Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect

The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated 1H-MRS and neuropsychological assessments during 4–6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H1-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect

Creatine Transporter (CrT; Slc6a8) Knockout Mice as a Model of Human CrT Deficiency

Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2–4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT−/y (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT−/y mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT−/y mice showed increased average distance from the platform site. CrT−/y mice showed reduced novel object recognition and conditioned fear memory compared to CrT+/y. CrT−/y mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder

Excellent Response to a Ketogenic Diet in a Patient with Alternating Hemiplegia of Childhood

International audienceAlternating hemiplegia of childhood (AHC) is a rare disorder caused by heterozygous mutations in ATP1A3. AHC is associated with early-onset plegic and tonic/dystonic attacks and permanent neurologic deficits. Attacks tend to persist through life. Flunarizine therapy occasionally reduces the severity, duration and frequency of attacks. A ketogenic diet/modified Atkins diet (KD/MAD) can attenuate paroxysmal movement disorders associated with GLUT1 deficiency syndrome (GLUT1DS), but there are no reports on the effect of KD/MAD in AHC. We describe the case of a young girl with AHC who had tonic/dystonic and plegic attacks, mostly triggered by exercise, together with mild permanent dystonia and mental retardation. Her family had a history of dominant (three affected generations) paroxysmal exercise-induced dystonia. A history of plegic attacks that ceased after childhood was retraced from the medical records of the three affected adults, leading to the diagnosis of familial AHC due to ATP1A3 p.Asp923Asn mutation (Roubergue et al 2013). KD/MAD was considered for the proband when she was 3½ years old, following initial misdiagnosis of GLUT1DS. MAD, a KD variant, was chosen because it is easier to manage than KD and is similarly effective to KD in most GLUT1DS patients. MAD resulted in complete disappearance of the attacks during 15 months of follow-up. A modified Atkins diet had a sustained beneficial effect on attacks associated with AHC. Although preliminary, this observation suggests that a ketogenic diet might be a therapeutic option for paroxysmal disorders in some patients with alternating hemiplegia of childhood