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ABSTRACTMyotonia congenita (MC) is a rare hereditary muscle disease caused by variants in the CLCN1 gene. Currently, the correlation of phenotype-genotype is still uncertain between dominant-type Thomsen (TMC) and recessive-type Becker (BMC). The clinical data and auxiliary examinations of MC patients in our clinic were retrospectively collected. Electromyography was performed in 11 patients and available family members. Whole exome sequencing was conducted in all patients. The clinical and laboratory data of Chinese MC patients reported from June 2004 to December 2022 were reviewed. A total of 11 MC patients were included in the study, with a mean onset age of 12.64 ± 2.73 years. The main symptom was muscle stiffness of limbs. Warm-up phenomenon and percussion myotonia were found in all patients. Electromyogram revealed significant myotonic charges in all patients and two asymptomatic carriers, while muscle MRI and biopsy showed normal or nonspecific changes. Fourteen genetic variants including 6 novel variants were found in CLCN1. Ninety-eight Chinese patients were re-analyzed and re-summarized in this study. There were no significant differences in the demographic data, clinical characteristics, and laboratory findings between 52 TMC and 46 BMC patients. Among the 145 variants in CLCN1, some variants, including the most common variant c.892 G>A, could cause TMC in some families and BMC in others. This study expanded the clinical and genetic spectrum of Chinese patients with MC. It was difficult to distinguish between TMC and BMC only based on the clinical, laboratory, and genetic characteristics.

Background: Primary serine deficiency disorders have a broad range of the phenotypic spectrum. As an inborn error of metabolism, individuals with severe phenotype may be easily recognized with Neu-Laxova syndrome. However, late-onset mild phenotypes may be underdiagnosed and will lead to disastrous consequences due to treatment delays.Materials and Methods: Clinical features of patients with serine deficiency disorders were summarized in two unrelated patients. Skin and sural nerve biopsies were conducted on the patients. Whole exome sequencing (WES) was performed in the index patients. Sanger sequencing was used to analyze family cosegregation.Results: Patient 1 was a 19-year-old male presenting with infancy-onset ichthyosis and juvenile-onset neuropathy. Patient 2 was a 17-year-old male manifesting childhood-onset ichthyosis and juvenile-onset neuropathy. Except for nystagmus, no other developmental or neurodegenerative disorders were found in the patients. Electrophysiological studies indicated a severe sensorimotor axonal neuropathy with a possible demyelinating component. High-dose oral L-serine and glycine completely alleviated skin lesions and only slightly improved neuropathy symptoms. Skin biopsies showed typical features consistent with ichthyosis and severe loss of unmyelinated axons. Sural biopsies revealed a severe loss of axons and a few thinly myelinated fibers. WES found the same homozygous variant c.43G > C (p.A15P) in the PSAT1 gene, which was cosegregated in the two families.Conclusions: The skin and nervous system may be the main affected targets in serine deficiency disorders. Our patients show a more simple and mild phenotype of PSAT1-related serine deficiency disorder. The pathological changes and regenerative ability of skin and peripheral nerves determine their response to serine supplements.

Abstract Introduction Mutations in the GFPT1 gene are associated with a particular subtype of congenital myasthenia syndrome (CMS) called limb‐girdle myasthenia with tubular aggregates. However, not all patients show tubular aggregates in muscle biopsy, suggesting the diversity of myopathology should be further investigated. Methods In this study, we reported two unrelated patients clinically characterized by easy fatigability, limb‐girdle muscle weakness, positive decrements of repetitive stimulation, and response to pyridostigmine. The routine examinations of myopathology were conducted. The causative gene was explored by whole‐exome screening. In addition, we summarized all GFPT1‐related CMS patients with muscle biopsy in the literature. Results Pathogenic biallelic GFPT1 mutations were identified in the two patients. In patient one, muscle biopsy indicated vacuolar myopathic changes and atypical pathological changes of myofibrillar myopathy characterized by desmin deposits, Z‐disc disorganization, and electronic dense granulofilamentous aggregation. In patient two, muscle biopsy showed typical myopathy with tubular aggregates. Among the 51 reported GFPT1‐related CMS patients with muscle biopsy, most of them showed tubular aggregates myopathy, while rimmed vacuolar myopathy, autophagic vacuolar myopathy, mitochondria‐like myopathy, neurogenic myopathy, and unspecific myopathic changes were also observed in some patients. These extra‐synaptic pathological changes might be associated with GFPT1‐deficiency hypoglycosylation and altered function of muscle‐specific glycoproteins, as well as partly responsible for the permanent muscle weakness and resistance to acetylcholinesterase inhibitor therapy. Conclusions Most patients with GFPT1‐related CMS had tubular aggregates in the muscle biopsy, but some patients could show great diversities of the pathological change. The myopathological findings might be a biomarker to predict the prognosis of the disease.

Abstract Background Benign monomelic amyotrophy of lower limb (BMALL) is a neurogenic syndrome representing an unclear field. Further studies might be helpful to elucidate uncertainties regarding causation, outcome, and the risk of progression to amyotrophic lateral sclerosis (ALS). Methods According to the inclusion and exclusion criteria, 37 patients with BMALL were retrospectively collected in three neuromuscular centers from January 2012 to October 2018. The detailed medical data were summarized. Multiple laboratory tests were examined. Routine electrophysiological examinations, muscle MRI of lower limbs, and muscle biopsy were conducted. Results The cohort included 24 male and 13 female cases with median age of onset 47 years. Muscle MRI revealed that the distribution of involved muscles matched with the extent of fat infiltration, so the pattern muscle atrophy can be divided into the following four types: six patients with thigh atrophy (type I), 14 patients with leg atrophy (type II); 10 patients with disproportionate atrophy in both thigh and leg (type III); and seven patients with well‐proportionate atrophy in both thigh and leg (type IV). Electrophysiological findings showed neurogenic pattern, spontaneous activity, and abnormal H reflex, which suggested a disorder of spinal anterior horn cell in the patients with types I‐III. However, no electrophysiological abnormalities were found in the patients with type IV. Muscle pathology varied from almost normal pattern to advanced neurogenic pattern in nine biopsied patients. Follow‐up showed that two patients with type II developed to ALS four years later, and all patients with type IV were in stable condition without any complaints. Conclusion Muscle MRI was useful to exactly localize the distribution of involved muscles in BMALL patients. The distribution of atrophic muscles can be roughly divided into four types based on the MRI features. The classification of distributing types might be as an indicator for the prognosis of BMALL.