Oxidant Stress as a Cause of Clinically Significant “Functional” Cobalamin (Cbl) Deficiency

Many patients (pts) with Cbl-responsive disorders identified in the ambulatory care setting have reversible neurologic abnormalities associated with increased levels of the Cbl-dependent metabolites, methylmalonic acid (MMA) and homocysteine (HCys), despite normal serum Cbl values. However, no mechanism to explain these findings has been proposed. Since this picture resembles both the CblC mutation (where reduction of CblCo(III) to CblCo(II) is impaired) and nitrous oxide exposure (which inactivates methionine synthase by oxidation of CblCo(I)), a pathophysiologic role for oxidant stress leading to “Functional” Cbl deficiency was considered. Thus, a retrospective review was performed of 39 pts with Cbl-responsive hematologic or neurologic disorders seen during a 14 yr period for the presence of 6 factors associated with increased oxidant stress: advanced age (>69 yrs); diabetes mellitus; cigarette abuse; alcohol abuse; renal insufficiency; and the presence of active inflammatory disorders. Pts were classified as Cbl-Deficient (Group A: serum Cbl <201 pg/ml; N=9); Possibly Cbl-Deficient (Group B: serum Cbl=201–300 pg/ml with MMA >250 nmol/l; N=12); and “Functional” Cbl Deficiency (Group C: serum Cbl >300 pg/ml with MMA >250 nmol/l; N=18). HCys values were increased (>12.1 μmol/l) in 67%, 75% and 50% of evaluable pts in Groups A, B and C respectively. Reversible neurologic abnormalities occurred in 44% of Group A pts, 67% of Group B pts and 100% of Group C pts. In Group C pts, 83% of cases had at least 2 oxidant risk factors. In contrast, only 22% of Group A pts had 1 risk factor and only 11% had 2 risk factors (p<0.002 vs Group C). Similarly, at least 1 oxidant risk factor was present in 67% of Group B pts (p<0.02 vs Group A) but only 17% had 2 risk factors (p<0.001 vs Group C). Moreover, within Group B, only 1 of 4 pts with serum Cbl values of 201–250 pg/ml had 1 oxidant risk factor (25%), while 7 of 8 pts with serum Cbl values of 251–300 pg/ml had at least 1 risk factor (88%)(p<0.03). Finally, when all 207 pts screened for Cbl deficiency during this period who had serum Cbl values >300 pg/ml were reviewed, MMA values were found to be >250 nmol/l in 81 of them (40%). At least 1 oxidant risk factor was present in 77% of the 81 pts with high MMA values but in only 20% of the 126 pts with normal MMA values (p<0.001). HCys levels were also increased in 42 of the 78 pts with high MMA values studied (54%) and Cbl therapy significantly decreased MMA and HCys values in 83% and 85% respectively of evaluable pts in this population. In contrast, only 11% of the 126 pts with normal MMA values had high HCys levels (p<0.001). It is concluded that “Functional” Cbl-deficiency is

1. associated with disorders known to induce oxidant stress;

2. more commonly encountered as a cause of elevated metabolite levels and neurologic abnormalities than classic Cbl Deficiency; and

3. often responds to Cbl therapy.

Taken together, these data suggest a cumulative effect of oxidant risk factors at higher serum Cbl values leading first to increases in MMA and then to clinically significant neurologic abnormalities. Thus, Cbl inactivation may play a role in the development of neuropathy when high risk individuals experience inflammatory illnesses or are exposed to prooxidant drugs and a possible prophylactic or therapeutic role for reduced Cbl vitamers should be considered.