Dados do Trabalho

Título

CLINICAL AND GENETIC FEATURES OF TTN-RELATED MYOPATHIES: A SINGLE-CENTER COHORT

Introdução

The TTN gene has the largest coding region of all human genes and encodes titin, a large protein that serves as a scaffold for sarcomere assembly. Titin consists of an amino-terminal Z-disc region, intermediate I- and A-band regions, and a carboxy-terminal M-band region. Six major isoforms of the protein have been identified: the major cardiac isoforms (N2BA, N2B), the minor cardiac isoforms (Novex-1, Novex-2, and Novex-3), and the major skeletal muscle isoform (N2A). Titinopathies encompass a complex spectrum of phenotypes involving both skeletal and cardiac muscle, with autosomal dominant and recessive inheritance.

Objetivo

In this work we present the clinical and genetic data of 10 patients with autosomal recessive congenital myopathy related to TTN, aged between 1 and 39 years (mean 15.1 years).

Método

Clinical, histological, and molecular data are presented. Patient information was collected from medical records for retrospective analysis. The TTN gene was analyzed by next-generation sequencing.

Resultados

Seventeen different variants were found. Seven were frameshift variants, six were splice site variants and four were nonsense. All variants were presumably compound heterozygous. Three variants were recurrent, being present in two patients each (c.36100G>T, p.(Glu12034*), c.35713+2T>A, p.(?) and c.38442dupA, p.(Pro12815fs)). Band A was the region that presented the largest number of variants, five. All patients had a history of neonatal hypotonia and delayed motor development. The last age of walking acquisition was 7 years, and one 19-year-old patient never acquired walking. Joint hypermobility was prominent in four patients. No patient had ophthalmoparesis. Most patients had spinal deformity, mainly due to scoliosis. Baseline CPK ranged from 27 to 4,619. Six patients had undergone prior muscle biopsy. Minicores, internalized nuclei, and mild dystrophic changes were the most prominent histologic findings.

Conclusão

Congenital titinopathy commonly presents with biallelic null variants. Patients presenting with distal hyperelasticity, normal or slightly increased CPK, and dystrophic findings on muscle biopsy may have an initial etiologic suspicion of collagen VI-related congenital muscular dystrophy, a more common group of congenital myopathies. Additional analyses are needed to correlate the clinical impact of variants in different transcripts and protein regions.

Referências

Oates EC et al. Congenital Titinopathy: Comprehensive characterization and pathogenic insights. Ann Neurol. 2018
Hackman P et al; Titinopathy Database Consortium. 219th ENMC International Workshop Titinopathies International database of titin mutations and phenotypes, Heemskerk, The Netherlands, 29 April-1 May 2016. Neuromuscul Disord. 2017

Palavras Chave

congenital myopathy; muscular dystrophy; titin