Creatine transporter deficiency in a family with unexplained intellectual disability

Background

Creatine transporter deficiency (CTD) is an X-linked genetic disorder caused by SLC6A8 mutations, characterized by seizures, behavior disorders, developmental delay and language disorders. In the literature, 1-2.6% of boys with intellectual disability of unknown etiology have mutations in the SLC6A8 gene. Heterozygous females are typically either asymptomatic or have mild intellectual disability.

Case Study

Here we report 4 cases of X-linked CTD – index case (male, 26 years-old), his sister (22 years-old), mother (43 years-old) and maternal uncle (45 years-old). The index case was studied due to intellectual disability, with a family history of similar symptoms (moderate to severe for males and mild in females). All family members had nonspecific dysmorphism (microcephaly and short stature) and delayed language development (more severe in males). Three of them have been diagnosed with epilepsy (index case, uncle and mother) and attention deficit hyperactivity disorder (index case, uncle and sister). Gastrointestinal issues were reported only in the index case and his mother, and there was no description of extrapyramidal movement abnormalities.

Results

MRI with spectroscopy (MRS) revealed markedly reduced peak creatine in all cases. Urine creatine/creatinine screening was normal in females. A probably pathogenic SLC6A8 variant c.212G>A p.(Gly71Asp) was found in hemizygosity in the index case and uncle and in heterozygosity in mother and sister.

Conclusion

CTD is an important cause of intellectual disability, particularly in males. Despite being rarely described, females can also have a severe phenotype and CTD should be considered in the diagnosis. Urinary screening in women is not an effective method but brain MRI appears to be helpful.