Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.

Autor: Longo N; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Department of Pathology, University of Utah, USA; ARUP Laboratories, Salt Lake City, UT 84108, USA; Division of Clinical Genetics, Department of Human Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: NLongo@mednet.ucla.edu., Voss LA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA., Frigeni M; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Don Gnocchi Foundation IRCCS S. Maria Nascente, Milan, Italy; Northwell Health, Division of Medical Genetics, Department of Pediatrics, Great Neck, New York, USA., Balakrishnan B; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA., Pasquali M; Department of Pathology, University of Utah, USA; ARUP Laboratories, Salt Lake City, UT 84108, USA.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Nov; Vol. 143 (3), pp. 108595. Date of Electronic Publication: 2024 Oct 12.
DOI: 10.1016/j.ymgme.2024.108595
Abstrakt: Cerebral creatine deficiency syndromes (CCDS) are rare inherited metabolic disorders caused by defective biosynthesis or transport of creatine. These conditions are characterized by reduced accumulation of creatine in the brain, mild to severe intellectual disability, global developmental delay, and speech-language disorders. The amount of brain creatine reduction needed to cause symptoms is not known. Here we report a new patient with creatine transporter deficiency (CTD) who presented at 15 months of age with seizures and global delays with no speech at 3 years of age. Brain MRI was normal, but brain MRS indicated creatine levels reduced to about 20 % of normal. He had normal levels of creatine and guanidinoacetate in plasma, but increased creatine/creatinine ratio in urine. DNA sequencing identified a hemizygous c.832C > T (p.Arg278Cys) variant in the creatine transporter gene SLC6A8. Fibroblasts from this patient had about 25 % of normal creatine transport activity, a value much higher than that measured in patients whose variants introduced premature stop codons in SLC6A8. The child was started on supplements of creatine, glycine, and arginine. His speech improved dramatically, and he had no more seizures, even during episodes of fever. Despite the clinical improvement, a repeat MRS demonstrated similar levels of brain creatine. This study suggests that a reduction in creatine transporter activity to 25 % or less is sufficient to cause symptoms of brain creatine deficiency and that functionally milder forms of CTD might respond to supplements aimed at replenishing brain creatine.
Competing Interests: Declaration of competing interest The authors have no conflicts of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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