Unique genotype-phenotype correlations within LAMA2-related limb girdle muscular dystrophy in Chinese patients

Abstract

BackgroundLAMA2-related limb girdle muscular dystrophy (LGMD R23) is rare. The detailed clinical phenotypes and genetic information associated with LGMD R23 are unknown.MethodsWe conducted a retrospective cross-sectional and longitudinal study on 19 LGMD R23 patients.ResultsNormal early motor development was observed in 84.2% patients. Mild orthopedic complications were observed in 42.1% patients. 36.8% patients had seizures, which is unusually frequent in LGMD. Epilepsy was eventually diagnosed in 26.3% patients. 46.7% patients presented with motor neuropathy. Genetic analysis identified 29 pathogenic variants, with missense and frameshift variants being the most common. The mutant sites were mainly distributed in the N-terminal and G-like domains of laminin. The missense variants are distributed near the N-terminus (exons 3–11), whereas frameshift variants are distributed in exons 12–65. Five patients were diagnosed with epilepsy and all of them harbor at least one missense variants in exon 4. 71.4% variants of patients with motor neuropathy located in the LN domain.ConclusionsMissense variants in exon 4 maybe correlated with epilepsy and variants in the LN domain maybe correlated with motor neuropathy in Chinese patients. Our study expands the clinical and genetic spectrum caused by LAMA2 variations and provides novel genotype-phenotype correlations of LGMD R23.

A Novel Mouse Model forLAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype

“…We also clearly demonstrated the cell types which expressed Lama2 and provided evidence for the impaired gliovascular basal lamina of BBB ( Severino et al, 2020; Devisme et al, 2012 ), which was associated with brain abnormalities in LAMA2 -MD ( Figure 6C ). The observation of occipital pachygyria in human patients is most likely related to the impaired gliovascular basal lamina of BBB and occurrence of seizures in these patients could be related to the aberrant neuronal network formation and the imbalance of excitability and inhibitory neuronal network and ionic homeostasis ( Barkovich et al, 2015; Jayakody et al, 2020; Sarkozy et al, 2020; Huang et al, 2023 ). This disturbance of ionic homeostasis might result in the accumulation of interstitial fluid within the myeline sheath and observed in the T2 hyperintensity in the brain MRI.…”

Limb–Girdle Muscular Dystrophies Classification and Therapies

“…Laminin α2-related muscular dystrophy (LGMDR23), associated with mutations in the LAMA2 gene, which is expressed as Laminin α2, a protein involved in myotube stability and apoptosis [73]. The phenotype is a progressive proximal muscle weakness and accounts for 36% of the patients reported having seizures without an epilepsy-related gene [74].…”