No abstract

Hereditary neuromuscular disorders (NMDs) are a broad group of clinically heterogeneous disorders with varying inheritance patterns, that are associated with over 500 implicated genes. In the context of a highly consanguineous Pakistani population, we expect that autosomal recessive NMDs may have a higher prevalence compared with patients of European descent. This is the first study to offer a detailed description of the spectrum of genes causing hereditary NMDs in the Pakistani population using NGS testing. To study the clinical and genetic profiles of patients presenting for evaluation of a hereditary neuromuscular disorder. This is a retrospective chart review of patients seen in the Neuromuscular Disorders Clinic and referred to the Genetics Clinic with a suspected hereditary neuromuscular disorder, between 2016 and 2020 at the Aga Khan University Hospital, Karachi and Mukhtiar A. Sheikh Hospital, Multan, Pakistan. The genetic testing for these patients included NGS‐based single gene sequencing, NGS‐based multi‐gene panel and whole exome sequencing. In a total of 112 patients studied, 35 (31.3%) were female. The mean age of onset in all patients was 14.6 years (SD ±12.1 years), with the average age at presentation to the clinic of 22.4 years (SD ±14.10 years). Forty‐seven (41.9%) patients had a positive genetic test result, 53 (47.3%) had one or more variants of uncertain significance (VUS), and 12 (10.7%) had a negative result. Upon further genotype–phenotype correlation and family segregation analysis, the diagnostic yield improved, with 59 (52.7%) patients reaching a diagnosis of a hereditary NMD. We also report probable founder variants in COL6A2, FKTN, GNE, and SGCB, previously reported in populations that have possible shared ancestry with the Pakistani population. Our findings reemphasizes that the rate of VUSs can be reduced by clinical correlation and family segregation studies.

A 56-year-old woman presented with 3 months history of all four limbs’ numbness in glove and stocking distribution. A week before admission, she developed all four limbs’ weakness and numbness. Brain and whole spine imaging revealed no lesions, and cerebrospinal fluid showed high protein. A nerve conduction study revealed severe sensorimotor polyneuropathy, and she was diagnosed with chronic inflammatory demyelinating polyneuropathy. We treated her with plasma exchange and later developed bilateral pulmonary embolism, deep venous thrombosis and worsening of weakness. The second set of seven sessions of plasma exchange gave her improvement in muscle strength. However, after a chest infection, another neurological deterioration occurred. The third set of plasma exchanges resulted in excellent response. Nineteen months into her illness she developed a headache followed by left upper limb weakness and focal seizures with left side involvement. Brain imaging revealed a right frontal enhancing lesion that required resection, and biopsy showed diffuse large B-cell lymphoma. She was treated with chemotherapy and whole-brain radiation therapy and remained with left-sided weakness.

A 53-year-old woman without medical problems presented with 5-month history of dizziness, difficulty speaking, severe ataxia, which worsened a day before admission to inability to stand unsupported. An extensive workup was initiated to find the cause of ataxia. The laboratory investigations and imaging of the brain and whole spine revealed no lesions. She was found to have autoimmune thyroiditis, positive coeliac disease antibodies without clinical features and vitamin D deficiency. No intravenous steroids or immunosuppressive therapy was given. Cerebrospinal fluid showed lymphocytic pleocytosis. The workup for the cause of severe ataxia revealed an oropharyngeal lesion with cervical lymph nodes, and the biopsy showed classical Hodgkin’s lymphoma of mixed cellularity. She was treated with chemotherapy followed by radiation therapy and made a remarkable recovery, and currently, she is in remission without distant metastases, 5 years after the initial diagnosis. Her neurological status improved, and she remained with mild ataxia.