Cerebral Creatine Deficiency Syndrome Research Center

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Cerebral Creatine Deficiency Syndromes Research Center

Cerebral Creatine Deficiency Syndromes (CCDSs) are devastating genetic disorders affecting the human central nervous system (CNS)1. Children born with these conditions suffer from mild to severe intellectual disability, autistic behavior, epilepsy, and extrapyramidal movement disorders. Associated symptoms outside of the CNS include gastrointestinal disturbances, urogenital anomalies, ophthalmological abnormalities, mild cardiomyopathy, and poorly developed muscle mass, but these symptoms show variable penetrance2. CCDSs are caused by mutations in three genes, two of which are responsible for de novo creatine synthesis: glycine amidinotransferase, mitochondrial (GATM, also referred to as L- Arginine:glycine amidinotransferase or AGAT)3 and guanidinoacetate N-methyltransferase (GAMT)4; and the last of which encodes the body’s principal creatine transporter solute carrier family 6 member 8 (SLC6A8)5. Children with CCDS type 1 (CCDS1) exhibit mutations in the X-linked gene SLC6A8 and have loss-of-function of the encoded sodium (Na+) and chloride (Cl-) dependent transporter, which is often referred to as creatine transporter 1 (CT1)6. CCDS1 is also called creatine transporter deficiency (CTD) and accounts for ~1-2% of all X-linked intellectual disability, making it the second most common non-chromosomal genetic cause in this large group of patients7. Although defects in AGAT and GAMT are treatable with dietary creatine supplementation (in addition to ornithine and benzoate for GAMT deficiency)1,8, therapeutic options are currently not available for patients with complete loss-of-function of SLC6A89. Complete loss-of-function mutations of this gene are found in the vast majority of children with CTD. Amongst CCDS patients, CTD accounts for 72% of cases and therefore developing a treatment for these individuals would meet a significant clinical need1,10.

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The University of Utah and the Association for Creatine Deficiencies (ACD) have teamed up to develop newborn screening techniques, novel diagnostics, and a strategy for gene therapy for these disorders. Together we have created the Creatine Deficiency Research Center (CDRC) housed at the University of Utah and ARUP. The efforts of the CDRC are spearheaded by Marzia Pasquali, PhD, FACMG, section chief of ARUP’s Biochemical Genetics department, and Nicola Longo, MD, PhD, a pediatric medical geneticist, chief of the Medical Genetics division at University of Utah Health, and a member of Biochemical Genetics at ARUP, Steven Baker, MD, PhD, an associate medical director of Transfusion Medicine at ARUP who also does basic science research at the U, and Filippo Ingoglia, PhD, ARUP medical director of Biochemical Genetics. Specifically, the CDRC aims to:

· Develop newborn screening for CTD: Dr. Pasquali is in the process of obtaining dried blood spots from patients with CTD to determine if this disorder has a characteristic profile by mass spectrometry

· Validate creatine transport testing in fibroblasts: Dr. Ingoglia is developing an assay using cultured patient derived fibroblasts that will be incubated with radioactively labeled creatine to determine the ability to accumulate creatine in the cytoplasm. Measurement of fibroblast creatine uptake can confirm or exclude the diagnosis

· Pioneer a PEG-arginase clinical trial: PEG-arginase is a potential enzyme therapy which could be used for treating patients with GAMT deficiency. Dr. Longo, who sees patients with GAMT deficiency, would like to try this investigational product in order to ameliorate symptoms by reducing GAA production in these patients.

· Test a novel gene therapy for CTD: clinical and pre-clinical data suggest that this disorder results from creatine deficiency in neurons (as well as potentially other cell types in the brain). Dr. Baker will investigate the possibility of delivering genes to neurons with the potential to synthesize creatine internally, in order to bypass the need for the creatine transporter in these cells.

AGAT Expression in the Brain

AGAT / Nuclei / Neurons

  1. Mercimek-Andrews, S. & Salomons, G. S. Creatine Deficiency Syndromes. (University of Washington, Seattle, Seattle (WA), 2022).
  2. van de Kamp, J. M. et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 50, 463 (2013).
  3. Battini, R. et al. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: Early treatment can prevent phenotypic expression of the disease. The Journal of Pediatrics 148, 828–830 (2006).
  4. Stöckler, S. et al. Creatine Deficiency in the Brain: A New, Treatable Inborn Error of Metabolism. Pediatric Research 36, 409–413 (1994).
  5. Salomons, G. S. et al. X-Linked Creatine-Transporter Gene (SLC6A8) Defect: A New Creatine-Deficiency Syndrome. The American Journal of Human Genetics 68, 1497–1500 (2001).
  6. Guimbal, C. & Kilimann, M. W. A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. Journal of Biological Chemistry 268, 8418–8421 (1993).
  7. Lion-François, L. et al. High frequency of creatine deficiency syndromes in patients with unexplained mental retardation. Neurology 67, 1713 (2006).
  8. Béard, E. & Braissant, O. Synthesis and transport of creatine in the CNS: importance for cerebral functions. Journal of Neurochemistry 115, 297–313 (2010).
  9. van de Kamp, J. M. et al. Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. Journal of Inherited Metabolic Disease 35, 141–149 (2012).
  10. Stenson, P. D. et al. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Human Genetics 139, 1197–1207 (2020).