Methylmalonic acid and homocysteine assessment in the detection of vitamin B12 deficiency in patients with bilateral visual loss

Abstract

Editor, In neuro-ophthalmology, vitamin B12 deficiency is a known cause for bilateral visual loss because of an optic neuropathy. Traditionally, the diagnosis of vitamin B12 deficiency has been based on clinical symptoms and on the determination of serum vitamin B12 levels. However, more recent studies have given evidence that measurements of serum methylmalonic acid (MMA) and homocysteine (HC) are more sensitive in the determination of a deficient state for vitamin B12 at tissue level (Savage et al. 1994; Stabler 1995). MMA and HC are metabolites that accumulate when the vitamin B12-dependent enzymatic reactions in human cells dysfunction. The aim of the present case series is to draw attention within the ophthalmologic community to the new insights in detection of vitamin B12 deficiency. We present a case series of seven patients with a bilateral optic neuropathy and an elevated MMA and/or HC level as evidence of a vitamin B12 deficiency. The patients were seen at our department between January 2009 and December 2010. Whenever a vitamin B12 level was determined to exclude a vitamin B12 deficiency as the cause of the bilateral optic neuropathy, serum MMA and, in most cases, HC were also measured. The values of serum vitamin B12, MMA and HC are shown in Table 1. In only three patients, the serum vitamin B12 level was below the established norm set by the laboratory. Present literature recommends measuring MMA and/or HC whenever vitamin B12 is below 200 or 300 pmol/l (Stabler 1995; Oh & Brown 2003). However, had we followed these recommendations, still three patients with a deficient state for vitamin B12 would have been missed. All patients received vitamin B12 substitution therapy. In the four patients where we repeated the measurement of MMA and HC after treatment, the metabolites normalized indicating that the abnormal levels of metabolites were indeed caused by the vitamin B12 deficiency. Two of the patients with an apparent normal B12 serum level had a history of alcohol abuse. Lambert et al. (1997) reported on patients suffering from alcoholic liver cirrhosis. These patients had normal to elevated serum vitamin B12, probably due to intracellular release of stored vitamin B12 from damaged liver cells. But they also had elevated MMA and HC, indicating a vitamin B12 deficiency at tissue level. They suggested poor cellular penetration of vitamin B12 owing to a deficit or malfunction of binding protein as an explanation for their results. Another striking finding in the present series is that two of seven patients had a pathogenic mutation for Leber hereditary optic neuropathy (LHON). LHON and optic neuropathy as a result of vitamin B12 deficiency have clinical similarities, and both diseases have their origin in mitochondrial metabolism. So it is conceivable that a subclinical vitamin B12 deficiency can trigger the expression of optic neuropathy in LHON patients. Reports on patients with both a LHON mutation and vitamin B12 deficiency have been published in the past (Pott & Wong 2006). The earliest descriptions of optic neuropathy in vitamin B12 deficiency are in patients with pernicious anaemia. However, this classical entity did not occur in any of the patients presented in this study. Two patients had proven macrocytosis, without anaemia. Five patients did not have macrocytosis or anaemia. Accompanying neurological symptoms were only present in two patients. The present results again point out that macrocytosis or neurological symptoms are not a requisite finding to suspect a vitamin B12 deficiency. In conclusion, the results of this study confirm that measurement of only vitamin B12 serum level will miss neuro-ophthalmologic patients with an actual deficiency. One should always measure MMA and HC levels when a vitamin B12 deficiency is suspected.