LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

Sárközy, Anna; Foley, A. Reghan; Zambon, Alberto A.; Bönnemann, Carsten G.; Muntoni, Francesco

doi:10.3389/fnmol.2020.00123

Cited by 66 publications

(77 citation statements)

References 80 publications

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“…Although 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].…”

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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“…Cases of muscle weakness and altered energy metabolism, like those observed in OI patients and mouse models exhibiting type I collagen mutations, are also found in animal models and patients with muscular dystrophies possessing gene defects in extracellular matrix proteins such as laminin α2 ( LAMA2 ) and type VI collagen ( COLVI ) [ 47 , 48 ]. The clinical presentation of LAMA2-associated muscular dystrophies closely resembles that of the COLVI-related Bethlem myopathy, including muscle weakness, muscle hypotonia, and joint contractures [ 49 ].…”

Section: Skeletal Muscle Weakness and Energy Metabolism In Oimentioning

confidence: 99%

Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

Gremminger

Phillips

2021

IJMS

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Bone and muscle are highly synergistic tissues that communicate extensively via mechanotransduction and biochemical signaling. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder of severe bone fragility and recently recognized skeletal muscle weakness. The presence of impaired bone and muscle in OI leads to a continuous cycle of altered muscle–bone crosstalk with weak muscles further compromising bone and vice versa. Currently, there is no cure for OI and understanding the pathogenesis of the skeletal muscle weakness in relation to the bone pathogenesis of OI in light of the critical role of muscle–bone crosstalk is essential to developing and identifying novel therapeutic targets and strategies for OI. This review will highlight how impaired skeletal muscle function contributes to the pathophysiology of OI and how this phenomenon further perpetuates bone fragility.

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“…One study from 1998 analysed a small cohort of patients with merosindeficiency, assessing ID and MRI changes and concluded that in the presence of cerebellar hypoplasia, children frequently presented with lower IQs on performance [26] . It is striking that in several publications the genetic diagnosis remained unconfirmed by either a missing second mutation in LAMA2 or inconsistencies between laminin α2 expression and white matter changes [27] . Seizures are not primarily attributed to the white matter hypointensity found in LAMA2-CMD, but may be associated with additional cortical malformations or ventricular dilation [27] .…”

Section: Laminin α2 Chain Related Congenital Muscular Dystrophiesmentioning

confidence: 99%

“…It is striking that in several publications the genetic diagnosis remained unconfirmed by either a missing second mutation in LAMA2 or inconsistencies between laminin α2 expression and white matter changes [27] . Seizures are not primarily attributed to the white matter hypointensity found in LAMA2-CMD, but may be associated with additional cortical malformations or ventricular dilation [27] .…”

Section: Laminin α2 Chain Related Congenital Muscular Dystrophiesmentioning

confidence: 99%

Intellectual disability in paediatric patients with genetic muscle diseases

Specht

Straub

2021

Neuromuscular Disorders

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LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

Cited by 66 publications

References 80 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

Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

Intellectual disability in paediatric patients with genetic muscle diseases

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