X-linked Creatine Transporter Defect: a Report on Two Unrelated Boys with a Severe Clinical Phenotype

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2006 Apr 8

PMID 16601897

Citations 22

Authors

I A Anselm

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

[F]FDG-PET and [F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation.

Day I, Tamboline M, Lueptow L, Zhuravka I, Diep T, Tkachyova I Sci Rep. 2025; 15(1):7280.

PMID: 40025148 PMC: 11873236. DOI: 10.1038/s41598-025-92022-8.

Whole exome sequencing reveals a dual diagnosis of -related syndrome and glutaric aciduria III.

Huggins E, Jackson D, Young S, Kishnani P Mol Genet Metab Rep. 2024; 40:101117.

PMID: 39101156 PMC: 11296045. DOI: 10.1016/j.ymgmr.2024.101117.

Selective Alteration of the Left Arcuate Fasciculus in Two Patients Affected by Creatine Transporter Deficiency.

Balestrino M, Adriano E, Ali P, Pardini M Brain Sci. 2024; 14(4).

PMID: 38671990 PMC: 11048612. DOI: 10.3390/brainsci14040337.

Catching the Culprit: How Chorea May Signal an Inborn Error of Metabolism.

Ortigoza-Escobar J Tremor Other Hyperkinet Mov (N Y). 2023; 13:36.

PMID: 37810989 PMC: 10558026. DOI: 10.5334/tohm.801.

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review.

Heath O, Pandithan D, Pitt J, Savva E, Raiti L, Bracken J JIMD Rep. 2023; 64(5):337-345.

PMID: 37701323 PMC: 10494507. DOI: 10.1002/jmd2.12390.

References

Leuzzi V . Inborn errors of creatine metabolism and epilepsy: clinical features, diagnosis, and treatment. J Child Neurol. 2003; 17 Suppl 3:3S89-97; discussion 3S97. View

Item C, Stockler-Ipsiroglu S, Stromberger C, Muhl A, Alessandri M, Bianchi M . Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet. 2001; 69(5):1127-33. PMC: 1274356. DOI: 10.1086/323765. View

Bizzi A, Bugiani M, Salomons G, Hunneman D, Moroni I, Estienne M . X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. Ann Neurol. 2002; 52(2):227-31. DOI: 10.1002/ana.10246. View

Corzo D, Gibson W, Johnson K, Mitchell G, Lepage G, Cox G . Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002; 70(6):1520-31. PMC: 419992. DOI: 10.1086/340849. View

OGorman E, Fuchs K, Tittmann P, Gross H, Wallimann T . Crystalline mitochondrial inclusion bodies isolated from creatine depleted rat soleus muscle. J Cell Sci. 1997; 110 ( Pt 12):1403-11. DOI: 10.1242/jcs.110.12.1403. View

OGorman E, Beutner G, Wallimann T, Brdiczka D . 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. 1996; 1276(2):161-70. DOI: 10.1016/0005-2728(96)00074-6. View

Brustovetsky N, Brustovetsky T, Dubinsky J . On the mechanisms of neuroprotection by creatine and phosphocreatine. J Neurochem. 2001; 76(2):425-34. DOI: 10.1046/j.1471-4159.2001.00052.x. View

Stromberger C, Bodamer O, Stockler-Ipsiroglu S . Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis. 2003; 26(2-3):299-308. DOI: 10.1023/a:1024453704800. View

Stockler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K . Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet. 1996; 58(5):914-22. PMC: 1914613. View

10.

Fulton A, Hansen R . The development of scotopic sensitivity. Invest Ophthalmol Vis Sci. 2000; 41(6):1588-96. View

11.

Kleinjan D, Heyningen V . Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet. 2004; 76(1):8-32. PMC: 1196435. DOI: 10.1086/426833. View

12.

Tarnopolsky M, Roy B, Macdonald J . A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve. 1997; 20(12):1502-9. DOI: 10.1002/(sici)1097-4598(199712)20:12<1502::aid-mus4>3.0.co;2-c. View

13.

Mancini G, Catsman-Berrevoets C, de Coo I, Aarsen F, Kamphoven J, Huijmans J . 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. 2005; 132A(3):288-95. DOI: 10.1002/ajmg.a.30473. View

14.

Rosenberg E, Almeida L, Kleefstra T, deGrauw R, Yntema H, Bahi N . High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 2004; 75(1):97-105. PMC: 1182013. DOI: 10.1086/422102. View

15.

Das A, Ullrich K, Isbrandt D . Upregulation of respiratory chain enzymes in guanidinoacetate methyltransferase deficiency. J Inherit Metab Dis. 2000; 23(4):375-7. DOI: 10.1023/a:1005643617251. View

16.

Salomons G, van Dooren S, Verhoeven N, Marsden D, Schwartz C, Cecil K . X-linked creatine transporter defect: an overview. J Inherit Metab Dis. 2003; 26(2-3):309-18. DOI: 10.1023/a:1024405821638. View

17.

Fulton A, Hansen R, Westall C . Development of ERG responses: the ISCEV rod, maximal and cone responses in normal subjects. Doc Ophthalmol. 2004; 107(3):235-41. DOI: 10.1023/b:doop.0000005332.88367.b8. View

18.

Salomons G, van Dooren S, Verhoeven N, Cecil K, Ball W, deGrauw T . X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet. 2001; 68(6):1497-500. PMC: 1226136. DOI: 10.1086/320595. View

19.

Hahn K, Salomons G, Tackels-Horne D, Wood T, Taylor H, Schroer R . 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. 2002; 70(5):1349-56. PMC: 447610. DOI: 10.1086/340092. View

20.

Cooper L, Hansen R, Darras B, Korson M, Dougherty F, Shoffner J . Rod photoreceptor function in children with mitochondrial disorders. Arch Ophthalmol. 2002; 120(8):1055-62. DOI: 10.1001/archopht.120.8.1055. View