Dados do Trabalho

Título

JAG2-related limb-girdle muscular dystrophy: first report in Latin America and description of a novel variant

RESUMO

Cases Presentation
Two mixed-race siblings, non-consanguineous parents, Rio Grande do Sul, Brazil, referred to our outpatient clinic this year at ages 35 (case 1) and 24 (case 2). Both had normal neuropsychomotor development up to 24 months and 12 months, respectively, when they developed progressive proximal weakness on 4 limbs and lost the ability to walk at ages 8 and 7. Evolution of motor disability with increased frailty and muscle atrophy in 4 limbs for the following 10 years, predominantly proximal in the lower limbs, associated with contractures with joint deformities and limited extension. Both presented dorsal scoliosis and mild cervical weakness. Case 1, at age 25 showed significant bulbar weakness, with dysphagia and dyspnea at rest with the need for intermittent bilevel positive airway pressure. Case 2 does not present dysphagia or symptomatic dyspnea. Both maintain support therapy with motor physiotherapy. The initial investigation included: normal CK, EMG showing myopathic pattern and muscle biopsy at ages 4 and 8 (case 1) and at age 3 (case 2) with no conclusive results. The molecular confirmation of the diagnosis was only reached in 2022, by means of a next-generation multigene sequencing (NGS) panel, which revealed a heterozygous pathogenic variant in the JAG2 gene [T>TGGCCP.His1171ArgFS*9] that promotes amino acid substitution histidine in code 1171 by Arginine and change in the reading matrix from this point promoting early interruption of protein translation in case 2.In addiction, case 1 was also tested with another NGS panel for neuromuscular conditions (which did not include JAG2) , but it resulted in no relevant variants.
Discussion
Autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27) is caused by pathogenic variants in the Jagged Canonical Notch Ligand 2 (JAG2). It was first described in 2021 in a single international cohort with no reported cases in Latin America. This variant is classified as pathogenic due to early interruption of protein translation that contributes to protein dysfunction in the notch signaling pathway, which is important in intercellular signaling.
Final Comments
This report expands the geographical distribution of LGMDR27 to Latin America, describes the clinical features of two new cases of this rare condition and contributes a novel variant affecting the JAG2 gene.