Journal of Inherited Metabolic Disease

, Volume 29, Issue 1, pp 214–219

X-linked creatine transporter defect: A report on two unrelated boys with a severe clinical phenotype

  • I. M. Anselm
  • F. S. Alkuraya
  • G. S. Salomons
  • C. Jakobs
  • A. B. Fulton
  • M. Mazumdar
  • M. Rivkin
  • R. Frye
  • T. Young Poussaint
  • D. Marsden

Summary

We report two unrelated boys with the X-linked creatine transporter defect (CRTR) and clinical features more severe than those previously described with this disorder. These two boys presented at ages 12 and 30 months with severe mental retardation, absent speech development, hypotonia, myopathy and extra-pyramidal movement disorder. One boy has seizures and some dysmorphic features; he also has evidence of an oxidative phosphorylation defect. They both had classical absence of creatine peak on brain magnetic resonance spectroscopy (MRS). In one, however, this critical finding was overlooked in the initial interpretation and was discovered upon subsequent review of the MRS. Molecular studies showed large genomic deletions of a large part of the 3′ end of the complete open reading frame of the SLC6A8 gene. This report emphasizes the importance of MRS in evaluating neurological symptoms, broadens the phenotypic spectrum of CRTR and adds knowledge about the pathogenesis of creatine depletion in the brain and retina.

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References

  1. Bizzi A, Bugiani M, Salomons GS, et al (2002) X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. Ann Neurol 52: 227–231.CrossRefPubMedGoogle Scholar
  2. Brustovetsky N, Brustovetsky T, Dubinsky JM (2001) On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem 76: 425–434.CrossRefPubMedGoogle Scholar
  3. Cooper LL, Hansen RM, Darras BT, et al (2002) Rod photoreceptor function in children with mitochondrial disorders. Arch Ophthalmol 120: 1055–1062.PubMedGoogle Scholar
  4. Corzo D, Gibson W, Johnson K, et al (2002) Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet 70: 1520–1531.CrossRefPubMedGoogle Scholar
  5. Das AM, Ullrich K, Isbrandt D (2000) Upregulation of respiratory chain enzymes in guanidinoacetate methyltransferase deficiency. J Inherit Metab Dis 23: 375–377.CrossRefPubMedGoogle Scholar
  6. deGrauw TJ, Salomons GS, Cecil KM, et al (2002) Congenital creatine transporter deficiency. Neuropediatrics 33: 232–238.CrossRefPubMedGoogle Scholar
  7. deGrauw TJ, Cecil KM, Byars AW, Salomons GS, Ball WS, Jakobs C (2003) The clinical syndrome of creatine transporter deficiency. Mol Cell Biochem 244: 45–48.PubMedGoogle Scholar
  8. Fulton AB, Hansen RM (2000) The development of scotopic sensitivity. Invest Ophthalmol Vis Sci41: 1588–1596.PubMedGoogle Scholar
  9. Fulton AB, Hansen RM, Westall CA (2003) Development of ERG responses: the ISCEV rod, maximal and cone responses in normal subjects. Doc Ophthalmol 107: 235–241.CrossRefPubMedGoogle Scholar
  10. Hahn KA, Salomons GS, Tackels-Horne D, et al (2002) X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. Am J Hum Genet 70: 1349–1356.CrossRefPubMedGoogle Scholar
  11. Hansen RM, Fulton AB (2005) Development of the cone ERG in infants. Invest Ophthalmol Vis Sci 46: 3458–3462.PubMedGoogle Scholar
  12. Item CB, Stockler-Ipsiroglu S, Stromberger C, et al (2001) Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69: 1127–1133.CrossRefPubMedGoogle Scholar
  13. Kleinjan DA, van Heyningen V (2005) Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet 76: 8–32.CrossRefPubMedGoogle Scholar
  14. Leuzzi V (2002) Inborn errors of creatine metabolism and epilepsy: clinical features, diagnosis, and treatment. J Child Neurol 17 (supplement 3): 3S89–97.PubMedGoogle Scholar
  15. Mancini GM, Catsman-Berrevoets CE, de Coo IF, et al (2005) Two novel mutations in SLC6A8 cause creatine transporter defect and distinctive X-linked mental retardation in two unrelated Dutch families. Am J Med Genet A 132: 288–295.PubMedGoogle Scholar
  16. O’Gorman E, Beutner G, Wallimann T, Brdiczka D (1996) Differential effects of creatine depletion on the regulation of enzyme activities and on creatine-stimulated mitochondrial respiration in skeletal muscle, heart, and brain. Biochim Biophys Acta 1276: 161–170.PubMedGoogle Scholar
  17. O’Gorman E, Fuchs KH, Tittmann P, Gross H, Wallimann T (1997) Crystalline mitochondrial inclusion bodies isolated from creatine depleted rat soleus muscle. J Cell Sci 110(12): 1403–1411.PubMedGoogle Scholar
  18. Rosenberg EH, Almeida LS, Kleefstra T, et al (2004) High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 75: 97–105.CrossRefPubMedGoogle Scholar
  19. Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C (2001) X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68: 1497–1500.CrossRefPubMedGoogle Scholar
  20. Salomons GS, van Dooren SJ, Verhoeven NM, et al (2003) X-linked creatine transporter defect: an overview. J Inherit Metab Dis 26: 309–318.CrossRefPubMedGoogle Scholar
  21. Schulze A (2003) Creatine deficiency syndromes. Mol Cell Biochem 244: 143–150.CrossRefPubMedGoogle Scholar
  22. Stockler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K (1996) Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 58: 914–922.PubMedGoogle Scholar
  23. Stromberger C, Bodamer OA, Stockler-Ipsiroglu S (2003) Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis 26: 299–308.CrossRefPubMedGoogle Scholar
  24. Tarnopolsky MA, Roy BD, MacDonald JR (1997) A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 20: 1502–1509.CrossRefPubMedGoogle Scholar
  25. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80: 1107–1213.PubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  • I. M. Anselm
    • 1
  • F. S. Alkuraya
    • 2
  • G. S. Salomons
    • 5
  • C. Jakobs
    • 5
  • A. B. Fulton
    • 3
  • M. Mazumdar
    • 1
  • M. Rivkin
    • 1
  • R. Frye
    • 1
  • T. Young Poussaint
    • 4
  • D. Marsden
    • 2
  1. 1.Department of Neurology, Children’s Hospital BostonHarvard Medical SchoolBostonUSA
  2. 2.Division of Genetics and Metabolism, Children’s Hospital BostonHarvard Medical SchoolBostonUSA
  3. 3.Department of Ophthalmology, Children’s Hospital BostonHarvard Medical SchoolBostonUSA
  4. 4.Department of Radiology, Children’s Hospital BostonHarvard Medical SchoolBostonUSA
  5. 5.Department of Clinical Chemistry, Metabolic UnitVU University Medical CenterAmsterdamThe Netherlands

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