Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings

Abstract

Homocystinuria due to 5,10‐methylenetetrahydrofolate reductase deficiency may present with variable neurological manifestations. Radiological features include white matter changes (leukoencephalopathy). Clinical, biochemical, and radiological response to treatment may again be variable. Here we present a 12‐year follow‐up of two siblings on the same treatment regimen, with contrasting long‐term findings. The first patient, a female presenting at 15 years, showed a good clinical response, substantial intellectual gain, and complete reversal of leukoencephalopathy. Her brother presented at 13 years 9 months and showed limited clinical and cognitive improvement with persistence of the leukoencephalopathy. Both siblings showed a partial biochemical response to treatment.

Pearls & Oy-sters: Familial epileptic encephalopathy due to methylenetetrahydrofolate reductase deficiency

“…7,8 Our 3 cases displayed similar findings, albeit with different degrees of severity. The reduction of brain volume and dysmyelination were more pronounced in P2 and P3 than in P1 (figure 2, A-E).…”

Acute leukoencephalopathy possibly induced by phenytoin intoxication in an adult patient with methylenetetrahydrofolate reductase deficiency

“…Severe MTHFR deficiency, which is usually diagnosed in infancy, is associated with progressive hypotonia, convulsions, and psychomotor retardation. Some patients with intermediate MTHFR deficiency develop schizophrenia‐like psychosis, leukoencephalopathy (Walk et al., 1994; Tallur et al., 2005), lower limb–dominant demyelinating polyneuropathy (Freeman et al., 1975; Kishi et al., 1994; Walk et al., 1994), or multiple thromboembolic episodes in adolescence or early adulthood. In addition, most of these patients develop mental retardation before such symptoms appear.…”

“…To date, >40 disease‐causing mutations of the MTHFR gene have been identified in patients with severe MTHFR deficiency, who display a residual enzyme activity equal to 0–30% of the control activity. However, phenotypic variability within family members carrying the same MTHFR gene mutation suggests that environmental factors, such as dietary supplements or other genes, modify the disease process (Tallur et al., 2005). Thus far, general anesthesia with nitrous oxide is the only known aggravating factor of remethylation defects in patients with MTHFR deficiency (Selzer et al., 2003).…”

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

“…A dose–response relationship was not observed (Holme and Ronge 1989). A combination of folic and folinic acid was associated with favourable outcome (Tallur et al 2005; Lossos et al 2014). It has recently been shown that folic acid may exacerbate cerebral CH3-THF deficiency (Hyland et al 2010) and it has therefore been suggested to avoid folic acid and preferably use folinic acid or 5-CH3-THF.…”