Clinical and genomic characteristics of LAMA2 related congenital muscular dystrophy in a patients’ cohort from Qatar. A population specific founder variant

Abdel-Aleem, Alice; Elsaid, Mahmoud F.; Chalhoub, Nader; Chakroun, Almahdi; Mohamed, Khalid; Al-Shami, Rana; Kuzu, Omer F.; Mohamed, Reem; Ibrahim, Khalid; AlMudheki, Noora; Osman, Omar; Ross, M. Elizabeth; Elalamy, Osama

doi:10.1016/j.nmd.2020.03.009

Cited by 19 publications

(5 citation statements)

References 38 publications

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“…However, the prevalence of LGMDR23 is not fully known. Although there are a few retrospective, cross-sectional studies exploring the natural history and genetic variations of LAMA2 -related muscular dystrophy [ 4 – 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 – 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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Tan

Lin

Fan

et al. 2021

Orphanet J Rare Dis

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Background LAMA2-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. Methods Clinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed. Results One 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). Conclusions This study provides better understandings of natural history and genotype–phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.

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Section: Introductionmentioning

confidence: 99%

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

Tan

Lin

Fan

et al. 2021

Orphanet J Rare Dis

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“…The clinical features of LAMA2 -MD can be divided into two subgroups: 1. severe, early-onset LAMA2 -related congenital muscular dystrophy ( LAMA2 -CMD, OMIM 607855), and 2. mild, late-onset autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23, OMIM 618138) ( Tan D et al, 2021 ). LAMA2 -MD has an estimated prevalence of 4 in 500,000 children ( Nguyen et al, 2019 ), and accounts for 36-48% of all patients diagnosed with congenital muscular dystrophies (CMDs) ( Sframeli et al, 2017; Abdel Aleem et al, 2020; Ge et al, 2019 ). Dystrophic muscle pathology and clinical motor weakness are the common characteristics of LAMA2 -MD patients.…”

Section: Introductionmentioning

confidence: 99%

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

Tan,

Liu,

Luo

et al. 2024

Preprint

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Understanding the underlying pathogenesis ofLAMA2-related muscular dystrophy (LAMA2-MD) have been hampered by lack of genuine mouse model. We created a newLama2knockout mouse (dyH/dyH) and reported here its close simulation to human neuropathology and symptoms. We first established thatLama2was predominantly expressed within the cortical surface of normal mouse brain, specifically, highly concentrated in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells with a modest presence within astrocytes. OurLama2knockout mice confirmed specific decreasedLama2expression in those cell types and resulted in disruption of gliovascular basal lamina assembly. This molecular pathogenesis mechanism was elucidated by a novel scRNA-seq. Furthermore, through transcriptomic investigation, these dyH/dyHmice were showed aberrant structure of muscle cytoskeletons which impaired normal muscle development and resulted in weakness. This is the first reported genuine model simulating humanLAMA2-MD. We can use it to study the molecular pathogenesis and develop effective therapies.

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“…It is characterized by congenital hypotonia, delayed motor development, progressive muscle weakness affecting the shoulder and pelvic girdles leading to the loss of independent ambulation and joint contractures. Brain magnetic resonance imaging (MRI) showed widespread WMC ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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Clinical and genomic characteristics of LAMA2 related congenital muscular dystrophy in a patients’ cohort from Qatar. A population specific founder variant

Cited by 19 publications

References 38 publications

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

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

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

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

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