X‐linked creatine transporter deficiency: clinical aspects and pathophysiology

Abstract

Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment.

Creatine as Biomarker

“…However, discrepancies in the treatment response were found showing an improvement of the neurological symptoms and an increase of cerebral Cr and PCr in some patients, while the absence of response was found in other patients. In addition, another report demonstrated some effectiveness of Cr precursor treatment in a female with CRTR deficiency (Leuzzi et al 2013;van de Kamp et al 2014). In the last years, several derivatives of Cr have been developed.…”

“…Moreover, these authors confirmed the high expression of SLC16A12 in the human kidney, retina, lung, and testis shown in a previous report (Kloeckener-Gruissem et al 2008), while CRTR was predominantly expressed in the brain, heart, and muscle tissue, showing tissue-specific differences in gene expression. In addition, several data indicate that both Cr transporters would occupy opposite localizations in the epithelial cells, since MCT12 is predominantly located at the basolateral membrane of the lens, while CRTR is found in the brush border membrane of the intestine and proximal tubule (van de Kamp et al 2014). These findings suggest that MCT12 could cooperate in the transepithelial transport of Cr (Abplanalp et al 2013;van de Kamp et al 2014).…”

“…In addition, several data indicate that both Cr transporters would occupy opposite localizations in the epithelial cells, since MCT12 is predominantly located at the basolateral membrane of the lens, while CRTR is found in the brush border membrane of the intestine and proximal tubule (van de Kamp et al 2014). These findings suggest that MCT12 could cooperate in the transepithelial transport of Cr (Abplanalp et al 2013;van de Kamp et al 2014). …”

“…In the last years, several derivatives of Cr have been developed. Some of them are more effective than Cr monohydrate (van de Kamp et al 2014).…”

Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes

“…With GAMT and AGAT deficiency patients, brain creatine levels can approach normal levels with creatine supplementation (3,23,25,26,29,(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) (Figure 3). In some instances for patients with GAMT deficiency, MRS can also illustrate an elevation of GAA.…”