Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort

Dandan Tan,Carsten G Bönnemann,Zhen Huang,Anne Rutkowski,Chengli Que,Shuo Wang,Ying Hua,Lin Ge,Yun Yuan,Kai Gao,Bingbing Zhang,Jia-Hua Ding ,Wenhua Zhu,Xueying Li,Xiru Wu,Cheng Zhang,Xiaoli Zhang,Xingzhi Chang,Chunde Li,Wei Cui ,Shuang Wang,Haiyuan Yang ,Yuwu Jiang,Bo Jin,Yanjuan Wang,Bing Mao,Ying Zhu,Yanbin Fan,Aijie Liu,Hui Xiong

doi:10.1186/s13023-021-01950-x

Abstract

BackgroundLAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype–phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy.MethodsClinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed.ResultsOne hundred and thirty patients (116 LAMA2-CMD and 14 LGMDR23) were included. LAMA2-CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of LAMA2-CMD patients at median ages of 6.0 months (range 2.0–36.0 months), 11.0 months (range 6.0–36.0 months), and 27.0 months (range 18.0–84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0–20.0 months). Motor regression in LAMA2-CMD mainly occurred concurrently with rapid progression of contractures during 6–9 years old. Twenty-four LAMA2-related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of LAMA2-CMD patients. Forty-six novel and 97 known LAMA2 disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In LAMA2-CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in LAMA2-CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in LAMA2-CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival (p = 0.029).ConclusionsThis study provides better understandings of natural history and genotype–phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.

Highlights

LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants
The clinical spectrum ranges from a severe, earlyonset LAMA2-related congenital muscular dystrophy (LAMA2-Congenital muscular dystrophy (CMD), OMIM 607,855) to a mild, childhoodonset autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23, OMIM 618,138) [2, 3]
Symptoms appeared within the first week of life in 75.9% (88/116) of LAMA2-CMD patients

Summary

Introduction

LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype–phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy. LAMA2-related muscular dystrophy is an autosomal recessive disorder caused by pathogenic variants in LAMA2 gene (OMIM 156,225). The clinical spectrum ranges from a severe, earlyonset LAMA2-related congenital muscular dystrophy (LAMA2-CMD, OMIM 607,855) to a mild, childhoodonset autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23, OMIM 618,138) [2, 3]. There are a few retrospective, cross-sectional studies exploring the natural history and genetic variations of LAMA2-related muscular dystrophy [4,5,6,7], long-term and large-scale studies of the natural history and genotype–phenotype correlations are limited. As promising therapeutic approaches (such as upregulation of LAMA1, mini-agrin, and laminin-α1 LN-domain nidogen-1 (αLNNd)) are getting closer to clinical application [9,10,11,12], the definition of natural history endpoints along with clinically relevant outcome measures is essential for both clinical care planning and clinical trial readiness [13]

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