Remethylation defects: guidelines for clinical diagnosis and treatment

Abstract

The main remethylation defects include disorders which all have defective methionine synthesis in common. Methylenetetrahydrofolate reductase deficiency impairs methyltetrahydrofolate synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of methionine synthase (CblE/G) are associated with defective methyl cobalamin synthesis. The clinical presentation is characterized by acute neurological distress in early infancy. In childhood, patients present with progressive encephalopathy with an end-stage which has many signs in common with the adult onset form. In fact, both have more or less severe signs of subacute degeneration of the cord. Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose). Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial. In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration.

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

“…At least 15 patients with cblC have been reported with cardiomyopathy (Table 1; Baumgartner et al 1979;Brandstetter et al 1990;Carmel et al 1980;Chenel et al 1993;De Bie et al 2009;Longo et al 2005;Geraghty et al 1992;Ogier de Baulny et al 1998;Profitlich et al 2009). However, the specifics regarding the type and echocardiographic manifestations of the cardiac lesions have not been fully delineated.…”

Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening

“…Although the age of onset varies significantly, most of the patients with remethylation disorders present during the first 3 years of life with predominantly neurological manifestations. 1,19,21 In one series, 92% of patients with cblG and cblE defects had disease onset before 3 years of age, with peak during the first year of life (75%). 21 Similar data are reported for cases of severe MTHFR deficiency.…”

“…19 Remethylation disorders diagnosed later in life have also been described. 1,21 Many of them have been subjected to long diagnostic work-up for nonspecific predominantly neurologic symptoms until elevation of tHcy was detected. Several patients presenting with isolated hematologic abnormalities, 23 acute psychosis in adult patients, 24 or asymptomatic patients 12,22 have also been reported.…”

“…Demyelination/brain abnormalities and hematologic abnormalities are frequent. 1,2 The biochemical hallmark of these disorders is low/low normal Met, high Hcy, and the absence of elevated methylmalonic acid levels. 1 Because homocystinuria, cblD type, variant 1, has similar biochemical characteristics, it is included in this group, which is referred to here as "remethylation disorders" henceforth.…”

“…1,2 The biochemical hallmark of these disorders is low/low normal Met, high Hcy, and the absence of elevated methylmalonic acid levels. 1 Because homocystinuria, cblD type, variant 1, has similar biochemical characteristics, it is included in this group, which is referred to here as "remethylation disorders" henceforth. Early diagnosis and treatment of at least severe MTHFR deficiency lead to either reduction or even prevention of symptoms if initiated at the earliest possible time in the first month of life before irreversible central nervous system central nervous system (CNS) damage occurs.…”