Laminin α2 Deficiency-Related Muscular Dystrophy Mimicking Emery-Dreifuss and Collagen VI related Diseases

Nelson, Isabelle; Stojkovic, Tanya; Allamand, Valérie; Leturcq, F.; Bécane, Henri-Marc; Babuty, Dominique; Toutain, Annick; Béroud, Christophe; Richard, Pascale; Romero, Norma B.; Eymard, B.; Yaou, Rabah Ben; Bonne, Gisèle

doi:10.3233/jnd-150093

Cited by 30 publications

(39 citation statements)

References 34 publications

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“…This missense substitution was initially identified in two patients with atypical presentations (Marques et al., ), prior to the six patients described above. A further three patients, from two unrelated families with Portuguese ancestry, have also been reported by other groups: one patient from Canada (with #102482 in LAMA2‐LOVD), and two brothers studied in France (Nelson et al., ). Thus far, all patients are reported to have milder muscle weakness and the majority were initially classified as possible LGMD or EDMD.…”

Section: Clinical Relevance: the Expanding Disease Spectrum Of Lama2‐mentioning

confidence: 58%

“…(b) Late‐onset (Emery–Dreifuss muscular dystrophy [EDMD]/COL6‐RD‐like): rigid spine syndrome; cardiac involvement in some patients; walking difficulties; dystrophic features in MD, normal and irregular laminin‐α2 staining in IHC. Pat.2—patient 2 (Marques et al., ); cases #3, #4 (Nelson et al., ); P5 (this work). (c) Late‐onset (limb‐girdle muscular dystrophy (LGMD)‐like): slow progression; dystrophic features, normal and irregular laminin‐α2 staining in IHC, walking difficulties later in life; P1–4, P6 (this work).…”

Section: Clinical Relevance: the Expanding Disease Spectrum Of Lama2‐mentioning

confidence: 65%

“…() and case #2 from Nelson et al. () share the same genotype (a homozygous nonsense variant p.Arg744*), but cortical polymicrogyria and lissencephaly were only reported in the latter patient. It is conceivable that other genetic factors besides LAMA2 variants are contributing to these phenotypes.…”

Section: Clinical Relevance: the Expanding Disease Spectrum Of Lama2‐mentioning

confidence: 94%

“…Furthermore, phenotypical discrepancies have been found in patients sharing with same genotype. For example, two siblings reported by Di Blasi et al (2001) and case #2 from Nelson et al (2015) share the same genotype (a homozygous nonsense variant p.Arg744*), but cortical polymicrogyria and lissencephaly were only reported in the latter patient. It is conceiv-able that other genetic factors besides LAMA2 variants are contributing to these phenotypes.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

“…Over the last few years there has been a significant increase in reports of late-onset LAMA2-related MD patients (Ding et al, 2016;Gavassini et al, 2011;Harris et al, 2017;Kevelam, van Engelen, van Berkel, Küsters, & van der Knaap, 2014;Kim et al, 2017;Løkken, Born, Duno, & Vissing, 2015;Marques et al, 2014;Nelson et al, 2015;Rajakulendran, Parton, Holton, & Hanna, 2011). Most of these patients have heterozygous or homozygous missense or splice variants.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

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LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

Oliveira

Gruber²,

Cardoso

et al. 2018

Human Mutation

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Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early-onset muscle disease, caused by disease-associated variants in the laminin-α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2-related muscular dystrophies (LAMA2-MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease-associated variants were identified in 86 patients, representing the largest number of patients and new disease-causing variants in a single report. The collaborative variant collection was supported by the LOVD-powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease-associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2-MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late-onset LAMA2-MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases.

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Section: Clinical Relevance: the Expanding Disease Spectrum Of Lama2‐mentioning

confidence: 58%

Section: Clinical Relevance: the Expanding Disease Spectrum Of Lama2‐mentioning

confidence: 65%

Section: Clinical Relevance: the Expanding Disease Spectrum Of Lama2‐mentioning

confidence: 94%

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

See 3 more Smart Citations

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

Oliveira

Gruber²,

Cardoso

et al. 2018

Human Mutation

View full text Add to dashboard Cite

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LAMA2‐related muscular dystrophy: Natural history of a large pediatric cohort

Zambon

Ridout

Main

et al. 2020

Ann Clin Transl Neurol

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Objective: To characterize natural history of Laminin-a2 related muscular dystrophies (LAMA2-RD) to help anticipating complications and identifying reliable outcome measures for clinical trial design and powering. Methods: We conducted a retrospective, single-center, cross-sectional and longitudinal study on 46 LAMA2-RD pediatric patients (37 families). Patients were seen at the Dubowitz Neuromuscular Centre, London between 1985 and 2019. Data were collected by case note reviews. Time-to-event analysis was performed to estimate median age at complications occurrence. Results: Forty two patients had complete deficiency of Laminin-a2 (CD) and four had partial deficiency (PD). Median age at first and last assessment was 2 years and 12.1 years, respectively. Median follow-up length was 7.8 years (range 0-18 years). Seven CD patients died at median age 12 years. One CD and two PD subjects achieved independent ambulation. We observed a linear increase in elbow flexor contractures in CD subjects. Thirty-two CD and one PD patient developed scoliosis, nine underwent spinal surgery. Twenty-two CD required nocturnal noninvasive ventilation (median age 11.7 years). CD subjects showed a 2.9% linear annual decline in forced vital capacity % predicted. Nineteen CD and one PD patient required gastrostomy insertion for failure to thrive and/or unsafe swallow (median age 10.9 years). Four CD patients had partial seizures. Mild left cardiac ventricular dysfunction and rhythm disturbances were identified in seven CD patients. Interpretation: This retrospective longitudinal study provides longterm natural history of LAMA2-RD. This will help management and identification of key milestones of disease progression that could be considered for future therapeutic intervention.

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Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin‐deficient congenital muscular dystrophy type 1A

Khorrami

Goleij

Karamad

et al. 2021

Clinical Laboratory Analysis

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Background Merosin‐deficient congenital muscular dystrophy type 1A (MDC1A) is occurred by mutations in LAMA2 gene that encodes the laminin α2 chain (merosin). MDC1A is a predominant subtype of congenital muscular dystrophy. Herein, we identified two missense mutations in LAMA2 gene in compound heterozygous status in an Iranian patient with MDC1A using whole‐exome sequencing (WES). Methods In the present study, we evaluated genetic alterations in an Iranian 35‐month‐old boy with MDC1A and his healthy family using WES method. The identified mutations further confirmed by Sanger sequencing method. Finally, in silico analysis was conducted to further evaluation of molecular function of the identified genetic variants. Results We identified two potentially pathogenic missense mutations in compound heterozygous state (c.7681G>A p.Gly2561Ser and c.4840A>G p.Asn1614Asp) in LAMA2 gene as contributing to the MDC1A phenotype. The healthy parents of our proband are single heterozygous for identified mutations. These variants were found to be pathogenic by in silico analysis. Conclusions In general, we successfully identified LAMA2 gene mutations in an Iranian patient with MDC1A using WES. The identified mutations in LAMA2 gene can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of MDC1A.

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Laminin α2 Deficiency-Related Muscular Dystrophy Mimicking Emery-Dreifuss and Collagen VI related Diseases

Cited by 30 publications

References 34 publications

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

LAMA2gene mutation update: Toward a more comprehensive picture of the laminin-α2 variome and its related phenotypes

LAMA2‐related muscular dystrophy: Natural history of a large pediatric cohort

Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin‐deficient congenital muscular dystrophy type 1A

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