Abstract
X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (−83% in gray and −79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (−50% to −33% in gray and −45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.
Competing interests: None declared
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Acknowledgment
This work has been supported by grants of the German Ministry of Education and Research through the German Leukonet (Grants 01GM0642 and 01GM0836; KB, SDK, JG); the MRNET (Grant 01GS08161; HHR); by the Project GENCODYS (241995), which is funded by the European Union Framework Program 7 (FP7); and the Volkswagen Stiftung (PD, GH). SDK has received funding from the Dorothea-Schloezer-Program of the Georg August University Goettingen, Germany. We thank Melanie Bienek and Ute Fischer for excellent technical assistance.
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Communicated by: Nicole Wolf, MD PhD
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Synopsis
The combination of the powerful technology exome-next-generation sequencing with thorough systematic clinical evaluation of patients, as in this study of a family with X-linked creatine transport deficiency, will work synergistically to further expand the clinical spectrum of neurometabolic diseases.
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Steffi Dreha-Kulaczewski, Vera Kalscheuer, Andreas Tzschach, HaoCougar Hu, Gunther Helms, Knut Brockmann, Almut Weddige, Peter Dechent, Gregor Schlüter, Ralf Krätzner, Hans-Hilger Ropers, Jutta Gärtner, and Birgit Zirn declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained for all patients being included in the study.
Details of the Contributions of Individual Authors
SDK: designed and conducted the MR studies, interpreted the MR data, wrote the manuscript
VMK, HHR: designed the genetic studies, interpreted the data, substantially revised the manuscript
AT, HH, GS: conducted the genetic studies, analyzed and interpreted the data
AW: conducted the neuropsychological investigations
RK: designed and conducted the biochemical studies, interpreted the data, revised the manuscript
GH, PD: designed the MR studies, interpreted the data, revised the manuscript
KB, JG, BZ: designed and conducted the clinical study, substantially revised the manuscript
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Dreha-Kulaczewski, S. et al. (2013). A Novel SLC6A8 Mutation in a Large Family with X-Linked Intellectual Disability: Clinical and Proton Magnetic Resonance Spectroscopy Data of Both Hemizygous Males and Heterozygous Females. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, Volume 13. JIMD Reports, vol 13. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_261
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DOI: https://doi.org/10.1007/8904_2013_261
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