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)

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.