Advancing clinical insight into creatine transporter deficiency: long term outcome and new observations from the Italian cohort

Background: Creatine Transporter Deficiency (CTD) is a rare X-linked disorder caused by pathogenic or likely pathogenic variants in the SLC6A8 gene, leading to a deficiency of cerebral Creatine. Clinically, CTD manifests as a complex neurodevelopmental disorder and is associated with Intellectual Disability (ID), language and socio-communicative impairments, behavioral challenges and, often, epilepsy. Methods: This study was conducted in two phases: (i) An eSurvey was distributed among major Italian clinics specializing in rare neurometabolic diseases to create a national census of CTD patients, with extensive clinical data; (ii) A retrospective observational study was performed on patients who had undergone regular long-term follow-up using a consistent neuropsychological assessment and treatment protocol. Results: We identified 18 CTD male patients, aged 18 months to 32 years at diagnosis. Within this cohort, 3 to 13 years follow-up clinical information was collected for 10 patients. A specific clinical protocol was applied to this subgroup, where a biochemical or 1H-MRS diagnosis was confirmed in 8 patients (urine Creatine/Creatinine ratio > 1), while in the remaining 2 patients, genetic testing was diagnostic and neurochemical tests followed. 1H-MRS consistently showed a decreased Creatine peak in all patients. All 10 patients exhibited ID with significant speech disorder, and 6 had epilepsy. The treatment protocol for this cohort involved oral Arginine supplementation. Conclusions: Diagnosing CTD remains clinically challenging due to the often negative results from a first tier clinical diagnostic test for intellectual disability (ID) (i.e. family history, cytogenetic testing and Fragile X) and neuroimaging without spectroscopy. CTD should be carefully considered when investigating severe ID with autistic-like traits and significant speech impairment, with or without epilepsy. The Urine Creatine/Creatinine ratio assay is a quick initial diagnostic step, which can be corroborated by a brain MRI/1H-MRS and molecular genetics. Even considering previouis literature findings, it is not yet possible, to demonstrate definite genotype-phenotype correlations, although a milder functional impairment has been suggested for missense SLC6A8 pathogenic or likely pathogenic variants. Treatment strategies supplementation with Creatine and its precursors have provided heterogeneous and inconsistent results. Recently proposed innovative therapeutic strategies such as lipophilic Creatine analogs and betaine supplementation in animal models need validation in human disease.