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Lookup NU author(s): Dr Ana TopfORCiD
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© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing–based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.
Author(s): Polavarapu K, Mathur A, Joshi A, Nashi S, Preethish-Kumar V, Bardhan M, Sharma P, Parveen S, Seth M, Vengalil S, Chawla T, Shingavi L, Shamim U, Nayak S, Vivekanand A, Topf A, Roos A, Horvath R, Lochmuller H, Nandeesh B, Arunachal G, Nalini A, Faruq M
Publication type: Article
Publication status: Published
Journal: Neurogenetics
Year: 2021
Volume: 22
Pages: 271-285
Online publication date: 01/08/2021
Acceptance date: 08/07/2021
ISSN (print): 1364-6745
ISSN (electronic): 1364-6753
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1007/s10048-021-00658-1
DOI: 10.1007/s10048-021-00658-1
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