High frequency of creatine deficiency syndromes in patients with unexplained mental retardation

Cerebral creatine deficiency syndromes (CCDSs) are inborn errors of metabolism that include two autosomal recessive creatine biosynthesis defects (arginine–glycine amidinotransferase [AGAT; OMIM 602360] and guanidinoacetate methyl transferase [GAMT; OMIM 601240] deficiency) and an X-linked creatine transporter defect (OMIM 300036).¹ The clinical phenotype is variable, associating nonspecific mental retardation, epilepsy, extrapyramidal movement disorders, and autistic behavior. The frequency of CCDS is unknown and probably underestimated. We report a high frequency of CCDS in mentally retarded children, mostly boys with an X-linked creatine transporter deficiency.

Methods.

Over a period of18 months, children referred to the Department of Pediatric Neurology with unexplained mild to severe mental retardation, normal karyotype, and absence of fragile X syndrome were prospectively screened for CCDS. Children were from diverse ethnic backgrounds. Children with polymalformative syndromes were excluded. Creatinine metabolism was evaluated using creatine/creatinine and guanidinoacetate (GAA)/creatinine ratios on a spot urine.² Diagnosis was further confirmed using brain proton MR spectroscopy (H-MRS) and mutation screening by DNA sequence analysis in either the SLC6A8 (creatine transporter defect) or the GAMT genes.

Results.

One hundred eighty-eight children were eligible to participate: 114 boys (61%) and 74 girls (39%); 118 children (63%) were severely retarded and 70 (37%) had mild to moderate mental retardation. Family history revealed 151 (80%) sporadic cases and 37 (20%) familial cases (siblings or first-degree relatives). Four boys from four unrelated families had elevated creatine/creatinine ratio, suggesting a creatine transporter defect. In another boy, elevated urinary GAA/creatinine ratio suggested GAMT deficiency. H-MRS and molecular investigation confirmed the diagnosis, and five new mutations either in the SLC6A8 or GAMT gene were identified. All five patients presented with severe mental retardation. Brain MRI showed minor and nonspecific abnormalities. Extensive clinical, radiologic, and biologic characteristics are depicted in the table on page 1714.

The prevalence of CCDS was 2.7% (5/188, CI: 0.36 to 4.96) in the whole population and 4.4% (5/114, CI: 0.63 to 8.15) in boys. None of the 74 girls had a CCDS. In the 151 sporadic cases, prevalence of CDDS was 1.9% (3/151, CI: 0 to 4.21). In the 37 familial cases, the prevalence was 5.4% (2/37, CI: 0 to 12.7).

Discussion.

These results show a high prevalence of CCDS either in sporadic or in familial unexplained mental retardation, especially in boys. The five diagnoses were suspected on the basis of increased urine creatine/creatinine or GAA/creatinine ratios measured as described elsewhere.² H-MRS revealed the lack of creatine peak in all patients except for Case 2, for whom the parents refused the analysis. All mutations were highly likely to be pathogenic due to either their nature (frame shift or splice error mutations) or location in a very conserved region of the gene. Moreover, we did not identify these mutations in 276 control chromosomes, and familial segregation was confirmed for each mutation. In our study, all boys presented late-onset walking and severe to profound mental retardation; three boys had autistic features, consistent with the existing literature.³ Brain MRI showed a thin corpus callosum³ in three patients with transporter defect. As expected, we did not observe any creatine transporter defect in mentally retarded girls.⁴ However, GAMT and AGAT deficiencies, which are sensitive to creatine intake, may affect girls and should be measured in both boys and girls with mental retardation.

High prevalence of mutations in the SLC6A8 gene (2.1%) was reported in a panel of 288 boys with nonspecific mental retardation.⁵ However, this population was composed only of familial cases. Recently, another study evoked the presence of a SLC6A8 mutation in approximately 1% of boys with mental retardation of unknown etiology.⁶ Another study reported a high prevalence (2.7%) of GAMT deficiency in 180 adults and children with severe mental handicap in an isolated population.⁷

We report a prospective biochemical screening method for CCDS in mentally retarded boys and girls, with sporadic or familial cases, from different ethnic backgrounds recruited in one Department of Pediatric Neurology. The high prevalence of CCDS in our study population (2.7%) suggests that urinary screening of creatine/creatinine and GAA/creatinine ratio should be considered in all patients with mental retardation.

Acknowledgment

The authors acknowledge the contributions of Luc Anselmini, Brigitte Soubeyrand, Marie-Claire Rochon, Patricia S. Darmin, Silvy J.M. van Dooren. and Lorna Landegge for technical assistance and Alexandre Kiazand for editing this manuscript.