Clinical Aspects of MTHFR Deficiency
Patients with severe MTHFR deficiency show enzyme activity at
less than 20% of normal levels, with some patients having no detectable
activity (Goyette, Frosst, Rosenblatt, and
As a result, these patients clinically present with increased
levels of homocysteine and methionine in both urine and plasma.
In individuals with normal MTHFR activity levels, the presence of
these compounds in urine and plasma is absent or extremely low (Rosenblatt,
These elevated homocysteine levels result in a
wide range of phenotypic manifestations that vary in both their severity
and age of onset (Rosenblatt, 1995).
Developmental delays in both physical and cognitive functioning
are commonly seen in patients with the disorder, as are mental
retardation and various psychiatric disturbances, including
schizophrenia. Motor and
gait abnormalities and muscle weakness are also prevalent, and most
patients suffer from epileptic seizures.
In addition, all patients tested have shown distinct
abnormalities in EEG, including overall slow brain activity and
epileptic discharges (Haan, Rogers, Lewis, & Rowe, 1985;
al, 1977; Rosenblatt, 1995).
While severe deficiency in MTHFR is
highly debilitating, as of 1995, only 50 cases of severe MTHFR
deficiency had been reported (Rosenblatt,
More commonly, however, is mild deficiency in the enzyme, leading
to slightly elevated levels of homocysteine.
Such mild deficiencies are believed to result from increased
enzyme thermolability and decreased affinity for the FAD cofactor.
Ongoing research has tentatively linked mild MTHFR deficiency to
increased risk for both cardiovascular disease (Frosst
et al, 1995)
and neural tube defects (Ou et al, 1996; van der
Put et al,
1998). Other work has
actually proposed benefits to mild deficiency in the enzyme, with
individuals mildly deficient in MTHFR showing decreased risk of
developing colorectal and/or other cancers (Ma
et al, 1997; Blount et