Hypohomocysteinemia: A Potentially Treatable Cause of Peripheral Neuropathology?

Perturbations of homocysteine metabolism are associated with increased risk for cardiovascular disease, stroke, dementia, and depression, among other major diseases. To assess the relationship between hypohomocysteinemia (HH) and idiopathic peripheral neuropathy (IPN), a retrospective review of 37,442 patients from a tertiary medical clinic was performed. Of patients with HH, 5.9% had IPN versus 0.6% of patients without IPN. Overall, 41% of patients with HH had IPN. These observations indicate that although HH is uncommon in the general population, there is a striking relationship between HH and the incidence of IPN. This article discusses the clinical ramifications of these findings.

Homocysteine is a homologue of the amino acid cysteine, differing by an additional methylene (-CH ₂ -) group. It is synthesized from methionine by the removal of its terminal Cϵ methyl group. Homocysteine can be converted into cysteine or recycled into methionine, via pathways that are facilitated by B vitamins. Detection of abnormal levels of homocysteine has been linked to cardiovascular disease and inflammatory bowel disease. Homocysteine-lowering interventions in people with or without preexisting cardiovascular disease does not reduce the risk of nonfatal or fatal myocardial infarction or stroke. Elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and thrombosis, as well as a variety of other pathologies such as birth defects, Alzheimer disease and other dementias, osteoporosis, diabetes, and renal disease.

Homocysteine metabolism is catalyzed by several enzymes that require B vitamins as cofactors, and homocysteine levels are particularly responsive to folate status. The predictive power of plasma homocysteine level as a risk factor for atherothrombotic disorders raised the appealing hypothesis that reduction of homocysteine levels by vitamin supplementation might result in a commensurate reduction in the risk of atherothrombotic events. Unfortunately, most clinical trials failed to show a significant benefit of vitamin supplementation on cardiovascular events, despite significant lowering of plasma homocysteine levels. Thus it is not clear whether homocysteine actually plays a causal role in many pathologies with which it is associated, or whether it is instead a marker for some other underlying mechanism. A large body of data links hyperhomocysteinemia and folate status with oxidant stress.

Homocysteine is synthesized from dietary methionine and cannot be obtained directly from the diet. Plasma homocysteine concentration is actually inversely related to intake and plasma levels of folate, vitamin B6, and vitamin B12. Homocysteine metabolism is important for two crucial biochemical pathways: remethylation, which is the focus of this article, and transsulfuration. Transsulfuration, the vitamin B6–dependent sulfuration of homocysteine to cysteine, requires pyridoxal-5′-phosphate, the vitamin B6 coenzyme. Remethylation requires folic acid and vitamin B12 coenzymes, and involves the methylation and recycling of homocysteine to methionine, then to the eventual formation of S -adenosylmethionine (SAMe). SAMe is a major donor of methyl groups for reactions involving methyltransferases throughout the body, and the principal donor in the brain. The methylation of homocysteine to methionine is accomplished by methionine synthase, a B12-dependent enzyme that uses 5-methylfolate, an essential cofactor, as the methyl donor. 5-Methylfolate is formed from folic acid through a series of steps with methylenetetrahydrofolate reductase (MTHFR), the enzyme at the rate-limiting step. Two common mutations of the MTHFR gene sequence (A128C and C677T) occur in 10% to 20% of the United States population, and are the most common of the known inborn errors of metabolism. Elevated homocysteine is considered a marker for the magnitude of dysfunction at this step ( Fig. 1 ).

Deficiencies of vitamin B12 or folic acid, or abnormalities caused by mutations in these and other enzymes in this metabolic sequence, result in derangements of this process and are associated with peripheral neuropathy (PN) as well as with various other central nervous system (CNS) disorders including depression and dementia. Treatment of vitamin B12 or folic acid deficiency with replacement may result in improvement or resolution of the neuropathic process. Often homocysteine levels are elevated in these deranged states and, again, elevation of homocysteine has been considered important evidence for the presence of metabolic derangement. Because homocysteine is continuously replenished via dietary methionine, the overall level in the blood must be determined by processes other than the ongoing recycling of these two amino acids alone. These other processes determine the ultimate catabolic fate of dietary methionine, in which the transsulfuration pathway could play a significant role. In humans, however, data suggest that it is difficult to assess any dose-response curve in terms of vitamin replacement. For example, a daily dose of 25 mg of vitamin B6 taken orally for 10 days reduces plasma folate but does not affect basal and postprandial homocysteine levels. This fact suggests the existence of either normal cellular folate availability or possibly increased transsulfuration to compensate for impaired homocysteine remethylation.

Further complicating the picture is a theorized metabolic methylfolate trap, hypothesizing that 5-methyltetrahydrofolate (5MTHF) becomes metabolically trapped. This trap arises because 5MTHF can neither be metabolized via the methionine synthase pathway nor reconverted to its precursor, methylenetetrahydrofolate (see Fig. 1 ). Other manifestations of the methylfolate trap include cellular folate loss resulting from reduced overall methylation. One report noted that global DNA methylation was 22% lower in a patient with vitamin B12 deficiency who was homozygous for the (MTHFR) C677T mutation.

Clinical ramifications

Case Study

Reduced levels of homocysteine, or hypohomocysteinemia (HH), resulting from variations in the aforementioned pathways, may represent a pathologic state not previously elucidated. This state would result in consequences similar to those of other derangements of the single carbon cycle, through diminished levels of SAMe and reduced methylation capacity. This scenario is clinically relevant, as it raises the possibility that a neuropathy secondary to or associated with HH is pathologically possible and is potentially treatable by dietary methionine supplementation.

To illustrate this, the clinical course of a 75-year-old woman with an idiopathic peripheral neuropathy (IPN) and HH who responded to oral methionine treatment is presented. The patient presented several years previously with complaints of burning, tingling, and numbness in her feet. In addition she also noted cramping in her lower extremities, and a feeling that her “legs were like dead.” There were no complaints of dysautonomia. She was otherwise in good overall health, with no history of diabetes or other neuroendocrine or metabolic disorders. On initial examination she appeared well-nourished but demonstrated atrophic shiny skin. On neurologic examination, her cranial nerves were normal. On motor examination, her muscle bulk and tone were relatively preserved, although she had absent deep tendon reflexes. She also showed significant muscle weakness, more than expected for the degree of atrophy. She exhibited symmetric mild distal predominant weakness in the upper and lower extremities. Her laboratory workup revealed a homocysteine level of 3.6 μmol/L (normal range 6–10 μmol/L), a vitamin B12 level of 605 pg/mL (normal range 150–750 pg/mL), and an MTHFR polymorphism with heterozygosity of the A1298C mutation. Folate status at this time was not known. She was begun on methylfolate 7.5 mg daily, SAMe 400 mg twice daily, and methionine 1500 mg twice daily. Over the next 4 months (assessed at initial assessment, then at 2 and 4 months) her electrodiagnostic testing (EDx) showed either stability or improvement in all parameters, including increasing amplitudes and decreasing latencies. The most striking improvements included her fibular (peroneal) sensory nerve action potential (SNAP) amplitudes, which increased on the left side from 3.7 to 4.7 and then finally 9 μV on serial EDx studies; on the right side, the values increased from 4 to 8 and then to 8.3 μV. Her fibular (peroneal) compound motor action potential (CMAP) amplitude, measured on the right side only, increased from 1.8 to 3.8 and then to 5 mV. Peroneal distal sensory latencies decreased from 5.0 to 4.1 and then to 3.6 ms on the left, and from 4.4 to 4.2 and then to 3.4 ms on the right. Over that same time, her homocysteine level rose to 7.9 μmol/L. She also reported subjective improvement and she had minimal residual neuropathic symptoms.

Retrospective Review

Provoked by these observations, a subsequent retrospective data search of the electronic health record database of a larger, tertiary medical group in southern Oregon was implemented, assessing data for the past 10 years. The data were collected from all patients born before 1965 who had at least one office encounter with a group provider and at least one homocysteine level in the stated range. These results are summarized in Table 1 . The study included a total of 37,442 patients. Of this group, 1547 patients carried the diagnosis of IPN (International Classification of Diseases–9 code = 356.9). Of the patients who were found to have an abnormally low homocysteine level below 6 μmol/L, 5.9% had IPN compared with 0.6% of patients without IPN ( P <.0001 by χ ²test with Yates correction). Overall, 86 of 210 (41%) patients with an abnormally low homocysteine level had IPN. These observations indicate that although reduced levels of homocysteine are uncommon in the general population, there is a striking relationship between hypohomocysteinemia and the incidence of IPN.

Table 1

Homocysteine levels in patients carrying the diagnosis of idiopathic peripheral neuropathy (IPN) versus controls without neuropathy

Homocysteine Level (μmol/L) (normal range 6–10 μmol/L)	No. of Patients Without IPN	No. of Patients With IPN (%)
4–5.1	180	66 (36)
3–4	22	14 (64)
<3	8 ^a	^a6 (75)

a History regarding the presence of neuropathy in 2 of these 8 patients was unobtainable. These 6 patients with available history all had the diagnosis of neuropathy. The total number of patients was 37,442, of whom 1547 (4%) carried the diagnosis of IPN (International Classification of Diseases–9 code = 356.9).

Only gold members can continue reading. Log In or Register to continue