Isolated remethylation disorders: do our treatments benefit patients?

Abstract

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), the very rare methionine synthase reductase (CblE) and methionine synthase (CblG) defects, and the recently identified CblD-variant-1 defect are primary remethylation defects characterized by an isolated defect in methionine synthesis without methylmalonic aciduria. The clinical signs are mainly neurological, and hematological signs are seen in CblE, CblG, and CblD-variant-1 defects. Patients with neonatal or early-onset disease exhibit acute neurological distress. Infants and children have unspecific mental retardation, often with acquired microcephaly. Without appropriate therapy, they may experience acute or rapidly progressive neurological deterioration, which may be fatal. Adolescents and adults show normal development or mild developmental delay initially and then experience rapid neurological or behavioral deterioration. A few patients may have signs of subacute combined degeneration of the spinal cord. Adults may be asymptomatic or present with isolated thromboembolism. All patients with suspected remethylation disorders should receive emergency treatment with parenteral administration of hydroxocobalamin and folate supplements combined with betaine orally. The long-term treatment of CblE, CblG, and CblD-variant-1 defects consists of parenterally administered hydroxocobalamin and orally administered folate and betaine supplements, whereas patients with MTHFR deficiency require long-term oral folate and betaine supplements. Long-term oral methionine therapy should also be considered. Early treatment may lead to a favorable outcome with developmental recovery and prevention of further neurological deterioration. In contrast, most late-treated patients have severe and irreversible neuromotor impairments. Hematological abnormalities are easily corrected.

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

“…With the increasing number of reported patients, the natural history of these disorders becomes clearer. 12,[19][20][21] The majority of patients are diagnosed after being symptomatic (with rare exceptions, including siblings of known patients 22 or populations with high carrier frequency 4 ). 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.…”

“…However, the delays in the diagnosis and treatment are recognized as the most important factor leading to residual morbidity in these patients. 1,4,20,21 In several cases specific therapy started very early in life or in asymptomatic patients 4,25 led to normal outcomes. The treatment of remethylation disorders is aimed at either bypassing the biochemical block or augmenting the residual activity with cofactors of the affected enzymes.…”

“…This is achieved by supplementation with Met and/or betaine in addition to vitamin B 12 and folic acid administration. The therapeutic utility of betaine either alone in cases of severe MTHFR deficiency 1,4,19,20 or in combination with vitamin B 12 in cblG and cblE complementation type disorders 1,20,21 has been well-established. Betaine increases Met and has Hcy-lowering effects, thus targeting the two predominant mechanisms involved in the pathogenesis of these disorders, defective regeneration of Met with subsequent hypomethioninemia and low S-adenosylmethionine levels (resulting in impaired methylation) and hyperhomocystinemia.…”

“…Betaine increases Met and has Hcy-lowering effects, thus targeting the two predominant mechanisms involved in the pathogenesis of these disorders, defective regeneration of Met with subsequent hypomethioninemia and low S-adenosylmethionine levels (resulting in impaired methylation) and hyperhomocystinemia. 20,26 Because the enzyme involved in the betaine metabolism (betaine-homocysteine methyltransferase, BHMT) is expressed predominantly in the liver and kidneys but not in the brain, 27 it has been suggested that oral Met supplementation might be a reasonable therapeutic intervention, at least in the neonatal period, for faster restoration of cerebral Met levels, especially when given in combination with betaine. 20 Pyridoxine was added to the treatment regimen to facilitate lowering the Hcy levels as a cofactor of cystathionine β-synthase.…”

Homocysteine Measurement in Dried Blood Spot for Neonatal Detection of Homocystinurias

“…The remethylation disorders share a somewhat similar clinical presentation with failure to thrive, acute or chronic neurological deterioration, developmental delay, and sometimes seizures, hypotonia, microcephaly, feeding difficulties, stomatitis, and microcephaly. The cbl defects also present with megaloblastic anaemia, although measured serum vitamin B12 may be normal (Digest 2007;Schiff et al 2011). In the cbl and folate deficiencies, megaloblastic anaemia is a classical clinical feature, and there are different neuropsychiatric abnormalities which can appear in cbl deficiency due to demyelination of peripheral nerves, the spinal cord, cranial nerves, and the brain (Whitehead 2006).…”