The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis.
Hyperhomocysteinemia is a risk factor for neurodegeneration, and binding of copper by homocysteine is a putative underlying mechanism. As mutations of the copper-dependent superoxide dismutase are observed in familial ALS, we tested whether genetic variants with influence on homocysteine metabolism are associated with ALS. We compared the frequency of seven variants of genes involved in homocysteine metabolism in 162 patients with sporadic ALS and 162 controls who did not significantly differ in age (t = 1.27, p = 0.205) and gender (χ(2) = 2.48, p = 0.115) using binary regression analysis. Results showed that the variant MTHFR c.677C>T was significantly associated with ALS, i.e. the T-allele was more frequent among patients. Explorative regression analysis revealed that MTHFR c.677C>T was not associated with spinal ALS, but with bulbar onset: CC/CT/TT in patients 0.33/0.51/0.16 versus 0.50/0.44/0.06 in controls; Wald = 5.73, p = 0.017. In addition, DHFR c.594+59del19bp was not associated with spinal, but with bulbar onset: del,del/del,ins/ins,ins in patients 0.16/0.67/0.18 versus 0.11/0.52/0.37 in controls; Wald = 5.02, p = 0.025. The other variants did not show significant associations. In summary, the variants MTHFR c.677C>T and DHFR c.594+59del19bp are involved in homocysteine metabolism. Homocysteine is neurotoxic and binds copper. Thus, the individual variability of homocysteine metabolism, e.g. due to genetic variants, may contribute to the vulnerability of ALS.
Department of Neurology, University of Ulm, Germany.
Peter
P
Kühnlein
Hans
H
Jung
Melinda
M
Farkas
Salla
S
Keskitalo
Benjamin
B
Ineichen
Ilijas
I
Jelcic
Jens
J
Petersen
Alexander
A
Semmler
Michal
M
Weller
Albert Christian
AC
Ludolph
Michael
M
Linnebank
D000293:Adolescent; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009410:Nerve Degeneration / Q000209:etiology; D012307:Risk Factors; D013696:Temperature; D055815:Young Adult
D007527:Isoenzymes; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)