Diagnostic timing in cerebral creatine deficiency syndromes: neurodevelopmental and genetic characterization of a multicenter cohort.

purposeCerebral creatine deficiency syndromes (CCDS) are rare inherited neurometabolic disorders comprising two creatine biosynthesis defects-guanidinoacetate methyltransferase (GAMT) and arginine:glycine amidinotransferase (AGAT) deficiencies-and creatine transporter (CRTR) deficiency. Because early diagnosis and presymptomatic treatment are critical, particularly in biosynthesis defects, this study aimed to delineate the clinical features, diagnostic timing, and genetic spectrum of CCDS, and to describe the outcomes of presymptomatically treated patients.

methodsThis was a retrospective, multicenter cohort study. Clinical, radiological, biochemical, and genetic data were reviewed, and all variants were classified according to the gene-specific ClinGen CCDS Variant Curation Expert Panel specifications. Patients with pathogenic or likely pathogenic variants were considered genetically confirmed; patients whose variants remained of uncertain significance (VUS) were described separately and excluded from comparative analyses.

resultsOf the 22 enrolled patients, 19 were genetically confirmed. Three presymptomatically treated patients with GAMT deficiency remained asymptomatic. Among the 16 symptomatic, genetically confirmed patients, the median diagnostic interval was 88.5 months (IQR 114; range 10-228). All symptomatic patients had global developmental delay or intellectual disability. Four novel variants were identified: the homozygous p.(Arg189His) variant (AGAT deficiency) was classified as likely pathogenic and the homozygous deletion c.242_327+63del (GAMT deficiency) as pathogenic; two hemizygous variants (CRTR deficiency), p.(Trp55Arg) and p.(Gly253Glu), remained VUS.

conclusionFavorable neurodevelopmental outcomes in patients with GAMT deficiency treated before symptom onset underscore the importance of clinical awareness and timely diagnosis, and support the rationale for newborn screening. The two novel disease-causing variants expand the genetic spectrum of CCDS. WHAT IS KNOWN: • Cerebral creatine deficiency syndromes are rare inherited neurometabolic disorders comprising AGAT, GAMT, and CRTR deficiencies. • Presymptomatic treatment of GAMT deficiency can prevent irreversible neurodevelopmental sequelae. WHAT IS NEW: • Two novel disease-causing variants (likely pathogenic in AGAT deficiency; pathogenic in GAMT deficiency) expand the genetic spectrum; two novel SLC6A8 variants remain of uncertain significance under ClinGen CCDS Expert Panel criteria. • Favorable outcomes in three presymptomatically treated patients with GAMT deficiency support the rationale for newborn screening.