Severe congenital muscular dystrophy in a Mexican family with a new nonsense mutation (R2578X) in the laminin α-2 gene

Coral‐Vázquez, Ramón Mauricio; Rosas-Vargas, Haydeé; Meza-Espinosa, Pedro; Mendoza, Irma Milagros Carhuancho; Huicochea, Juan Carlos; Ramon, G; Salamanca, F

doi:10.1007/s100380300013

Cited by 7 publications

(5 citation statements)

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“…Coral-Vazquez et al . [ 12 ] reported an 8-month-old Mexican female infant, from a consanguineous family, with MDC1A and they detected homozygous mutation p.R2578 in LAMA2 gene as similarly in our patient 4 and 5. This patient was the second child of healthy consanguineous parents.…”

Section: Discussionsupporting

confidence: 79%

Merosin-negative congenital muscular dystrophy: Report of five cases

et al. 2015

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Context:Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the laminin α-2 gene encoding laminin-a2.Aims:The purpose of this study is to determine clinical and genetic results in five Turkish patients with MDC1A.Setting and Designs:Five children with MDC1A were retrospectively analyzed.Results:Three (60%) were boys, and 2 (40%) were girls. Parental consanguinity was found in all the families. In all the patients, hypotonia, weakness, delayed motor milestones, markedly elevated creatine phosphokinase (CPK) concentration, and brain white matter abnormalities on magnetic resonance imaging were detected. Mutation analysis was performed in all the patients, and 3 different mutations were detected. However, a mutation in patient 1 and 2 has not been previously described in the literature.Conclusions:When a patient presents with severe congenital hypotonia, muscle weakness, high serum CPK levels, and white matter abnormalities, should be suspected as MDC1A.

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Section: Discussionsupporting

confidence: 79%

Merosin-negative congenital muscular dystrophy: Report of five cases

et al. 2015

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“…Laminin-211 promotes axon growth, migration of muscle cells, and Schwann cell functionality [56, 70, 71]. Mice harboring mutations of the laminin α2 gene display a muscular dystrophy-like syndrome [67], which is also observed in humans harboring genetic mutations in the gene encoding laminin α2 ( lama2 ) [37, 72–75]. Laminin α2 mutant mice with a spontaneous hypomorphic allele (i.e., dy and dy 2J mice) and other laminin α2 mutant models (dy W and dy 3K mice) do not develop post-synaptic junctional folds at motor endplates, display partial detachment of motor neuron terminals from the endplate, have demyelination of motor axons, and minor Schwann cell infiltration into synaptic cleft (Figure 1E) [35, 36, 76–86].…”

Section: The Role Of Laminins In Nmjs and Active Zone Organizationmentioning

confidence: 99%

“…Cerebral white matter abnormalities have been found by magnetic resonance imaging (MRI) in many cases, and seizures and mental retardation have been reported in a small portion of cases [66]. A number of different mutations have been observed resulting in a complete or partial loss of laminin α2 protein [37, 66, 72–75, 146–150]. Some patients have only a partial decrease in laminin α2 protein levels, and these patients have better prognosis becoming ambulatory with longer life expectancy although a progressive muscle weakness may persist [72, 149].…”

Section: Diseases Associated With the Loss Of Laminins Or Laminin-recmentioning

confidence: 99%

The role of laminins in the organization and function of neuromuscular junctions

Rogers

Nishimune

2017

Matrix Biology

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The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.

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“…All patients had genetic confirmation before enrollment in the study ( Table 2 ). 2 , 22 - 30 The Dutch founder mutation (homozygous and compound heterozygous) was most prevalent (c.5562+5G>C splice site mutation in exon 38). No individuals were excluded from this study because of variants of unknown significance.…”

Section: Resultsmentioning

confidence: 99%

LAMA2 -Related Muscular Dystrophy Across the Life Span

et al. 2023

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Background and ObjectivesLAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness.MethodsWe performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry.ResultsTwenty-seven patients with genetically confirmedLAMA2-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, −0.928,p< 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients.DiscussionLAMA2-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed.Clinical Trials RegistrationThis study was registered atclinicaltrials.gov(NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

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Severe congenital muscular dystrophy in a Mexican family with a new nonsense mutation (R2578X) in the laminin α-2 gene

Cited by 7 publications

References 24 publications

Merosin-negative congenital muscular dystrophy: Report of five cases

Merosin-negative congenital muscular dystrophy: Report of five cases

The role of laminins in the organization and function of neuromuscular junctions

LAMA2 -Related Muscular Dystrophy Across the Life Span

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