CRTR belongs to a novel group of inborn errors of metabolism, the creatine deficiency syndromes (Rosenberg et al 2004
; Salomons et al 2001
; Schulze 2003
; Stromberger 2003
). A number of reviews have been published to further characterize the clinical, laboratory, molecular and imaging profiles of CRTR (deGrauw et al 2002
; Salomons et al 2003
). Dystonia and choreoathetoid movements, prominent features of our cases, are common in GAMT but were only reported once in CRTR (Hahn et al 2002
). Similarly, the seizure disorder seen in our cases contrasts with the relatively milder form reported previously in CRTR. That the guanidinoacetate (GAA) level was normal in both cases raises doubt about the suggestion that the movement disorder seen in GAMT deficiency is due to high levels of GAA (Leuzzi 2002
). It appears that creatine deficiency plays a more important role in the pathogenesis of the movement disorder seen in these conditions.
The various indicators of mitochondrial dysfunction clouded the clinical picture in both patients whose work-up initially focused on a primary mitochondrial pathology (see below). It was only after MRS studies revealed the absence of creatine peak, the classical sign shared by all three disorders of creation metabolism, that the possibility of CRTR was entertained. As seen in the example of the second case, that classical sign was overlooked initially. Realization of the powerful potential of MRS to detect this group of disorders, and that it is not as rare as initially thought (see below), should improve the detection rate.
The lack of biochemical or clinical response in our two patients to creatine supplementation, even at high doses, is not surprising. Trials of treatment of males affected with CRTR deficiency with creatine monohydrate only have not proved to be successful (Bizzi et al 2002
; deGrauw et al 2002
). Supplementation with high doses of arginine and glycine, which are the primary substrates for creatine biosynthesis, combined with high doses of creatine monohydrate, is being investigatedv (unpublished data, Mancini GMS, van der Knaap N, Salomons GS).
Both of our patients showed evidence of disturbance in mitochondrial energy metabolism, with transient hyperammonaemia and lactic acidaemia, along with specific mitochondrial respiratory chain enzyme deficiencies in one patient and evidence of mild myopathy (increased CPK and/or abnormal muscle histology) in both. This suggests that some of the underlying pathogenesis of the creatine disorders is due to mitochondrial energy depletion, at least in these two patients. This is of interest given the well-described role of creatine in mitochondrial metabolism, which includes a protective and beneficial role of creatine for mitochondria (Brustovetsky et al 2001
; O’Gorman et al 1997
;Tarnopolsky et al 1997
). In addition, the specific importance of creatine to the mitochondrial respiratory chain and the detrimental effect of blocking the uptake of creatine with specific analogues have been demonstrated (O’Gorman et al 1996
). Moreover, there is some evidence, at least in fibroblasts of patients with GAMT deficiency, that different components of respiratory chain are upregulated (Das et al 2000
), suggesting that in the absence of the short-term energy buffering of creatine and phosphocreatine the cells rely almost exclusively on mitochondrially generated ATP, which puts extra stress on the respiratory chain. While some tissues with low energy requirement can compensate for this by upregulating their respiratory chain, as demonstrated in fibroblasts, in other tissues with high energy requirement, such as brain, retinal photoreceptors and muscle, the compensatory upregulation may be overwhelmed with the resulting deficiency in respiratory chain components.
Interestingly, patient 2 also had evidence of pigmentary retinopathy and significant deficits in retinal function, as do some children with mitochondrial disorders (Cooper et al 2002
). Although the retinopathy and ERG deficits in mitochondrial disorders have a broad spectrum, the most subtle ERG signature of a mitochondrial disorder is low scotopic b-wave sensitivity with good preservation of the amplitude of the scotopic b-wave (Cooper et al 2002
). The mechanism appears to be energy depletion and depressed ionic pumps in the rod photoreceptors. In contrast, patient 2 had attenuated amplitudes, while sensitivity was relatively better preserved. Thus, mechanisms other than energy depletion warrant consideration.
The clinical description of previously reported patients with CRTR does not allow for a definitive conclusion about evidence of mitochondrial disturbance in those cases. Nevertheless, our report suggests that CRTR should be considered in the differential diagnosis of patients with evidence of mitochondrial pathology. Likewise, clinical description of patients with CRTR should include mitochondrial studies to better characterize this association.
Patient 2 also had mild dysmorphic features, as did some previously reported patients (Hahn et al 2002
). It is possible that this or other features encountered in our patients may be due to (partial) deletion of other genes flanking SLC6A8
. However, gene sequences in the upstream and downstream genes could be properly amplified, suggesting that this is not the case for those currently known to be flanking SLC6A8
. Work is under way to characterize the breakpoints. Even if we fail to show direct involvement of other genes, one should remember that the deleted regions may contain long-range control sequences affecting other genes (Kleinjan and van Heyningen 2005
). So far, all other patients with CRTR have had small base changes leading to nonsense mutations, single amino acid deletions, missense mutations and splice site errors (Salomons et al 2003
). Therefore, the presence of large deletions in our patients may also suggest genotype–phenotype correlation, although this cannot be clearly established because of the small number of cases reported. It is of note that a contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1
) and DXS1357E, with features of seizures and hypotonia that are also seen in our patients, has been described (Corzo et al 2002
); this locus is telomeric to the SLC6A8
locus. Very long-chain fatty acids were checked in both patients and the results were unremarkable.
Recent studies in a panel of X-linked mental retardation males from the European consortium showed that approximately 2.1% of males had CRTR (Rosenberg et al 2004
), suggesting that this disorder is a relatively frequent cause of mental retardation. Accordingly, in the absence of a confirmed alternative diagnosis, we recommend that all mentally retarded males should be tested for CRTR.