Summary
The urinary creatine:creatinine (Cr:Crn) ratio was measured in males from 49 families with a family history compatible with X-linked mental retardation (XLMR) in order to estimate the prevalence of SLC6A8 deficiency in Estonia. We identified 11 boys from 9 families with an increased urinary Cr:Crn ratio (18%). In three related boys, a hemizygous missense mutation (c.1271G>A; p.Gly424Asp) was identified. Their mother was heterozygous for the same mutation. Although many missense mutations have been described, the p.Gly424Asp mutation has not been previously reported. The clinical expression varied widely among affected males of this family. Patients 1 and 3 had relatively mild clinical expression (mild mental retardation (MR) and attention deficit disorder), but patient 2 had all typical clinical signs of SLC6A8 defect such as moderate MR, autistic features, expressive dysphasia and epilepsy. Among our patients, we saw significant problems in speech and language development combined with attention and behavioural difficulties. The number of false-positive biochemical results with increased urinary Cr:Crn ratio was higher (18%) in our study than in previous reports (1.8–10%). We therefore suggest that repeated biochemical testing should be performed before DNA sequencing analysis. Our study suggests that 2% (95% confidence limits: 0.05–11.1%) of this Estonian XLMR panel are due to mutations in the SLC6A8, which is similar to the prevalence reported in other populations. We therefore conclude that creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar MR and diagnostic screening of them should always include screening for SLC6A8 deficiency.
Abbreviations
- Cr:Crn:
-
creatine:creatinine
- CT-1:
-
creatine transporter-1
- ENMG:
-
electroneuromyography
- MR:
-
mental retardation
- MRS:
-
magnetic resonance spectroscopy
- RPM:
-
Raven Progressive Matrices
- SLC6A8 :
-
creatine transporter-1 gene
- XLMR:
-
X-linked mental retardation
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Acknowledgements
This work was supported by TARLA 2695. G. S. Salomons was supported by the Dutch Society for Scientific Research (ZonMW/NWO), VIDI grant number 917.56.349. We thank the participating parents and children, and their family doctors, whose cooperation made this study possible. We also thank Dr Michael Field and Ms Anne Proos for helping with manuscript preparation.
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Communicating editor: Michael Gibson
Competing interests: None declared
References to electronic databases: Creatine deficiency syndrome, X-linked: OMIM 300352. SLC6A8 (creatine transporter-1 (CT1)) gene: OMIM 300036.
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Puusepp, H., Kall, K., Salomons, G.S. et al. The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation. J Inherit Metab Dis 33 (Suppl 3), 5–11 (2010). https://doi.org/10.1007/s10545-008-1063-y
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DOI: https://doi.org/10.1007/s10545-008-1063-y