Reduced brain choline in homocystinuria due to remethylation defects.
OBJECTIVE
To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects.


METHODS
Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine.


RESULTS
MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p < 0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed.


CONCLUSIONS
Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.
Debray
F-G
FG
Division of Medical Genetics, University of Montreal and Ste-Justine Hospital, Montreal, Quebec, H3T 1C5, Canada.
Boulanger
Y
Y
Khiat
A
A
Decarie
J-C
JC
Orquin
J
J
Roy
M-S
MS
Lortie
A
A
Ramos
F
F
Verhoeven
N M
NM
Struys
E
E
Blom
H J
HJ
Jakobs
C
C
Levy
E
E
Mitchell
G A
GA
Lambert
M
M
D000293:Adolescent; D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D002794:Choline / Q000378:metabolism*; D002796:Choline Deficiency / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D003401:Creatine / Q000097:blood / Q000652:urine; D005260:Female; D050904:Homocysteine S-Methyltransferase / Q000378:metabolism*; D006712:Homocystinuria / Q000097:blood* / Q000503:physiopathology / Q000652:urine*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008745:Methylation; D012436:S-Adenosylmethionine / Q000378:metabolism
D001224:Aspartic Acid; D012436:S-Adenosylmethionine; C000179:N-acetylaspartate; D050904:Homocysteine S-Methyltransferase; D003401:Creatine; D002794:Choline