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    Is ATP Elevated in Patients With GAMT Deficiency? | American Journal of Neuroradiology  
    



















    

































    
  
  




    
    

  

      


    

      

  
  
  

    

  

    

  

                
    

      

  

    

  
      
  
  

    


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Is ATP Elevated in Patients With GAMT Deficiency?
  
    	
W.K.J. Renema, H.E. Kan and A. Heerschap

  
    	
American Journal of Neuroradiology February 2008,  29 (2) 214; DOI: https://doi.org/10.3174/ajnr.A0803 

  
  
  



  


  
  



			

		

	
	
 	
	  
  

		
		

			

			  

  
      
  
  

    
  


  
  



  
      
  
  

    

  

    

  
      
  
  

    
We read with interest the paper by Bianchi et al,1 in which the authors report on the treatment monitoring of 2 patients with guanidinoacetate methyltransferase (GAMT) deficiency and 3 patients with an arginine:glycine amidinotransferase defect (AGAT-d). Repetitive MR measurements of these patients are not trivial, and some interesting observations are presented in this paper that may be very useful for their treatment.
Bianchi et al1 studied the levels of brain creatine (Cr) and phosphocreatine in 1 patient with GAMT deficiency using 31P- and 1H-MR spectroscopy (phosphorous and proton MR spectroscopy) before and after therapy. The authors conclude from the 31P-MR spectra that levels of adenosine triphosphate (ATP) are elevated in the brain of this patient before therapy, and that these levels normalize with treatment. Furthermore, they speculate that this may be the result of redistribution in the creatine kinase (CK) reaction (ATP + Cr − ADP + PCr) from the reduced levels of Cr in the brains of other patients.1 In our opinion, this conclusion on increased ATP and the speculation on its origin are debatable.
Tissue levels of ATP are tightly balanced by consumption and production of ATP. Because the brain is a highly oxidative organ, most production of ATP occurs by mitochondrial oxidative phosphorylation, though other processes such as glycolysis also contribute. The primary function of the CK reaction is more to dampen large fluctuations in the ratios of ATP and adenosine diphosphate (ADP) during periods of high energy demand,2 all in close relationship to the energy-producing and energy-consuming sites. Therefore, it is unlikely that a mere shift in the concentration of Cr will result in the drastic, global elevation of ATP as reported.
According to Bianchi et al,1 the supposed elevation of ATP is based on the 31P-MR spectrum of GAMT; in patient 1, in particular, the signal intensity for β-ATP (at 16.5 ppm) is increased. However, ATP has 3 phosphate groups, all giving a distinct signal intensity at different positions on the 31P-MR spectrum. If ATP were elevated, why are not all 3 signals equally elevated, since they belong to the same molecule? Although the other ATP signals (α-ATP and γ-ATP) also represent other phosphorus compounds such as ADP, these are present at much lower concentrations (∼μM range) than ATP (∼mM). Therefore, changes in the levels of these compounds cannot account for a selective elevation in the signal intensity of β-ATP. We believe that the increase in the signal intensity of β-ATP may be because of experimental issues in the 31P-MR spectroscopy method. Factors such as incorrect phasing of the MR spectrum, the absence of a first-order phase correction, and insufficient bandwidth of the excitation pulse in combination with a misplaced carrier resonance could all play a role here. Unfortunately, Bianchi et al1 did not provide sufficient information on data acquisition and quantification of the 31P-MR signals to resolve this issue.
Finally, the authors state that my colleagues and I,3 in GAMT-deficient mice, and Schulze et al,4 in a patient, display the same abnormality in the signal intensity of ATP and that both my colleagues and I and Schulze et al failed to provide a comment on this. However, in our opinion, our 31P-MR spectra of the GAMT-deficient mouse brain did not reveal a similar abnormality in the signal intensity of β-ATP,3 as Bianchi et al1 observed. As indicated in the legend to Fig 6 of our paper, the 31P-MR spectra are scaled arbitrarily. Also, in the paper of Schulze et al,4 it seems that signal intensity is scaled arbitrarily. At least when the reference signal intensity (ie, phosphodiester signal intensity) applied by Bianchi et al1 is used, no significant change in the signal intensity of ATP is observed. Therefore, in our opinion, the ATP increase in GAMT deficiency before treatment with Cr is not supported by other studies.
References
  1. ↵
    Bianchi MC, Tosetti M, Battini R, et al. Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study. AJNR Am J Neuroradiol 2007;28:548–54
    Abstract/FREE Full Text
  2. ↵
    Wyss M, Smeitink J, Wevers RA, et al. Mitochondrial creatine kinase: a key enzyme of aerobic energy metabolism. Biochim Biophys Acta 1992;1102:119–66
    CrossRefPubMed
  3. ↵
    Renema WK, Schmidt A, van Asten JJ, et al. MR spectroscopy of muscle and brain in guanidinoacetate methyltransferase (GAMT)-deficient mice: validation of an animal model to study creatine deficiency. Magn Reson Med 2003;50:936–43
    CrossRefPubMed
  4. ↵
    Schulze A, Hess T, Wevers R, et al. Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr 1997;131:626–31
    CrossRefPubMed
  


  
  



  
      
  
  

    
  


  
  



  




  


  
  



  
      
  
  

    
  


  
  



  
      
  
  

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Is ATP Elevated in Patients With GAMT Deficiency?
  
    	
W.K.J. Renema, H.E. Kan, A. Heerschap

  
    	
American Journal of Neuroradiology Feb 2008, 29 (2) 214; DOI: 10.3174/ajnr.A0803 

  
  
  



  


  
  



  
      
  
  

    

  
    
  
  
    
  
  
    
  


  


  
  



  
      
  
  

    
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