SLC6A8-associated creatine transporter deficiency in a female individual with normal urine and plasma creatine metabolite levels, but a 50% reduction in the cerebral creatine peak on quantitative reanalysis of MR spectroscopy

We report the clinical, genetic, and neuroimaging findings of a young female patient presenting with paroxysmal gait disturbances, developmental regression, and epilepsy, ultimately diagnosed with an X-linked creatine transporter deficiency (SLC6A8). This case highlights the diagnostic challenges and phenotype variability in female carriers of SLC6A8 mutations.
Introduction:
Creatine transporter deficiency (CTD), caused by mutations in the SLC6A8 gene on the X chromosome, is characterized primarily by intellectual disability, speech delay, epilepsy, and behavioral abnormalities. While predominantly affecting males due to its X-linked inheritance, heterozygous females may exhibit milder but clinically significant symptoms due to X-chromosome inactivation variability.
Case Presentation:
The patient began developing paroxysmal gait disturbances at age 4, marked by sudden episodes of leg trembling and falls during routine activities such as tooth brushing. Episodes occurred multiple times daily, lasting approximately one minute, with preserved consciousness but impaired speech and inability to stand. Initial treatment for suspected periodic ataxia with acetazolamide was ineffective. At age 10, the patient experienced a generalized tonic-clonic seizure, prompting initiation of lamotrigine-based anticonvulsive therapy, which controlled further generalized seizures.
Parents reported regression in developmental milestones, including reduced arithmetic skills, slurred speech, a gait described as “drunken,” impaired fine motor skills, frequent hand cramps, and heightened anxiety in response toenvironmental stimuli.
Diagnostic Workup:
EEG revealed irregular generalized spike-wave complexes from disease onset, initially considered idiopathic. Comprehensive investigations including brain MRI, metabolic panels, lumbar puncture, and tests for episodic ataxia and alternating hemiplegia were unremarkable.
Whole exome sequencing identified a variant of uncertain significance in the NTRK2 gene, inherited from the asymptomatic father and likely benign. Subsequent trio exome analysis detected a heterozygous SLC6A8 variant absent from prior reports. The variant was present at low-level mosaicism in the father. Functional metabolic assays of creatine and its metabolites were within normal or nonspecific ranges. Proton magnetic resonance spectroscopy initially showed a normal creatine peak.
Following literature review and expert radiologic consultation, a quantitative reanalysis of the patient’s MR spectroscopy revealed a 50% reduction in the cerebral creatine peak, consistent with female heterozygous carriers of pathogenic SLC6A8 mutations.
Discussion:
SLC6A8 deficiency manifests with neurodevelopmental delay, speech impairment, epilepsy, and behavioral symptoms including anxiety and autism spectrum features. Movement disorders such as dystonia and ataxia can occur. Female carriers often present a variable phenotype, with subtler biochemical abnormalities and partial creatine depletion detectable via advanced imaging methods.
Despite normal urine and plasma creatine metabolite levels and an initially normal spectroscopic creatine peak, quantitative analysis and genetic findings support a diagnosis of CTD. Treatment with creatine and glycine over 2.5 months showed no clinical improvement to date, consistent with variable therapeutic responses reported in the literature.
Conclusion:
This case underscores the importance of considering SLC6A8-associated creatine transporter deficiency in females presenting with unexplained neurodevelopmental regression, epilepsy, and movement abnormalities. Comprehensive genetic testing, detailed metabolic workup, and sensitive imaging modalities are critical to diagnosis. Female heterozygotes may benefit from tailored diagnostic and therapeutic approaches despite atypical presentations.