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International retrospective natural history study of LMNA-related congenital muscular dystrophy.

ABSTRACT: Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

SUBMITTER: Ben Yaou R

PROVIDER: S-EPMC8260964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice.

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International retrospective natural history study of LMNA-related congenital muscular dystrophy.

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