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Introduction/aims: Oculopharyngodistal myopathy type 4 (OPDM4) arises from a CGG repeat expansion in the 5' UTR of the RILPL1 gene. Reported cases of OPDM4 have been limited. The aim of this study was to investigate the clinical and myopathological characteristics of OPDM4 patients with advanced disease., Methods: We assessed a total of 8 affected and 12 unaffected individuals in an OPDM4 family with autosomal dominant inheritance. Muscle biopsy tissue from the proband underwent histological, enzyme histochemical, and immunohistochemical stains, and electron microscopy analysis. Whole exome sequencing and repeat primer PCR (RP-PCR) were conducted to investigate underlying variants., Results: OPDM4 patients displayed a progressive disease course. Most experienced lower limb weakness and diminished walking ability in their 20s and 30s, followed by ptosis, ophthalmoplegia, swallowing difficulties, and dysarthria in their 30s to 50s, By their 50s to 70s, they became non-ambulatory. Muscle magnetic resonance imaging (MRI) of the proband in advanced disease revealed severe fatty infiltration of pelvic girdle and lower limb muscles. Biopsied muscle tissue exhibited advanced changes typified by adipose connective tissue replacement and the presence of multiple eosinophilic and p62-positive intranuclear inclusions. Immunopositivity for the intranuclear inclusions was observed with anti-glycine antibody and laboratory-made polyA-R1 antibody. RP-PCR unveiled an abnormal CGG repeat expansion in the 5' UTR of the RILPL1 gene., Discussion: The clinical and radiological features in this family broaden the phenotypic spectrum of OPDM4. The presence of intranuclear inclusions in the proliferative adipose connective tissues of muscle biopsy specimens holds diagnostic significance for OPDM4 in advanced disease., (© 2024 Wiley Periodicals LLC.)

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., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Mutations in the fused in sarcoma (FUS) gene have been associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor. Among the FUS mutations, p.P525L as a hot spot variant has been reported in more than 20 patients with ALS. Apart from the typical ALS phenotype, patients with p.P525L mutation exhibit some atypical symptoms. However, movement disorders related to p.P525L mutation have not been emphasized currently., Methods: Two unrelated patients with ALS were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through next-generation sequencing. Muscle biopsies were performed on the 2 patients. Muscle samples were stained according to standard histological and immunohistochemical procedures., Results: The first patient presented with juvenile-onset neurogenic weakness and wasting and simultaneously had dropped head, ophthalmoplegia, tremor, involuntary movements, and cognitive impairments. The second patient showed a typical ALS phenotype and prominent adventitious movements. Genetic screening disclosed de novo p.P525L FUS mutation in the 2 patients by family cosegregation analysis. Muscle biopsy showed neurogenic patterns and numerous lipid droplets aggregating in the fibers., Conclusion: Apart from the typical ALS phenotype, patients with p.P525L mutation in the FUS gene can present with great clinical heterogeneity including multiple movement disorders. Numerous lipid droplets in muscle fibers indicate that skeletal muscle is likely an important therapeutic target for ALS., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)