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A founder mutation in the GMPPB gene [c.1000G A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients
- Source :
- Neurogenetics. 22(4)
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- Adult
Male
Weakness
Pathology
medicine.medical_specialty
Medizin
Muscle hypertrophy
Cellular and Molecular Neuroscience
Atrophy
Genetics
Medicine
Humans
Repetitive nerve stimulation
Genetic Testing
Child
Genetics (clinical)
Myasthenic Syndromes, Congenital
Muscle biopsy
medicine.diagnostic_test
business.industry
Muscles
Congenital myasthenic syndrome
Middle Aged
medicine.disease
Disease gene identification
Magnetic Resonance Imaging
Nucleotidyltransferases
Phenotype
Muscular Dystrophies, Limb-Girdle
Mutation
Female
medicine.symptom
business
Limb-girdle muscular dystrophy
Subjects
Details
- ISSN :
- 13646753
- Volume :
- 22
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Neurogenetics
- Accession number :
- edsair.doi.dedup.....759a1ee3de3e3a9092ec020b80320767