MITOCHONDRIAL DISEASES & METABOLIC MYOPATHIES: P.321 Mitochondrial myopathy in X-linked creatine transporter deficiency due to a novel mutation of SLC6A8 gene

Abstract

Creatine (Cr) is essential in energy metabolism since it allows the ADP-ATP conversion. Creatine transporter (CRTR) gene SLC6A8 is required for brain and muscle creatine uptake from the blood. Mutations in SLC6A8 are responsible for X-linked CRTR deficiency (CRTR-D) leading to mental retardation, global development delay, seizures and behavioral disorders. Excepted motor milestone delay, muscle involvement has been only exceptionally reported in CRTR-D. We aim to report a novel SLC6A8 mutation in a family with a particular clinical picture including a muscle mitochondrial phenotype. A 44-year-old man developed early infantile hypotonia and mental retardation and delayed motor milestones. At the time of assessment, he harbored a profound intellectual disability associated with mutism, facial dysmorphia, epilepsy, generalized muscle weakness and diarrhea. His eldest brother had severe intellectual disability, epilepsy, ptosis, muscle weakness and died at the age of 35 years. The proband's work-up results were: normal CK level, a major increase of urinary creatine/creatinine ratio: 2.5 (N≤0.37), a decreased creatine peak on brain magnetic resonance imaging spectroscopy and mitochondrial myopathic changes on muscle biopsy. A severe decrease of Cr uptake was measured on cultured fibroblasts: 0.3/8.6 nmol/mg-protein (N>18.8/31.9) with [Cr] of 25/500 µM. Clinical exome (4427 genes) allowed the identification of the novel missense mutation c.827T>C (p.Leu276Pro) on the SLC6A8 gene. It was inherited from his asymptomatic mother, absent in an asymptomatic brother and in the control database gnomAD (gnomad.broadinstitute.org). Moreover, it was predicted pathogenic from 4 prediction tools (SIFT, PolyPhen2, Mutation Taster, Mutation Assessor). In conclusion, reporting a novel pathogenic missense mutation in SLC6A8 gene associated with an unexpected mitochondrial myopathy taking part of the clinical picture, we expand the genetic and phenotypic spectrum of CRTR-D.