Clinical Aspects of MTHFR Deficiency

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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 Rozen, 1995).  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, 1995). 

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; Mudd et 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, 1995).  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 al, 1997).