Search

Background: The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. Methods: Whole‐exome sequencing (WES) and long‐read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. Results: We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. Interpretation: These phenotypes enrich the class of features associated with NOTCH2NLC‐related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype–genotype relationship. Methods: Patient 1 is a 23‐year‐old man with congenital foot deformity and life‐long distal muscle weakness and atrophy. Patient 2 is a 48‐year‐old woman with adult‐onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole‐exome sequencing followed by functional study of identified variants. Results: Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α‐tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α‐tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. Interpretation: We identify two novel DCTN1 mutations causing different phenotypes: (1) early‐onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1‐related spectrum is still expanding. [ABSTRACT FROM AUTHOR]

Objective: GDP‐mannose pyrophosphorylase B (GMPPB) related phenotype spectrum ranges widely from congenital myasthenic syndrome (CMS), limb‐girdle muscular dystrophy type 2T (LGMD 2T) to severe congenital muscle‐eye‐brain syndrome. Our study investigates the clinicopathologic features of a patient with novel GMPPB mutations and explores the pathogenetic mechanism. Methods: The patient was a 22‐year‐old woman with chronic proximal limb weakness for 9 years without cognitive deterioration. Weakness became worse after fatigue. Elevated serum creatine kinase and decrements on repetitive nerve stimulation test were recorded. MRI showed fatty infiltration in muscles of lower limbs and shoulder girdle on T1 sequence. Open muscle biopsy and genetic analysis were performed. Results: Muscle biopsy showed myogenic changes. Two missense mutations in GMPPB gene (c.803T>C and c.1060G>A) were identified in the patient. Western blotting and immunostaining showed GMPPB and α‐dystroglycan deficiency in the patient's muscle. In vitro, mutant GMPPB forming cytoplasmic aggregates completely colocalized with microtubule‐associated protein 1 light chain 3‐II (LC3‐II), a classical marker of autophagosome. Degradation of GMPPB was accompanied by an upregulation of LC3‐II, which could be restored by lysosomal inhibitor leupeptin. Interpretation: We identified two novel GMPPB mutations causing overlap phenotype between LGMD 2T and CMS. We provided the initial evidence that mutant GMPPB colocalizes with autophagosome at subcellular level. GMPPB mutants degraded by autophagy‐lysosome pathway is associated with LGMD 2T. This study shed the light into the enzyme replacement which could become one of the therapeutic targets in the future study. [ABSTRACT FROM AUTHOR]