Creatine Transporter Deficiency: A Rare Neurodevelopmental Disorder with ASD Symptomatology

Background:  Creatine transporter deficiency (CTD) is a rare X-linked inherited neurometabolic condition associated with intellectual disability, minimal verbal development and, in some cases, ASD. Seizures are also common. CTD is caused by mutations in the SLC6A8 gene, and was discovered in 2001. It is estimated that 0.2% to 3.5% of males with Intellectual Disability or Autism Spectrum Disorder (ASD) may have CTD (Thurm et al., 2016). Unfortunately, CTD cannot be identified through microarrays, which are commonly ordered for children with ASD. Like other genetic conditions associated with ASD characteristics, it is important to increase identification and to understand the behavioral phenotype, as these children may have a distinct developmental trajectory.

Objectives:  The objective of the study was to understand the potential relationship between CTD and ASD with regard to identification, characteristics, and developmental course.

Methods:  We studied 20 children and adults with CTD, ages 1-21 years, through parent interviews, questionnaires, medical records and direct testing. Parent interviews were relatively unstructured but were informed by our familiarity with the ADI-R. We asked about first concerns, concerns in hindsight, the path to diagnosis, and parents’ top current concerns. We administered the Vineland Adaptive Behavior Scales, Social Communication Questionnaire (SCQ) and Aberrant Behavior Checklist (ABC) to all 20; the Mullen Scales of Early Learning to seven (some of whom were older than 60 months).

Results:  Six participants had a documented diagnosis of ASD in addition to CTD. One participant had a biological sibling with ASD, but not ASD himself. The quality of early concerns was not different between children with CTD+ASD or CTD alone. Across the entire group, parents’ first concerns were most often about delayed speech or motor milestones (most often walking, but sometimes crawling). In hindsight, parents reported high rates of vomiting in the first year of life (66%). Across the entire group, the average SCQ was 20.8 (range 10-34), with 16/20 (81.25%) individuals scoring 15 or higher. ABC average Irritability domain score was 17.6 (range: 4-38). Vineland and Mullen scores were generally in the very low ranges such that it would be difficult to calculate mental ages accurately. Even with high SCQ scores, parent top concerns were: language, negative behaviors, independence skills, attention, and emotion regulation. Most individuals with CTD continue to struggle with basic self-help skills such as dressing and bathing, but parents did not describe the social aloofness or withdrawal often seen in severely impaired children with ASD.

Conclusions:  As new genetic disorders are discovered, it will be important for ASD researchers and clinicians to consider whether they have undiagnosed individuals in their caseloads or samples. Individuals with CTD are likely to have a different developmental trajectory and diminished response to behavioral treatment than most children with ASD. While not universal, possible signs of CTD include minimal verbal development, a history of delayed crawling or walking, vomiting during the first year of life, and possible seizures. Challenging, attention-seeking behaviors are also common. Referral to a metabolic geneticist is important for both diagnosis and treatment.