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

• Published in: Blood 2008-11, Vol.112 (11), p.2877-2877
• Main Author: Solomon, Lawrence R.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.2877.2877

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 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