4.2 Article

Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes-A recognizable clinical phenotype

期刊

EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY
卷 31, 期 -, 页码 54-60

出版社

ELSEVIER SCI LTD
DOI: 10.1016/j.ejpn.2021.02.005

关键词

VAMP1; Congenital myasthenic syndrome; Pre-synaptic defect; Autosomal recessive; India

资金

  1. Canadian Institutes of Health Research [FDN-167281]
  2. Muscular Dystrophy Canada
  3. Canada Foundation for Innovation [CFI-JELF 38412]
  4. Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health) [950-232279]

向作者/读者索取更多资源

Three unrelated girls with VAMP1 mutations causing CMS, one showing prominent ocular and bulbar symptoms, while the other two had no initial ocular signs. Early genetic diagnosis is crucial for identifying potentially treatable CMS phenotypes.
Three unrelated girls, all born to consanguineous parents had respiratory distress, severe hypotonia at birth along with prominent fatigable muscle weakness and characteristic myopathic facies. In addition, patient 1 had fatigable ptosis, ophthalmoparesis and profound bulbar weakness and required nasogastric feeding from birth. A feeding gastrostomy was inserted at 9 months of age. She continued to have severe bulbar and limb weakness with dropped head at 5 years of age. Patient 2 and 3 did not have ocular signs at the time of initial presentation during infancy and at 2 years of age respectively. None of the patients attained independent walking. Patient 3, currently aged 16 years continues to be wheelchair bound and has only mild non-progressive bulbar weakness with normal cognitive development. Muscle biopsy in patient 1 and 3 showed predominant myopathic features admixed with small sized (atrophic/hypoplastic) fibres. Next generation sequencing confirmed the presence of a homozygous loss of function VAMP1 mutations in all three patients: A single nucleotide deletion resulting in frameshift: c.66delT (p.Gly23AlafsTer6) in patient 1 and nonsense mutations c.202C>T (pArg68Ter) and c.97C>T (p.Arg33Ter) in patient 2 and 3 respectively. Minimal but definite improvement in muscle power with pyridostigmine was reported in patients 1 and 2. This is the first report of VAMP1 mutations causing CMS from the Indian subcontinent, describing a clinically recognizable severe form of VAMP1-related CMS and highlighting the need for a strong index of suspicion for early genetic diagnosis of potentially treatable CMS phenotypes. (c) 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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