CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.225Clinical, genetic and neuropathological heterogeneity in a pediatric cohort with nemaline myopathy

Abstract

Nemaline myopathies are a vast group of rare muscle diseases sharing a common pathognomonic histological marker: nemaline rods - dark-blue structures visualized in muscle fibers stained with Gomori Trichrome. A pediatric cohort from a reference center in the north of Portugal (between 2002-2017) was reassessed. Eight patients (4 of each gender) with ages between 1 and 18 yrs were diagnosed. Two patients were siblings and other two had family history. Six had a neonatal presentation with tetraparesis, distal arthrogryposis, and severe axial and bulbar involvement, 4 required invasive ventilatory support and 4 tube feeding. One patient died with 3m of age. All 8 patients needed ventilation support and one performed scoliosis surgery. Five were able to walk between 18 and 72m (34m average). Muscle biopsy was reviewed in 5: rods, mainly in the periphery, variable proportion of affected fibers, without correlation with clinical severity. In terms of their genetic etiology, the most frequent defective gene in this cohort was nebulin (NEB) affecting 5 patients (1 homozygous and 4 compound heterozygous). Six distinct pathogenic variants in NEB gene were identified: 3 affecting splice-sites, 2 causing frameshift and 1 nonsense. All give rise to premature termination codons. Several unrelated patients shared at least one NEB variant meaning that these could be preliminary targeted in future cases. One patient has a de novo pathogenic missense variant in ACTA1 gene. Finally, in the kindred with two affected siblings, a novel heterozygous missense variant in KLHL41 gene was identified. Further research is being carried-out to identify an eventual missing variant that would justify an autosomal recessive inheritance pattern. Considering the variability presented here and the size of the patient cohort, no genotype-phenotype correlations were drawn. Nevertheless, the absence of cardiac involvement in this cohort is concordant with previous reports.