Clinical features and X-inactivation in females heterozygous for creatine transporter defect.
The creatine transporter defect is an X-linked cause of mental retardation. We investigated the clinical features and pattern of X-inactivation in a Dutch cohort of eight female heterozygotes. We show that symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female heterozygotes. We further show that the diagnosis in females is not straightforward: (i) The creatine/creatinine ratio in urine was elevated only in three of eight females. (ii) Although as a group the females had a significantly decreased cerebral creatine concentration, individual females had creatine concentrations overlapping with normal controls. (iii) Skewed X-inactivation was found in the cultured fibroblasts, in favour of either the mutated or the wild-type allele, leading to either deficient or normal results in the creatine uptake studies in fibroblasts. Thus, screening by these tests is unreliable for the diagnosis. In addition, we found no consistent skewing of the X-inactivation in peripheral tissues indicating that there is no selection against the creatine transporter defect. We conclude that testing for creatine transporter defect should be considered in females with (mild) mental retardation. Screening by DNA analysis of the SLC6A8 gene is recommended.
van de Kamp
J M
JM
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. jm.vandekamp@vumc.nl
Mancini
G M S
GM
Pouwels
P J W
PJ
Betsalel
O T
OT
van Dooren
S J M
SJ
de Koning
I
I
Steenweg
M E
ME
Jakobs
C
C
van der Knaap
M S
MS
Salomons
G S
GS
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003401:Creatine / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009426:Netherlands; D009483:Neuropsychological Tests; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics*
D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C094770:SLC6A8 protein, human; D003401:Creatine