Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Abstract

Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT-and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not coexpressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT-to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

Upregulation of Na+,Cl--Coupled Betaine/ γ-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2

“…Those carriers may similarly be candidates for regulation by TTBK2. Genetic defects affecting the creatine transporter CreaT result in mental retardation with seizures [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82]. Defective cellular taurine uptake by TauT fosters apoptosis [83,84,85,86,87,88,89,90,91].…”

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

“…4 AGAT and GAMT are also expressed in neurons and microglia, suggesting that central nervous system creatine synthesis might be necessary to compensate for the limited passage of creatine across the blood-brain barrier. 24 Uptake and storage of both endogenously synthesized and dietary creatine is facilitated by CRTR, a sodium-dependent, solute carrier-type protein of 635 amino acids encoded by SLC6A8 (NM_001142805.1) on Xq28. 25,26 While the majority of creatine is stored in skeletal muscle, CRTR is also found in the plasma membrane of kidney, brain, heart, colon, testis, and prostate cells.…”

“…27 CRTR deficiency is the most prevalent 30 GAMT deficiency often shows a more complex phenotype (intractable seizures, extrapyramidal movement abnormalities, and dysfunction of the basal ganglia), which may be attributed to the specific toxicity of accumulating guanidinoacetate. 5,24 Females heterozygous for SLC6A8 pathogenic variants may be asymptomatic or present with signs and symptoms of variable severity, ranging from learning disabilities to seizures. [31][32][33] treatment Deficiency of both AGAT and GAMT can be treated with oral supplementation of creatine monohydrate.…”

Creatine in health, medicine and sport: an introduction to a meeting held at Downing College, University of Cambridge, July 2010

“…Brain is the main organ affected in creatine-deficiency diseases arising from the absence of Cr synthesizing enzymes or expression of the Cr transporter (Braissant et al 2011). Patients show delayed neurological development presenting with symptoms from early infancy.…”

“…Today, it is known that Cr may cross the blood-brain barrier, albeit only with poor efficiency and that CNS must ensure parts of its Cr needs are met by endogenous synthesis. However, as discussed by Braissant et al (2011), in many brain structures the enzymes of Cr synthesis, while found in every brain cell type, are not necessarily co-expressed, but expressed in a dissociated manner. As noted, the new understanding of Cr metabolism and transport in CNS will not only allow a better comprehension of the consequences of Cr deficiency in the brain, but will also help in delineating the physiological role of Cr in CNS.…”