Abstracts

Creatine transporter 1 (CT1) deficiency (CTD) is a main cause of male intellectual disability. Variants in the X-linked SLC6A8 gene cause a spectrum of autism, neurodevelopmental disability, and epilepsy. Epilepsy is typically responsive to conventional antiseizure medications.¹ However, there is no effective treatment for CTD, and for some the epilepsy becomes drug refractory. Supplementation with creatine, arginine, and glycine have not shown sustained improvements.²

Phenylbutyrate (PBA), 4-phenylbutyric acid, is an FDA-approved treatment for urea cycle disorders. PBA may have a chaperone effect in six CTD variants in vitro³. PBA also shows promise in mouse models of SLC6A1 and STXBP1.⁴ We hypothesized that in one boy with CTD, severe epilepsy, and autism, PBA may improve EEG background, seizure burden, caregiver impression of behavior, or increased creatine peak on MR spectroscopy (MRS).

A nine year old boy was diagnosed with CTD (c.321_323delCTT [p.Phe107del]) at three months of age due to a proband older sibling. Seizures began at age two with a febrile illness, well controlled on levetiracetam. At age seven, he had an episode of refractory status epilepticus, and subsequently developed drug refractory localization-related epilepsy failing phenobarbital, lacosamide, oxcarbazepine, cannabidiol, and perampanel. Seizures were right frontal onset; he underwent stereotactic EEG and right middle frontal gyrus focal resection at age eight. Surgical pathology demonstrated focal cortical dysplasia type IIa. Following resection, he had 1.5 months of seizure freedom before seizures recurred at a similar frequency every three weeks. 

The patient was admitted for continuous EEG and initiation of glycerol phenylbutyrate. Titration schedule followed FDA approved guidelines to goal 11.2 mL/m²/day⁵. The patient was evaluated at 1, 2, 3, and 6 months of therapy. MRI brain with MRS was obtained at three and six months of therapy.

The patient experienced no adverse effects related to PBA. Immediately after initiation, there was no change in EEG background which showed moderate diffuse slowing with occasional right frontal spikes. Seizure burden (focal to bilateral tonic clonic) remained unchanged at three and six months by caregiver report. Caregivers reported subjective mild to moderate improvement in behaviors (hyperactivity and impulsivity) from pre-treatment baseline at one and two months, and a mild improvement at three and six months, though did request a trial of stimulant medications at six months. MRS showed no change in creatine peak at three and six months.

Improvement in caregivers’ impression of behaviors was not sustained. Notably, functional studies on this individual’s variant are not available, and this variant was not one of the six CTD variants included in the study suggesting PBA has a chaperone effect. The variant is in a highly conserved phenylalanine in transmembrane domain 2, but whether this produces a misfolded protein amenable to chaperone therapy is unknown.⁶ Finally, time to treatment response is unknown; it is possible that a longer treatment duration is necessary. Further studies of PBA in other variants are needed.