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The Phenotype and Genotype of Congenital Myopathies Based on a Large Pediatric Cohort
Daniel Natera-de Benito1, Carlos Ortez2, Cristina Jou3
1Neuromuscular Unit, Neuropediatrics Department, Institut de Recerca and Hospital Sant Joan de Déu, Barcelona, Spain.
Insights
Congenital myopathies (CMs) are diverse genetic muscle disorders. Muscle biopsy findings like fibrosis and fatty replacement correlate with CM severity, and TTN gene mutations are more common than previously recognized.
Area of Science:
- Neurology
- Genetics
- Pathology
Background:
- Congenital myopathies (CMs) represent a heterogeneous group of inherited neuromuscular disorders with varied genetic and histologic subtypes.
- The precise genotype-phenotype correlations and subtype distributions in CMs remain incompletely understood.
Purpose of the Study:
- To comprehensively characterize the clinical, histopathological, and molecular features of congenital myopathies.
- To investigate the relationship between specific histologic findings and clinical severity.
- To update the understanding of genetic etiologies, including the prevalence of TTN gene mutations.
Main Methods:
- Retrospective cross-sectional study involving 104 patients with congenital myopathies.
- Detailed clinical assessment, histopathological analysis of muscle biopsies, and molecular genetic testing.
- Data collection focused on subtype distribution, functional outcomes, and causative gene identification.
Main Results:
- Core myopathy was the most frequent histopathologic subtype (42%).
- Severe endomysial fibrosis and fatty replacement in muscle biopsies were significantly associated with reduced ambulation and increased clinical severity.
- A molecular diagnosis was achieved in 62% of patients, with RYR1 and TTN identified as the most common causative genes. TTN mutations were found to be more prevalent than previously reported.
Conclusions:
- This study offers an updated overview of the congenital myopathy landscape, integrating clinical, histopathological, and molecular data.
- Muscle biopsy indicators of fibrosis and fatty infiltration are crucial markers of disease severity, irrespective of the underlying genetic cause.
- The significant role of TTN mutations in congenital myopathies warrants further investigation.
Background:
Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts, and the relationship between phenotypes and genotypes is only partially understood.
Methods:
This is a retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological, and molecular characterization of 104 patients with CM is reported.
Results:
The most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild-grade endomysial fibrosis (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with "specific" histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65 of 104 patients (62%), with RYR1 (24/104) and TTN (8/104) being the most frequent causative genes. Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in one of three patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%.
Conclusions:
This study provides an updated picture of the clinical, histopathological, and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy specimens are associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought.
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