterenol, while the “corrected id50” for carteolol, reflecting the dissociation constant of the antagonist-receptor complex, was 1–3 μg/kg. It is concluded that the beta-adrenergic receptors of the same character concerning the affinity to agonists and antagonists mediate the increase of blood levels of these carbohydrate and lipid intermediary metabolites, and that the affinity of carteolol is one order higher than that of isoproterenol, which in turn is ten times higher than that of epinephrine. In contrast, much higher ed50 for isoproterenol and “corrected id50” for carteolol were obtained when hyperinsulinemia was used as a measure of beta action, suggesting that the beta-adrenergic receptor mediating pancreatic secretion of insulin is distinct in nature from the receptors involved in the control of carbohydrate and lipid metabolism. Comparison of the potency of carteolol with those of propranolol and pindolol showed that carteolol is the most potent beta-adrenergic blocking agent.

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.

Abstract Objective Mitochondrial DNA mutations are associated with an increased risk of heart disease. Whether an increased prevalence of cardiovascular disease is present in patients presenting with mitochondrial abnormalities on skeletal muscle biopsy remains unknown. This study was designed to determine the prevalence of cardiac conduction disease and structural heart disease in patients presenting with mitochondrial abnormalities on skeletal muscle biopsy. Methods This is a retrospective cohort study of 103 patients with mitochondrial abnormalities on skeletal muscle biopsy who were referred for evaluation of muscle weakness at a single tertiary care referral center from 2012 to 2018. Of these patients, 59 (57.3%) had an electrocardiogram available and were evaluated for the presence of conduction disease. An echocardiogram was available in 43 patients (42%) who were evaluated for the presence of structural heart disease. The prevalence of cardiac disease was compared to control cohort populations (Framingham and the Atherosclerosis Risk in Communities, ARIC cohorts). Results Mitochondrial abnormalities associated with cardiac conduction disease (defined as QRS duration ≥ 120 msec) were present in 8.9%, versus 2.0% (p < 0.001) in the Framingham population and 2.6% (p = 0.003) in the ARIC cohort. LV systolic dysfunction (LVEF ≤ 50%) was present in 11.6%, versus 3.6% (p < 0.01) in the Framingham and 3% (p < 0.01) in the ARIC populations. Left ventricular hypertrophy was present in 28.6%, versus 13.6% (p < 0.02) in the Framingham and 10.4% (p < 0.001) in the ARIC populations. Interpretation Given the increased prevalence of cardiovascular disease, patients with mitochondrial abnormalities on skeletal muscle biopsy should undergo routine cardiac screening with physical exam, electrocardiography, and cardiac imaging.

Background We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres. Methods WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays. Results Molecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1 . Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients. Conclusions Integrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.

Objective The primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures. Methods In this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures. Results Sixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32–65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3 (SD 97 cells/mm3, range 1–416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147–657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r = −0.344, p = 0.04) and sural nerve amplitude (r = −0.359, p = 0.004). Conclusions Both IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.

Background: The COVID-19 pandemic mandated rapid transition from face-to-face encounters to teleneurology visits. While teleneurology is regularly used in acute stroke care, its application in other branches of neurology was limited. Here we review how the recent pandemic has created a paradigm shift in caring for patients with chronic neurological disorders and how academic institutions have responded to the present need. Method: Literature review was performed to examine the recent changes in health policies. Number of outpatient visits and televisits in the Department of Neurology was reviewed from Yale University School of Medicine and Johns Hopkins School of Medicine to examine the road to transition to televisit. Results: The federal government and the insurance providers extended their supports during the COVID-19 pandemic. Several rules and regulations regarding teleneurology were revised and relaxed to address the current need. New technologies for video conferencing were incorporated. The transition to televisits went smoothly in both the institutions and number of face-to-face encounters decreased dramatically along with a rapid rise in televisits within 2 weeks of the declaration of national emergency. Conclusion and relevance: The need for "social distancing" during the COVID-19 pandemic has created a major surge in the number of teleneurology visits, which will probably continue for the next few months. It may have initiated a more permanent transition to virtual technology incorporated medical care.

Mitochondria play an essential role in cellular energy production and calcium homeostasis. Abnormalities in mitochondrial homeostasis and function are seen in several acquired as well as genetic neuropathies, emphasizing their prominent role in neuronal cell activities. Chronic infection with HIV, even when appropriately treated, is a risk factor for developing peripheral neuropathy. In this chapter, we discuss the way in which HIV infection, the resultant toxic viral products that are generated, and some of the viral inhibitors used in its treatment may lead to abnormal mitochondrial function. Of importance are the effects on mitochondrial DNA replication and the neurotoxic effects of the viral gp120 protein. One aspect of mitochondrial dysfunction that remains unexplored is the role of the interaction between mitochondria and the endoplasmic reticulum as a possible target of disruption in HIV neuropathy.

Rituximab is a chimeric monoclonal antibody that binds CD20 and causes the depletion of B-cell subsets. Although initially designed to treat lymphoma, it has found wide use in the management of various autoimmune conditions, including myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction. Treated myasthenia patients are often on an oral steroid-sparing agent. To determine the safety of stopping oral steroid-sparing agents at the initiation of rituximab therapy and its effectiveness we reviewed the records of 27 MG patients with rituximab, including 13 with anti-MuSK+ MG, 10 with anti-AChR+ MG, and 4 double seronegative MG patients. All patients that were on an oral steroid-sparing agent (21 of 27) were able to stop it, and they did not require re-introduction of the medication. Also, the daily prednisone dosage was significantly decreased in 20/24 patients across all three serotype groups. MGFA post intervention status analysis also showed 15/27 of all patients achieved minimal manifestation status or remission across all groups. Antibody titers decreased dramatically and promptly in anti-MuSK+ MG patients. Our data suggests that stopping oral steroid-sparing agents at initiation of rituximab therapy is safe. Also, our data indicates that rituximab is highly effective in the management of seropositive MG patients.

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus‐, and chemotherapy‐induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi‐center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease‐altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted‐omics methodologies.

Mutations in DRP2 (OMIM #300052) encoding dystrophin-related protein 2, a 957 amino acid protein, were identified in a single patient with X-linked Charcot-Marie-Tooth (CMT) disease and are associated with familial autism.1,2 DRP2 is predominantly expressed in the brain and spinal cord and functionally interacts with periaxin (PRX, OMIM #605725), a known causative CMT gene (OMIM #614895 and #145900), in the PRX-DRP2-dystroglycan (PDG) complex.3 The PDG complex supports and maintains Cajal bands, which are cytoplasmic extensions that run along the length of myelinated axons and are required for establishing a proper internodal length.4–6

Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1-78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum-shaping protein are well-known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely-related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c.119T > G, p.Met40Arg) in REEP2 at a highly-conserved residue very close to another known pathogenic missense change. This represents only the second autosomal dominant SPG72 missense mutation reported.

Spinocerebellar ataxia types 1 (SCA1, OMIM# 164400) and 8 (SCA8, OMIM# 608768) are autosomal dominant, inherited ataxias. SCA1 is caused by abnormal expansion of a CAG triplet repeat in the ATXN1 gene, while SCA8 results from CAG and complementary CUG expansions from a bidirectionally transcribed locus comprising the ATXN8OS and ATXN8 genes.1 In both cases, the expansions are thought to act as toxic gain-of-function mutations, although loss of normal protein function could also play a role. Although expansions in SCA1 have been clearly determined as pathogenic, those in SCA8 have been more difficult to study. Some investigators have suggested that very large expansions of repeats in SCA8 may not be pathogenic at all, since these might be unstable and in fact have been reported both in clinically affected and unaffected persons.2–6 To further complicate matters, pathogenic expansions in SCA1 along with SCA8 have been reported to coexist, just as for SCA1 and SCA6.7 Acknowledgment: The authors thank Elizabeth Hartnett for helping with patient scheduling.

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

The MAG gene encodes myelin-associated glycoprotein (MAG), an abundant protein involved in axon-glial interactions and myelination during nerve regeneration. Several members of a consanguineous family with a clinical syndrome reminiscent of Pelizaeus-Merzbacher disease and demyelinating leukodystrophy on brain MRI were recently found to harbor a homozygous missense p.Ser133Arg MAG mutation. Here, we report two brothers from a nonconsanguineous family afflicted with progressive cognitive impairment, neuropathy, ataxia, nystagmus, and gait disorder. Exome sequencing revealed the homozygous missense mutation p.Arg118His in MAG. This Arg118 residue in immunoglobulin domain 1 is critical for sialic acid binding, providing a compelling mechanistic basis for disease pathogenesis.