Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder, often leading to wheelchair dependence by age 13 with limited treatment options, largely relying on glucocorticosteroids. We assessed the efficacy and safety of vamorolone, a modified synthetic corticosteroid, for DMD. We performed a systematic review and meta-analysis using seven databases including prospective studies comparing vamorolone with glucocorticosteroids or placebo in DMD patients. We extracted data on efficacy and safety outcomes. We built fixed effects models to assess mean differences. (PROSPERO: CRD42023396908). Out of 210 identified records, two study reports were included in meta-analysis providing data from 210 patients. Vamorolone at 2.0 mg/kg/day was associated with improvement time to climb four stairs velocity (MD = 0.05 95

A 37-year-old patient with biopsy-proven neurosarcoidosis was admitted for a follow-up cranial MRI. Because of obstructive hydrocephalus at initial presentation, a ventriculoperitoneal shunt system had previously been implanted.

Maternally inherited mitochondrial diseases are caused by pathogenic mitochondrial (mt)DNA variants. Affecting individuals at any age, they are often multi-systemic and manifest extreme clinical variability. We have limited understanding of the cause of this heterogeneity, which makes disease diagnosis and prognosis exceptionally challenging. This is clearly demonstrated by disease caused by m.3243A>G, the most common pathogenic mtDNA variant. m.3243A>G can cause a severe syndrome characterised by mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), but individuals who carry m.3243A>G may be asymptomatic or manifest with any number of a range of phenotypes. There is strong evidence for the presence of nuclear factors that modify phenotype; we set out to characterise the nature of this nuclear involvement using genetic linkage analysis. We assembled a multi-centre cohort of well-characterised patients and their maternal relatives, comprising 76 pedigrees, and characterised the nuclear genetic landscape of m.3243A>G- related disease phenotypes using non-parametric genetic linkage analysis. We considered eight of the most common m.3243A>G-related phenotypes, accounted for known risk factors using logistic regression, and determined empirical significance using simulation to identify regions of the nuclear genome most likely to contain disease modifying variants. We identified significant genetic linkage to encephalopathy on chromosome 7q22, and suggestive regions for encephalopathy, stroke-like episodes and psychiatric involvement on chromosomes 1, 5, 6, 11 and 13. These findings suggest that these neurological features are likely to be influenced by a small number of nuclear factors with a relatively large effect size. In contrast, no linkage regions were identified for cerebellar ataxia, migraine, diabetes mellitus, hearing impairment or chronic progressive external ophthalmoplegia. The genetic architecture of the nuclear factors influencing disease related to m.3243A>G differs between phenotypes. Severe and cardinal neurological features of MELAS are likely to be strongly influenced by a small number of nuclear genes, whereas the nuclear influence over other phenotypic presentations is more likely to be polygenic and complex in nature, composed of a larger number of factors that each exert a small effect. These results will inform strategies for future studies to identify the genes and pathways that influence clinical heterogeneity in m.3243A>G-related disease, with the ultimate aim of better understanding disease development and progression. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was also supported by a Wellcome Career Re-entry Fellowship to S.J.P. (204709/Z/16/Z); the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z); the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1); the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust; the Lily Foundation; the Pathological Society; and the UK NHS Specialist Commissioners which funds the "Rare Mitochondrial Disorders of Adults and Children" Diagnostic Service in Newcastle upon Tyne. Funding for open access charge: Charity open access fund (COAF). The German network for mitochondrial disorders (mitoNET) is funded by the German Ministry of Education and Research (01GM1906A, 01GM1906B) and as part of a global registry initiative by the German Ministry of Education and Research and Horizon2020 through the E-Rare project GENOMIT (01GM1920A, 01GM1920B). The Centre of Pisa is partially supported by Telethon Grant GUP09004, Telethon-MITOCON grant GSP16001, RF-2016-02361495 and the EJPRD2019 project GENOMIT. MM from Pisa is member of the European Reference Networks on rare neuromuscular diseases (EURO NMD) and on rare neurological diseases (ERN RND). KAP is a Wellcome Trust fellow (219606/Z/19/Z). Exeter collaboration was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre and National Institute for Health and Care Research Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Wellcome Trust or the Department of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Newcastle and North Tyneside Research Ethics Committee (13/NE/0326) gave ethical approval for this work. Queen Square Research Ethics Committee, London, UK (09/H0716/76) gave ethical approval for this work. Ethics committee of the Technical University Munich (200/15 S-SR) gave ethical approval for this work. North Wales ethics committee (17/WA/0327) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data available upon request to the authors

Purpose of review Tremor is a common neurological symptom with a plethora of potential etiologies. Apart from physiological tremor, the vast majority of tremor syndromes are linked to a pacemaker in the central nervous system (CNS) or, less common, in the peripheral nervous system. Myogenic tremor is a novel tremor entity, first reported in 2019 and believed to originate in the muscle itself. In this review, we describe the clinical properties of myogenic tremor and discuss its presumed pathogenesis on the basis of all of the patient cases published so far. Recent findings Myogenic tremor manifests itself as a high frequency, postural, and kinetic tremor with onset in infancy. To date, only myopathies affecting the contractile elements, in particular myosin and a myosin-associated protein, have been recognized to feature myogenic tremor. The generator of the tremor is believed to be located in the sarcomere, with propagation and amplification of sarcomeric oscillatory activity through CNS reflex loops, similar to neuropathic tremor. Summary True myogenic tremor must be distinguished from centrally mediated tremor due to myopathies with central nervous system involvement, i.e., mitochondrial myopathies or myotonic dystrophies. The presence of myogenic tremor strongly points toward a sarcomere-associated mutation and may thus be a valuable clinical tool for the differential diagnosis of myopathies.

Purpose: Neurofilament light chain in serum (sNfL) has been suggested as a biomarker for the assessment of neuroaxonal damage. Since NfL are not expressed in muscle, elevated sNfL in patients with primary myopathies suggest additional nervous system involvement. To verify this hypothesis, we measured sNfL in a series of patients with myopathies.Methods: sNfL were determined in 62 patients with molecular proven primary myopathies in whom some nervous system involvement may be predicted: myotonic dystrophy type I and II (DM I, II) and mitochondrial disease. In addition, sNfL were measured in 8 patients with facioscapulohumeral muscular dystrophy (FSHD) and in a disease control group caused by genetic defects exclusively expressed in muscle.Results: sNfL values were significantly elevated in the DM I, the DM II and the mitochondrial group, with FSHD patients showing the lowest sNfL elevations. sNfL levels in the disease control group were not different from the healthy controls. A significant correlation between repeat length and sNfL levels was found in the DM I patients, but not in the DM II patients. Mitochondrial patients with encephalopathy showed significantly higher sNfL concentrations compared to patients with only muscular symptoms.Conclusion: sNfL levels are elevated in myopathies with, based on the underlying molecular defect or clinical features, established nervous system involvement, i.e., myotonic dystrophies and mitochondrial disorders. sNfL were also raised in FSHD, where involvement of the nervous system is not usually clinically apparent. Thus, sNfL concentrations may serve as a biomarker for additional neuronal damage in primary myopathies.

Background Limb–girdle muscular dystrophy (LGMD) is a genetically and clinically heterogeneous group of rare muscular dystrophies. Subtype 2A (LGMD2A) also known as “calpainopathy” is an inherited autosomal recessive gene defect. Cardiac dysfunction is common in several forms of LGMD. Cardiac involvement in LGMD2A, however, is not clear. The aim of this study was to perform cardiac magnetic resonance (CMR)-based strain analysis in LGMD2A patients, as this is a diagnostic parameter of subclinical cardiac involvement and a powerful independent predictor of mortality. We conducted the largest prospective cardiac magnetic resonance study to date, including 11 genetically verified LGMD2A patients and 11 age- and sex-matched control subjects and performed CMR-based strain analysis of the left and right ventricles. Results Left and right global longitudinal strain (GLS) were not significantly different between the two groups and within normal reference ranges (left ventricle: control − 21.8 (5.1) % vs. patients − 22.3 (3.2) %, p = 0.38; right ventricle: control − 26.3 (7.2) % vs. patients − 26.8 (5.8) %, p = 0.85). Also, global circumferential and radial strains did not significantly differ between the two groups ( p = 0.95 and p = 0.86, respectively). LGMD2A patients did not show relevant amounts of late gadolinium enhancement (LGE) or malignant ventricular arrhythmias. Conclusions No evidence of even subtle cardiac dysfunction is evident form CMR-based strain analysis in LGMD2A patients. Malignant ventricular arrhythmias were not detected. Thus, in case of non-pathological initial echocardiographic and electrocardiographic examination, a less frequent or even no cardiac follow-up may be acceptable in these patients. However, if there are signs and symptoms that suggest an underlying cardiac condition (e.g. palpitations, angina, shortness of breath), this approach needs to be individualized to account for the unknown.

BACKGROUND:Unlike infections with mycobacteria, reports of unusual viral infections in interferon-gamma-receptor (IFNγR) deficient patients are scarce. Therefore, discussion about increased susceptibility to viral infections in these patients is ongoing.CASE PRESENTATION:We describe a 51-year-old male with dominant partial interferon-gamma-receptor-1 (IFNγR1)-deficiency and recurrent Herpes simplex 2 meningoencephalitis as well as other viral reactivations since childhood.CONCLUSIONS:This case further confirms an enhanced risk for viral disease in IFNγR-deficient patients and a role of interferon gamma for human antiviral defense.

Background Hepatitis E infection affects over 20 million people worldwide. Reports of neurological manifestations are largely limited to the peripheral nervous system. We report a middle-aged genotype 3c male patient with acute hepatitis E virus (HEV) infection and severe neurological deficits with evidence of multiple disseminated inflammatory lesions of the central nervous system. Case presentation A 42-year-old male patient presented to our emergency department with musculoskeletal weakness, bladder and bowel retention, blurred vision and ascending hypoesthesia up to the level of T8. Serology showed elevated liver enzymes and positive IgM-titers of hepatitis E. Analysis of cerebrospinal fluid (CSF) showed mild pleocytosis and normal levels of glucose, lactate and protein. HEV-RNA-copies were detected in the CSF and stool. Within 3 days after admission the patient became paraplegic, had complete visual loss and absent pupillary reflexes. MRI showed inflammatory demyelination of the optic nerve sheaths, multiple subcortical brain regions and the spinal cord. Electrophysiology revealed axonal damage of the peroneal nerve on both sides with absent F-waves. Treatment was performed with methylprednisolone, two cycles of plasma exchange (PLEX), one cycle of intravenous immunoglobulins (IVIG) and ribavirin which was used off-label. Liver enzymes normalized after 1 week and serology was negative for HEV-RNA after 3 weeks. Follow-up MRI showed progressive demyelination and new leptomeningeal enhancement at the thoracic spine and cauda equina 4 weeks after admission. Four months later, after rehabilitation was completed, repeated MRI showed gliotic transformation of the spinal cord without signs of an active inflammation. Treatment with rituximab was initiated. The patient remained paraplegic and hypoesthesia had ascended up to T5. Nevertheless, he regained full vision. Conclusions Our case indicates a possible association of acute HEV infection with widespread disseminated central nervous system inflammation. Up to now, no specific drugs have been approved for the treatment of acute HEV infection. We treated our patient off-label with ribavirin and escalated immunomodulatory therapy considering clinical progression and the possibility of an autoimmune response targeting nerve cell structures. While response to treatment was rather limited in our case, detection of HEV in patients with acute neurological deficits might help optimize individual treatment strategies.

Fatty acids and glucose are the main bioenergetic substrates in mammals that are alternatively used during the transition between fasting and feeding. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data show that Aldh2+/mice exhibits impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in CoQ biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation. 46 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 August 2019 doi:10.20944/preprints201908.0069.v1 © 2019 by the author(s). Distributed under a Creative Commons CC BY license.

OBJECTIVE:To define a distinct, dominantly inherited, mild skeletal myopathy associated with prominent and consistent tremor in two unrelated, three-generation families.METHODS:Clinical evaluations as well as exome and panel sequencing analyses were performed in affected and nonaffected members of two families to identify genetic variants segregating with the phenotype. Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations.RESULTS:Two novel missense mutations in MYBPC1 (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families. MYBPC1 encodes slow myosin binding protein-C (sMyBP-C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments. The Y247H and E248K mutations are located in the NH2 -terminal M-motif of sMyBP-C. Both mutations result in markedly increased binding of the NH2 terminus to myosin, possibly interfering with normal cross-bridge cycling as the first muscle-based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology.INTERPRETATION:Here, we link two novel missense mutations in MYBPC1 with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as "myogenic tremor." ANN NEUROL 2019.

Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data showed that Adck2+/- mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.

Neurometabolic disorders are often inherited and complex disorders that result from abnormalities of enzymes important for development and function of the nervous system. Recently, biallelic mutations in NAXE ( APOA1BP ) were found in patients with an infantile, lethal, neurometabolic disease. Here, exome sequencing was performed in two affected sisters and their healthy parents. The best candidate, NAXE , was tested for replication in exome sequencing data from 4351 patients with neurodevelopmental disorders. Quantitative RT-PCR, western blot and form factor analysis were performed to assess NAXE expression, protein levels and to analyze mitochondrial morphology in fibroblasts. Vitamin B3 was administered to one patient. Compound heterozygous missense (c.757G>A: p.Gly253Ser) and splicing (c.665-1G>A) variants in NAXE were identified in both affected sisters. In contrast to the previously reported patients with biallelic NAXE variants, our patients showed a milder phenotype with disease onset in early adulthood with psychosis, cognitive impairment, seizures, cerebellar ataxia and spasticity. The symptoms fluctuated. Additional screening of NAXE identified three novel homozygous missense variants (p.Lys245Gln, p.Asp218Asn, p.Ile214Val) in three patients with overlapping phenotype (fluctuating disease course, respiratory insufficiency, movement disorder). Lastly, patients with the c.665-1G>A splicing variant showed a significant reduction of NAXE expression compared to control fibroblasts and undetectable NAXE protein levels compared to control fibroblasts. Based on the metabolic pathway, vitamin B3 and coenzyme Q treatment was introduced in one patient in addition to antiepileptic treatment. This combination and avoidance of triggers was associated with continuous motor and cognitive improvement. The NAXE variants identified in this study suggest a loss-of-function mechanism leading to an insufficient NAD(P)HX repair system. Importantly, symptoms of patients with NAXE variants may improve with vitamin B3/coenzyme Q administration.

To develop specific diagnostic ultrasound (US) models for hereditary motor and sensory neuropathies (HMSN) in patients with primarily demyelinating or axonal polyneuropathies (PNP) according to standard nerve conduction studies (NCS) criteria.

The objective of this study is to compare the diagnostic accuracy of nerve ultrasound (US) and nerve conduction studies (NCS) for acquired non-entrapment peripheral neuropathies (PNP) and hereditary motor and sensory neuropathies (HMSN) in a routine clinical setting. The methods are based on a single-center, prospective, examiner-blinded cross-sectional study on three subject groups of healthy controls, PNP (both enrolled by a consecutive recruitment strategy), and HMSN patients (convenience sample). A clinical reference standard based on the neuropathy impairment (NIS) and neuropathy symptoms scores (NSS) was used for PNP as the external validation criterion. Diagnostic accuracy was assessed by receiver-operating curve (ROC) analyses of single-nerve measurements and logit models. Of a total of 676 consecutively screened subjects, 107 (15.8 %) were recruited, of which 36 (33.6 %) had a PNP. HMSN group consisted of 53 subjects (30 subjects (56.6 %) with genetic confirmation). AUCs of best diagnostic logit models to distinguish between controls and PNP patients were 0.86 for US and 0.97 for NCS corresponding to an equivalent specificity [US 93 % (95 % CI: 83–98 %), NCS 89 % (95 % CI: 78–95 %)], but inferior sensitivity of US [US 56 % (95 % CI: 35–74 %), NCS 97 % (95 % CI: 84–100 %)]. For differentiation between PNP and HMSN, both methods had equivalent AUCs of 0.95 corresponding to similar sensitivities/specificities. Simpler diagnostic models based on measurement protocols feasible for clinical routine revealed similar diagnostic accuracies. US has an inferior sensitivity than NCS for acquired PNP, but comparable specificity. For identification of HMSN in a PNP population, US and NCS show comparable performance.