Guanidinoacetate methyltransferase (GAMT) deficiency in two Tunisian siblings: clinical and biochemical features.
BACKGROUND
Guanidinoacetate methyltransferase (GAMT) deficiency is a recently described disorder and few cases have been reported to date. As it is a treatable pathology, we seek to contribute to its better understanding, particularly to further elucidate its biochemical diagnosis for early treatment.


METHODS
The patients, two brothers aged 13 years (P1) and 11 years (P2), have been explored for signs and symptoms suggestive of inborn errors of metabolism. The quantification of creatine (Cr), guanidinoacetate (GAA), and GAMT activity was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).


RESULTS
The two brothers presented a similar clinical picture: developmental delay, epilepsy, axial hypotonia, spastic tetraparesis, severe mental and language delay, and autistic behaviour. GAA concentrations were markedly increased in plasma and in urine [2796 and 3342 micromol/mmol creatinine (control range: 4 - 220 micromol/mmol creatinine)/14 and 29 micromol/L (control range: 0.35 - 1.8 micromol/L), respectively] while plasma and urine creatine concentrations were at the lower normal range limit. Activity of GAMT in lymphoblasts was extremely reduced (< 0.01 nmol/mg protein/hour) compared to healthy subjects. GAMT activity was found to be intermediary in patients' parents.


CONCLUSIONS
It appears that the clinical picture is heterogeneous but should be considered as potential signs of creatine metabolism disorders, however, the biochemical diagnosis is reliable as the enzyme activity is zero in most cases. To date, it is still too early to establish correlations between symptoms and biochemical profile. However, the identification of additional cases of GAMT deficiency should help elucidate such relationships and the progress of patients treated with creatine in conjunction with ornithine supplementation.
Laboratory of Biochemistry, Rabta Hospital, Jebbari, 1007 Tunis, Tunisia.
Fahmi
F
Nasrallah
Ichraf
I
Kraoua
Marie
M
Joncquel-Chevalier Curt
Marie-Adelaïde
MA
Bout
Sameh Hadj
SH
Taieb
Moncef
M
Feki
Néziha
N
Khouja
Gilbert
G
Briand
Naziha
N
Kaabachi
D000015:Abnormalities, Multiple / Q000201:enzymology*; D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003241:Consanguinity; D003401:Creatine / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology; D008297:Male; D035781:Siblings; D053719:Tandem Mass Spectrometry; D014416:Tunisia
D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine