X-linked Creatine transport deficiency: Phenotypic variability in a family with SLC6A8 gene mutation

Case Report: The X-linked creatine transporter deficiency (CRTD) caused by a mutation in the creatine transporter gene SLC6A8 is a common cause of X-linked mental retardation. The clinical phenotype ranges from mild to severe mental retardation, seizures, short stature, poor language skills, and autism spectrum disorders. Female carriers may exhibit learning disabilities of varying degrees and behavioral problems.

We report on a German family affected by a mutation in SLC6A8 gene. Two brothers (aged 17 and 10 years) presented with similar symptoms including short stature, lack of speech development, hyperactive and impulsive behavior as well as generalized epileptic seizures, but variable cognitive abilities. An affected sister also presented with short stature, complex focal seizures, learning difficulties and language delay. The mother was healthy except for mild learning difficulties; the unaffected sister was healthy with normal cognitive abilities.

Anticonvulsive therapy with valproate and lamotrigine was not effective neither for the boys nor for the girls, with continued breakthrough seizures. DNA sequence analysis of the SLC6A8 gene highlighted a hemizygous missense mutation (c.1169 C>T; p.Pro390Leu, exon 8) in both brothers and a heterozygous mutation in the mother and the affected sister. cMRI-scan indicated no groß structural abnormalities, whereas voxel based morphometric analysis showed a white matter volume below the first percentile in the severely affected boy compared with the other family members and the control database. Furthermore, ntCr concentrations differed significantly between the individuals (p < 0.05).

The present observations suggest a gender independent correlation between intellectual capability and total creatine concentration in the brain of patients with X-linked CRTD. The variable severity of the affected female suggests selective X-inactivation during development. In addition to observations from literature, evidence arises that differences in mental development might be related to atrophy of the subcortical white matter.