Oxidative phosphorylation in creatine transporter deficiency

Abstract: X-linked creatine transporter deficiency (CTD) is one of the three types of the cerebral creatine deficiency disorders. CTD arises from pathogenic variants in the X-linked gene SLC6A8. We report the first phosphorus (31P) MRS study of patients with CTD, where both phosphocreatine and total creatine concentrations were found to be markedly reduced. Despite the diminished role of creatine and phosphocreatine in oxidative phosphorylation in CTD, we found no elevation of lactate or lowered pH, indicating that the brain energy supply still largely relied on oxidative metabolism. Our results suggest that mitochondrial function is a potential therapeutic target for CTD.

Parent Summary: Magnetic resonance spectroscopy (MRS) of the brain is a noninvasive technique that allows researchers to study the levels of chemical components of the brain’s tissues. It was actually the technique used to discover creatine deficiency in the brain. Here, the authors (for the first time with respect to creatine transporter deficiency [CTD]) used a type of MRS called phosphorus MRS, which provides a better glimpse into energy metabolism in the brain. Even though levels of creatine and phosphocreatine (which are reduced in patients with CTD) are critical for energy metabolism in the brain, these authors did not find evidence to suggest energy metabolism differed in patients with CTD. Because the reduced phosphocreatine may reflect changes in how mitochondria are functioning (i.e., mitochondria are responsible for energy production), these authors suggest that development and application of techniques to enhance the brain’s mitochondrial function may benefit patients with CTD.

Link to article: https://pubmed.ncbi.nlm.nih.gov/32990357/

PubMed:  https://pubmed.ncbi.nlm.nih.gov/32990357/

Authors: Shizhe Li, Simona Bianconi, Jan Willem van der Veen, An Dang Do, JoEllyn Stolinski, Kim M. Cecil, Fady Hannah-Shmouni, Forbes D. Porter, and Jun Shen

Key Terms: CTD, MRS, Diagnostic, Clinical Study, Pediatric Patient, Male Patient