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  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

Dreha-Kulaczewski, S., Kalscheuer, V., Tzschach, A., Hu, H., Helms, G., Brockmann, K., et al. (2014). 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. JIMD Reports, 13, 91-99. doi:10.1007/8904_2013_261.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-F39E-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C2C8-D
Genre: Journal Article

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Dreha-Kulaczewski.pdf (Publisher version), 283KB
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© 2013 Springer, Part of Springer Science+Business Media
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Dreha-Kulaczewski, S., Author
Kalscheuer, V.1, Author              
Tzschach, A.2, Author
Hu, H.2, Author              
Helms, G., Author
Brockmann, K., Author
Weddige, A., Author
Dechent, P., Author
Schluter, G., Author
Kratzner, R., Author
Ropers, H. H.2, Author              
Gartner, J., Author
Zirn, B., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, Germany, ou_1479642              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr, 73, 14195 Berlin, Germany, ou_1433549              

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 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.

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Language(s): eng - English
 Dates: 2013-11-052014
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1007/8904_2013_261
ISSN: 2192-8304 (Print)
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Title: JIMD Reports
Source Genre: Journal
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Publ. Info: Berlin, Heidelberg : Springer
Pages: - Volume / Issue: 13 Sequence Number: - Start / End Page: 91 - 99 Identifier: -