RESUMO
Phosphoglycerate kinase-1 (PGK1) deficiency is a rare X-linked disorder caused by pathogenic variants in the PGK1 gene. Complete loss-of-function variants have not been reported in this gene, indicating that residual enzyme function is critical for viability in males. Therefore, copy number variants (CNVs) that include single exon or multiple exon deletions or duplications are generally not expected in individuals with PGK1 deficiency. Here we describe a 64-year-old male presenting with a family history (three additional affected males) and a personal history of childhood-onset metabolic myopathy that involves episodes of muscle pain, stiffness after activity, exercise intolerance, and myoglobinuria after exertion. Biochemical analysis on a muscle biopsy indicated significantly reduced activity (15% compared to normal) for phosphoglycerate kinase (PGK1), a glycolytic enzyme encoded by PGK1. A diagnosis of PGK1 deficiency was established by molecular analysis which detected an approximately 886 kb deletion involving the polyadenylation site in the 3'UTR of the PGK1 gene. RNA analysis showed significantly reduced PGK1 transcript levels (30% compared to normal). This is the first deletion reported in the PGK1 gene and is the first pathogenic variant involving the 3'UTR polyadenylation site of this gene. Our report emphasizes the role of 3'UTR variants in human disorders and underscores the need for exploring noncoding regions of disease-associated genes when seeking a molecular diagnosis.