Objective:To summarize the clinical manifestations, electrophysiological, muscle magnetic resonance imaging (MRI), pathological, and genetic characteristics of 8 patients with Emery-Dreifuss muscular dystrophy (EDMD) to improve the recognition and diagnosis of EDMD.Methods:Eight patients with EDMD confirmed by gene analysis admitted to Hebei Medical University Third Hospital from 2011 to 2022 were enrolled. The detailed clinical symptoms, neurophysiological examination, electrophysiological changes (electromyography and electrocardiography), skeletal muscle MRI characters, skeletal muscle pathological features and gene mutations were analyzed retrospectively.Results:The age of onset ranged from 2.0 to 6.0 (3.6±1.2) years. All patients had insidious onset and progressive development. Muscle weakness was the first symptom for 7 cases that manifested as difficulty in squatting and walking up stairs. Later, spinal ankylosis and joint contracture occurred. One patient had scoliosis as the first symptoms. Abnormal electrocardiogram was found in 4 cases. The electromyography of all patients showed myogenic damage. Muscle biopsy demonstrated dystrophic features in 1 patient, and other myopathic features, including a variation in muscle fiber size, a marked increase in internal nuclei, and, smaller diameter of typeⅠfibers. Next-generation sequencing result showed that 6/8 cases carried 4 LMNA heterozygous mutations (c.1583C>G, c.1357C>T, c.148C>T, c.1336A>G); 1/8 case carried EMD hemizygous mutation (c.501C>G); 1/8 carried SYNE1 heterozygous mutation (c.4364G>A). Conclusions:EDMD has highly clinical and genetical heterogeneity. The onset age is usually in childhood. The first symptom is characterized by weakness of lower limbs and abnormal walking posture. Electromyography shows myogenic lesion. Skeletal muscle MRI shows selective fat infiltrations. Muscle biopsy pathology lacks characteristic pathological findings. It is difficult to make diagnosis and differential diagnosis by clinical manifestations and auxiliary examination in the early stage of the disease. The second generation sequencing technology can improve the early diagnosis rate of EDMD.

Introduction GNE myopathy is an autosomal recessive distal myopathy caused by a biallelic mutation in UDP-N-acetylglucosamine 2-epomerase/N-acetylmannosamine kinase. In this study, we discuss the clinical features, pathological characteristics, genetic profiles, and atypical clinical manifestations of 22 Chinese GNE patients. Materials and methods Retrospective analysis was performed for GNE myopathy patients at our institute between 2005 and 2021. Histopathological analysis and gene testing were done according to standard protocols. Results Molecular analysis revealed 14-reported and 7 novel mutations, including c.125G > A (p.P42Q), c.226G > A (p.V76I), c.970C > G (p.H324D), c.155A > G (p.D52G), c.1055G > A (p.R352H), c.1064G > A (p.G355E), and c.491 T > C (p.I164T) in GNE. D207V was the most frequent mutation showing an allele frequency of 25%. A total of 21 patients presented classic clinical manifestation, and only 1 patient had signs of proximal muscle weakness. A patient containing p.V603L and p.R160X mutations showed idiopathic thrombocytopenia and distal weakness. There were 4 female patients who experienced rapid deterioration after pregnancy. Discussion Our study revealed 7 novel mutations in GNE, where p.D207V was shown as a potential hotspot mutation in Chinese patients. Idiopathic thrombocytopenia should be a concern in GNE myopathy patients. Twenty-seven percent of female patients experienced rapid deterioration during pregnancy or after delivery.

Background Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis. Methods Twenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented. Results A total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe’s disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained. Conclusions HSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis.

Objective Oculopharyngodistal myopathy (OPDM) is an adult‐onset neuromuscular disease characterized by progressive ptosis, dysarthria, ophthalmoplegia, and distal muscle weakness. Recent studies revealed that GGC repeat expansions in 5′‐UTR of LRP12 , GIPC1 , and NOTCH2NLC are associated with OPDM. Despite these advances, approximately 30% of OPDM patients remain genetically undiagnosed. Herein, we aim to investigate the genetic basis for undiagnosed OPDM patients in two unrelated Chinese Han families. Methods Parametric linkage analysis was performed. Long‐read sequencing followed by repeat‐primed polymerase chain reaction and amplicon length polymerase chain reaction were used to determine the genetic cause. Targeted methylation sequencing was implemented to detect epigenetic changes. The possible pathogenesis mechanism was investigated by quantitative polymerase chain reaction, immunoblotting, RNA fluorescence in situ hybridization, and immunofluorescence staining of muscle biopsy samples. Results The disease locus was mapped to 12q24.3. Subsequently, GGC repeat expansion in the promoter region of RILPL1 was identified in six OPDM patients from two families, findings consistent with a founder effect, designated as OPDM type 4. Targeted methylation sequencing revealed hypermethylation at the RILPL1 locus in unaffected individuals with ultralong expansion. Analysis of muscle samples showed no significant differences in RILPL1 mRNA or RILPL1 protein levels between patients and controls. Public CAGE‐seq data indicated that alternative transcription start sites exist upstream of the RefSeq‐annotated RILPL1 transcription start site. Strand‐specific RNA‐seq data revealed bidirectional transcription from the RILPL1 locus. Finally, fluorescence in situ hybridization/immunofluorescence staining showed that both sense and antisense transcripts formed RNA foci, and were co‐localized with hnRNPA2B1 and p62 in the intranuclear inclusions of OPDM type 4 patients. Interpretation Our findings implicate abnormal GGC repeat expansions in the promoter region of RILPL1 as a novel genetic cause for OPDM, and suggest a methylation mechanism and a potential RNA toxicity mechanism are involved in OPDM type 4 pathogenesis. ANN NEUROL 2022;92:512–526