Synaptotagmin-2-related disease is an ultrarare entity, characterized by distal muscle atrophy in the lower limbs, foot deformities and, in some cases, neonatal hypotonia. Most mutations are concentrated in the C2B domain, critical for the protein's function. Here, our objective is to review clinical, electrophisiological and pathological aspects of this disease. We describe a previously unreported variant, comparing it with another 27 cases described in the literature. A 14-year-old boy was born with neonatal hypotonia, weak cry, and dysphonia. During childhood, he had recurrent respiratory infections, delayed motor development, and developed glaucoma. Creatine phosphokinase level was 501 U/L; EMG showed reduced compound muscle action potential, myopathic findings, and incremental response. A comprehensive next-generation sequence panel revealed a homozygous variant in the SYT2 gene. The data summarized here and our case provide a general characterization of the phenotypic spectrum of SYT2-related disease and point out to its electrophysiological and pathological features. We discuss the intriguing aspects of a neuromuscular junction disease considered as a distal hereditary motor neuropathy.

The review begins with epidemiology studies that show an increased incidence of later onset myasthenia gravis (MG) and higher short-term mortality rates, especially in females, compared with the general population in Denmark. In the United States, a study showed increased mortality especially in older patients, and there was racial disparity. In France, a study showed higher mortality with male gender, older age, and higher comorbidities. Economic burden is addressed in another article. Regarding clinical features, light sensitivity in MG is discussed along with differentiating thyroid eye disease symptoms and signs from those of ocular MG. MG-specific measures are highlighted with consensus recommendations for their use. Several articles contain data regarding diagnostic laboratory assays and test sensitivity and specificity among other measures. The role of thymectomy in older patients with MG is considered. The medical treatment section addresses corticosteroid regimens, intravenous immunoglobulin as maintenance therapy, a phase 3 study of the recently approved neonatal Fc receptor (FcRN) blocker nipocalimab, use of complement inhibitors and FcRN blockers in general, regimens for efgartigimod, and positive studies on the interleukin-16 receptor monoclonal antibody (Ab) satralizumab and the CD19 B-cell-depleting monoclonal Ab inebilizumab.

To describe a 51-year-old woman with early-onset weakness and foot deformities carrying a biallelic truncating mutation in the VWA1 gene. The patient underwent laboratory tests, nerve conduction studies with electromyography, muscle magnetic resonance imaging, muscle biopsy, and genetic testing. Neurophysiological studies and biopsy revealed both myopathic and neuropathic features. Muscle magnetic resonance imaging showed a distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies. Whole-exome sequencing identified a homozygous pathogenic variant in VWA1, which encodes an extracellular matrix protein found in the basement membranes of nerves and muscles. Recently, truncating mutations in VWA1 have been associated with previously unsolved neuromyopathy cases. In one of these reports, as in the current case, the MRI pattern mimicked that of type VI collagen disorders. Biallelic VWA1 mutations may account for some genetically undiagnosed cases of neuropathy with myopathic features.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare, yet treatable, disorder of fatty acid β-oxidation with clinical presentations ranging from neonatal to very-late-onset forms. Very-late-onset MADD often has no identifiable genetic mutations and has been linked to sertraline exposure. We report a case of very late-onset MADD with negative genetic testing, potentially associated with sertraline use. A 75-year-old woman presented with 3-year history of progressive, proximal-predominant weakness, dysphagia, and dysarthria. Examination revealed severe axial and proximal-predominant limb weakness. Laboratory studies showed elevation of multiple acylcarnitines. Muscle biopsy demonstrated a lipid storage myopathy. Comprehensive genetic testing was negative. Sertraline use was identified as a potential trigger. Treatment with riboflavin, coenzyme Q10, and levocarnitine, along with discontinuation of sertraline, led to rapid clinical improvement within weeks. This case supports the recent findings that sertraline can be associated with very-late-onset MADD. Neurologists should maintain a high index of suspicion for MADD in sertraline-treated patients with unexplained weakness because prompt initiation of riboflavin is crucial for strength recovery.

X-linked Charcot-Marie-Tooth disease Type 1 (CMTX1), caused by gap junction beta-1 (GJB1) mutations, is the second most common form of CMT. Patients present with length-dependent sensorimotor polyneuropathy and split hand syndrome. Males are more severely affected; females show variable symptoms because of skewed X-inactivation. This study reclassifies a GJB1 variant of uncertain significance as pathogenic using American College of Medical Genetics criteria. A family with neurologic symptoms underwent clinical evaluation, electrodiagnostic studies, genetic testing, and imaging. Affected individuals exhibited a sensorimotor polyneuropathy in an X-linked inheritance pattern with males having earlier, more severe symptoms. Characteristic findings included split hand syndrome and the suggestion of stroke-like episodes. Genetic testing revealed a GJB1 c.841T>C p.(Ser281Pro) variant. Analysis met American College of Medical Genetics criteria (1 strong, 3 moderate, 1 supporting) for pathogenicity. The Ser281Pro GJB1 variant meets pathogenic criteria for CMTX1, extending known pathogenic regions beyond the C-terminal Arg220 codon.