Creatine Transporter Deficiency: Screening of Males with Neurodevelopmental Disorders and Neurocognitive Characterization of a Case.
Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene. Prevalence studies suggest this disorder may be underdiagnosed. We sought to identify cases from a well-characterized cohort of children diagnosed with neurodevelopmental disorders.



Urine screening for CTD was performed on a cohort of 46 males with autism spectrum disorder (ASD) and 9 males with a history of non-ASD developmental delay (DD) classified with intellectual disability.



We identified 1 patient with CTD in the cohort based on abnormal urine Cr/Crn, and confirmed the diagnosis by the identification of a novel frameshift mutation in the SLC6A8 gene. This patient presented without ASD but with intellectual disability, and was characterized by a nonspecific phenotype of early language delay and DD that persisted into moderate-to-severe intellectual disability, consistent with previous descriptions of CTD.



Identification of patients with CTD is possible by measuring urine Cr and Crn levels and the current case adds to the growing literature of neurocognitive deficits associated with the disorder that affect cognition, language and behavior in childhood.
*Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; †Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; ‡Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD; §Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT; ‖Associated Regional and University Pathologists (ARUP) Laboratories, Salt Lake City, UT; ¶Department of Pathology, University of Utah, Salt Lake City, UT; **Department of Clinical Chemistry, Metabolic Unit, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
Audrey
A
Thurm
Daniel
D
Himelstein
Precilla
P
DʼSouza
Owen
O
Rennert
Susanqi
S
Jiang
Damilola
D
Olatunji
Nicola
N
Longo
Marzia
M
Pasquali
Susan
S
Swedo
Gajja S
GS
Salomons
Nuria
N
Carrillo
D000067877:Autism Spectrum Disorder / Q000652:urine*; D020739:Brain Diseases, Metabolic, Inborn / Q000503:physiopathology* / Q000652:urine*; D002648:Child; D003401:Creatine / Q000172:deficiency* / Q000652:urine; D002658:Developmental Disabilities / Q000652:urine*; D006801:Humans; D008607:Intellectual Disability / Q000652:urine*; D008297:Male; D026901:Membrane Transport Proteins / Q000652:urine*; D038901:X-Linked Intellectual Disability / Q000503:physiopathology* / Q000652:urine*; D009419:Nerve Tissue Proteins / Q000235:genetics; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000652:urine
D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C094770:SLC6A8 protein, human; C080679:creatine transporter; D003401:Creatine