Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study

Abstract

Background and purpose: Brain creatine (Cr) deficiencies (BCr-d) are rare disorders of creatine biosynthesis and transport. We performed consecutive measures of total Cr (tCr) and of its phosphorylated fraction, phosphocreatine (PCr), in the brains of children affected by Cr synthesis defects during a long period of therapy. The aim was to identify the optimal treatment strategy for these disorders.

Materials and methods: Two patients with guanidinoacetate methyltransferase defect (GAMT-d) were treated with different amounts of Cr and with diet restrictions aimed at reducing endogenous guanidinoacetate (GAA) synthesis. Three patients with arginine:glycine amidinotransferase defect (AGAT-d) were treated with different Cr intakes. The patients' treatments were monitored by means of (1)H- and (31)P-MR spectroscopy.

Results: Cr and PCr replenishment was lower in GAMT-d than in AGAT-d even when GAMT-d therapy was carried out with a very high Cr intake. Cr and especially PCr replenishment became more efficient only when GAA blood values were reduced. Adenosine triphosphate (ATP) was increased in the baseline phosphorous spectrum of GAMT-d, and it returned to a normal value with treatment. Brain pH and brain P(i) showed no significant change in the AGAT-d syndrome and at any Cr intake. However, 1 of the 2 GAMT-d patients manifested a lower brain pH level while consuming the GAA-lowering diet.

Conclusions: AGAT-d treatment needs lower Cr intake than GAMT-d. Cr supplementation in GAMT-d treatment should include diet restrictions aimed at reducing GAA concentration in body fluids. (1)H- and especially (31)P-MR spectroscopy are the ideal tools for monitoring the therapy response to these disorders.

Fig 1.

Metabolic pathway of creatine/phosphocreatine.

Fig 2.

Single-voxel proton spectroscopy (¹H-MRS) and whole-brain phosphorous spectroscopy (³¹P-MRS) of patient 2, before (A and B) and after (C and D) 6 months of therapy with Cr at 400 mg/kg/bw/day and guanidinoacetate (GAA)-lowering diet restrictions. The baseline studies demonstrate, besides a strong reduction of tCr and PCr peaks, an abnormal peak of guanidinoacetate (GAA) at 3.8 ppm on proton spectrum (A), of GAA-phosphate (GAA-P) at −0.5 ppm on phosphorous spectrum (B), and a high level of brain ATP. In contrast, in the on-therapy spectra, the GAA and GAA-P peak are not resolved, ATP turns to normal but there is an incomplete recovery of the tCr and PCr signal intensity.

Fig 3.

Total Cr (right axis, empty dot) and PCr (left axis, solid square) modifications recorded in patients 1 (A), 3 (B), and 5 (C) with different Cr daily amounts. Normative data in the bars are presented as mean ± SD.

Fig 4.

AGAT-d versus GAMT-d CK reaction rate evaluation. The angular coefficient (b value) of the fitting lines is an index of the CK system efficacy (b [pt 1] = 0.16 and b [pt 5] = 1.04). The CK system is down-regulated in GAMT-d (pt 1) with respect to AGAT-d (pt 5) because PCr remains low even when tCr availability is almost 90% of normal. These measures were recorded when patient 1 was treated only with Cr.