Download PDF
Semin Neurol 2014; 34(03): 350-356
DOI: 10.1055/s-0034-1386772
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders

Sylvia Stockler-Ipsiroglu
1   Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada
2   Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), University of British Columbia, Vancouver, Canada
3   Child and Family Research Institute, University of British Columbia, Vancouver, Canada
,
Clara D.M. van Karnebeek
1   Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada
2   Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), University of British Columbia, Vancouver, Canada
3   Child and Family Research Institute, University of British Columbia, Vancouver, Canada
4   Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
05 September 2014 (online)

    Permissions and Reprints

Corrected by:

Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental DisordersSemin Neurol 2014; 34(04): 479-480
DOI: 10.1055/s-0034-1394130

Abstract

Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders.

Keywords

GATM - guanidinoacetate methyltransferase - SLC6A8 - magnetic resonance spectroscopy - treatment - intellectual disability - developmental delay - autism
 

  • References

  • 1 van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012; 105 (3) 368-381
    CrossrefPubMedGoogle Scholar
  • 2 van Karnebeek CDM, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab 2014; 111 (4) 428-438
    CrossrefPubMedGoogle Scholar
  • 3 Stöckler S, Holzbach U, Hanefeld F , et al. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 1994; 36 (3) 409-413
    CrossrefPubMedGoogle Scholar
  • 4 Stöckler 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) 914-922
    PubMedGoogle Scholar
  • 5 Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A , et al. GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 2006; 67 (3) 480-484
    CrossrefPubMedGoogle Scholar
  • 6 Dhar SU, Scaglia F, Li FY , et al. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 2009; 96 (1) 38-43
    CrossrefPubMedGoogle Scholar
  • 7 Stockler-Ipsiroglu S, van Karnebeek C, Longo N , et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab 2014; 111 (1) 16-25
    CrossrefPubMedGoogle Scholar
  • 8 Morris AA, Appleton RE, Power B , et al. Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. J Inherit Metab Dis 2007; 30 (1) 100
    CrossrefPubMedGoogle Scholar
  • 9 Stöckler-Ipsiroglu S, Battini R, de Grauw T, Schulze A. Disorders of creatine metabolism. In: Blau N, Hoffmann GF, Leonard J, Clarke JTR, , eds. Physician's Guide to the Treatment and Follow Up of Metabolic Diseases. Heidelberg, Germany: Springer Verlag; 2005: 255-265
    Google Scholar
  • 10 Pasquali M, Schwarz E, Jensen M , et al. Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis 2014; 37 (2) 231-236
    CrossrefPubMedGoogle Scholar
  • 11 Sinclair G, Vallance H, Nelson T, van Karnebeek C, Stockler S. A pilot newborn screening program for guanidinoacetate methyltransferase (GAMT) deficiency in British Columbia. Paper presented at: Canadian Newborn and Child Screening Symposium; April 11–12, 2013; Ottawa, Ontario, Canada
    PubMedGoogle Scholar
  • 12 Item CB, Stöckler-Ipsiroglu S, Stromberger C , et al. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 2001; 69 (5) 1127-1133
    CrossrefPubMedGoogle Scholar
  • 13 Battini R, Leuzzi V, Carducci C , et al. Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 2002; 77 (4) 326-331
    CrossrefPubMedGoogle Scholar
  • 14 Edvardson S, Korman SH, Livne A , et al. I-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Mol Genet Metab 2010; 101 (2-3) 228-232
    CrossrefPubMedGoogle Scholar
  • 15 Nouioua S, Cheillan D, Zaouidi S , et al. Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency. Neuromuscul Disord 2013; 23 (8) 670-674
    CrossrefPubMedGoogle Scholar
  • 16 Verma A. Arginine:glycine amidinotransferase deficiency: a treatable metabolic encephalomyopathy. Neurology 2010; 75 (2) 186-188
    CrossrefPubMedGoogle Scholar
  • 17 Bianchi MC, Tosetti M, Battini R , et al. Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study. AJNR Am J Neuroradiol 2007; 28 (3) 548-554
    PubMedGoogle Scholar
  • 18 Battini R, Alessandrì MG, Leuzzi V , et al. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 2006; 148 (6) 828-830
    CrossrefPubMedGoogle Scholar
  • 19 Ndika JD, Johnston K, Barkovich JA , et al. Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Mol Genet Metab 2012; 106 (1) 48-54
    CrossrefPubMedGoogle Scholar
  • 20 Salomons GS, van Dooren SJ, Verhoeven NM , et al. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 2001; 68 (6) 1497-1500
    CrossrefPubMedGoogle Scholar
  • 21 Cecil KM, Salomons GS, Ball Jr WS , et al. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?. Ann Neurol 2001; 49 (3) 401-404
    CrossrefPubMedGoogle Scholar
  • 22 Rosenberg EH, Almeida LS, Kleefstra T , et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 2004; 75 (1) 97-105
    CrossrefPubMedGoogle Scholar
  • 23 Newmeyer A, deGrauw T, Clark J, Chuck G, Salomons G. Screening of male patients with autism spectrum disorder for creatine transporter deficiency. Neuropediatrics 2007; 38 (6) 310-312
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Mercimek-Mahmutoglu S, Muehl A, Salomons GS , et al. Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry. Mol Genet Metab 2009; 96 (4) 273-275
    CrossrefPubMedGoogle Scholar
  • 25 van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S , et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 2013; 50 (7) 463-472
    CrossrefPubMedGoogle Scholar
  • 26 deGrauw TJ, Salomons GS, Cecil KM , et al. Congenital creatine transporter deficiency. Neuropediatrics 2002; 33 (5) 232-238
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 van de Kamp JM, Mancini GM, Pouwels PJ , et al. Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 2011; 79 (3) 264-272
    CrossrefPubMedGoogle Scholar
  • 28 Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ , et al. Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab 2010; 101 (4) 409-412
    CrossrefPubMedGoogle Scholar
  • 29 Yu H, van Karnebeek C, Sinclair G , et al. Detection of a novel intragenic rearrangement in the creatine transporter gene by next generation sequencing. Mol Genet Metab 2013; 110 (4) 465-471
    CrossrefPubMedGoogle Scholar
  • 30 Stockler S, Schutz PW, Salomons GS. Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem 2007; 46: 149-166
    PubMedGoogle Scholar
  • 31 Braissant O, Henry H, Loup M, Eilers B, Bachmann C. Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res 2001; 86 (1-2) 193-201
    CrossrefPubMedGoogle Scholar
  • 32 Braissant O, Béard E, Torrent C, Henry H. Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 2010; 37 (2) 423-433
    CrossrefPubMedGoogle Scholar
  • 33 van de Kamp JM, Jakobs C, Gibson KM, Salomons GS. New insights into creatine transporter deficiency: the importance of recycling creatine in the brain. J Inherit Metab Dis 2013; 36 (1) 155-156
    CrossrefPubMedGoogle Scholar
  • 34 Valayannopoulos V, Boddaert N, Chabli A , et al. Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 2012; 35 (1) 151-157
    CrossrefPubMedGoogle Scholar
  • 35 van de Kamp JM, Pouwels PJ, Aarsen FK , et al. Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. J Inherit Metab Dis 2012; 35 (1) 141-149
    CrossrefPubMedGoogle Scholar
  • 36 Chilosi A, Casarano M, Comparini A , et al. Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency. Orphanet J Rare Dis 2012; 7: 43
    CrossrefPubMedGoogle Scholar
  • 37 Dunbar M, Jaggumantri S, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD. Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab 2014; ; doi: 10.1016/j.ymgme.2014.05.011. [Epub ahead of print]
    PubMedGoogle Scholar
  • 38 Kurosawa Y, Degrauw TJ, Lindquist DM , et al. Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. J Clin Invest 2012; 122 (8) 2837-2846
    CrossrefPubMedGoogle Scholar
  • 39 Skelton MR, Schaefer TL, Graham DL , et al. Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency. PLoS ONE 2011; 6 (1) e16187
    CrossrefPubMedGoogle Scholar
  • 40 Trotier-Faurion A, Passirani C, Béjaud J , et al. Dodecyl creatine ester and lipid nanocapsule: a double strategy for the treatment of creatine transporter deficiency. Nanomedicine (Lond) 2014; ; [Epub ahead of print]
    PubMedGoogle Scholar
  • 41 Garbati P, Adriano E, Salis A , et al. Effects of amide creatine derivatives in brain hippocampal slices, and their possible usefulness for curing creatine transporter deficiency. Neurochem Res 2014; 39 (1) 37-45
    CrossrefPubMedGoogle Scholar