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

Xiuli Huang; Dandan Tan; Zaiqiang Zhang; Lin Ge; Jieyu Liu; Juan Ding; Haipo Yang; Cuijie Wei; Xingzhi Chang; Yun Yuan; Chuanzhu Yan; Hui Xiong

doi:10.3389/fneur.2023.1158094

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

Front Neurol. 2023 May 3:14:1158094. doi: 10.3389/fneur.2023.1158094. eCollection 2023.

Authors

Xiuli Huang¹, Dandan Tan¹, Zaiqiang Zhang², Lin Ge¹, Jieyu Liu¹, Juan Ding¹, Haipo Yang¹, Cuijie Wei¹, Xingzhi Chang¹, Yun Yuan³, Chuanzhu Yan⁴, Hui Xiong^{1

5}

Affiliations

¹ Department of Pediatrics, Peking University First Hospital, Beijing, China.
² Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
³ Department of Neurology, Peking University First Hospital, Beijing, China.
⁴ Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Disease, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁵ Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases, Beijing, China.

Abstract

Background: LAMA2-related limb girdle muscular dystrophy (LGMD R23) is rare. The detailed clinical phenotypes and genetic information associated with LGMD R23 are unknown.

Methods: We conducted a retrospective cross-sectional and longitudinal study on 19 LGMD R23 patients.

Results: Normal 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.

Conclusions: Missense 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.

Keywords: LAMA2-related limb girdle muscular dystrophy; LGMD R23; genotype; genotype-phenotype correlations; phenotype.

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (No. 82171393), National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital) (No. 2022CR69), and Natural Science Foundation of Beijing Municipality (No. 7212116).