Acquired and inherited disorders of cobalamin and folate in children

Abstract

SummaryCobalamin deficiency in the newborn usually results from cobalamin deficiency in the mother. Megaloblastic anaemia, pancytopenia and failure to thrive can be present, accompanied by neurological deficits if the diagnosis is delayed. Most cases of spina bifida and other neural tube defects result from maternal folate and/or cobalamin insufficiency in the periconceptual period. Polymorphisms in a number of genes involved in folate and cobalamin metabolism exacerbate the risk. Inborn errors of cobalamin metabolism affect its absorption, (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and transport (transcobalamin deficiency) as well as its intracellular metabolism affecting adenosylcobalamin synthesis (cblA and cblB), methionine synthase function (cblE and cblG) or both (cblC, cblD and cblF). Inborn errors of folate metabolism include congenital folate malabsorption, severe methylenetetrahydrofolate reductase deficiency and formiminotransferase deficiency. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions, both before and after birth.

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

“…Mild to moderate hyperhomocysteinaemia is common in vitamin B12 or folate deficiencies but also in very severe vitamin B6 deficiency and in patients with renal failure or hypothyroidism. While megaloblastic anaemia with increased MCV and hypersegmented neutrophils on blood film are found in both vitamin B12 and folate deficiencies, elevated MMA is only observed in functional vitamin B12 deficiency (Whitehead 2006). …”

“…It is well recognised that despite treatment and improved metabolic parameters, severe complications such as developmental delay and progressive visual loss may still develop (Andersson et al 1999; Enns et al 1999; Patton et al 2000; Fischer et al 2014; Weisfeld-Adams et al 2015). Even if the neurologic status stabilises or improves with therapy, the sequelae remain in a large proportion of patients (Whitehead 2006; Watkins and Rosenblatt 1989), especially if the initiation of treatment was delayed or insufficient (Huemer et al 2014). Haematological symptoms and failure to thrive generally resolve with treatment (Martinelli et al 2011; Fischer et al 2014).…”

Genetic disorders of vitamin B12metabolism: eight complementation groups – eight genes

“…Although TC binds only a minor fraction of circulating cobalamins (10–25%), it is the protein responsible for facilitating the uptake of cobalamin by cells (Refs 69, 70). Mutations in the gene encoding TC ( TCN1 ) result in severe tissue cobalamin insufficiency, megaloblastic anaemia, failure to thrive and often neurological complications, despite normal plasma cobalamin concentrations (Refs 71, 72). Additionally, TC acts as a final screening mechanism because, like IF, TC is very specific for cobalamin forms that have the lower DMB intact (Refs 73, 74).…”

High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring

“…Relatively rare severe deficiencies in MTHFR (usually <20% of enzyme activity) are a cause of homocystinuria, an inborn error of metabolism characterized by a variety of neurologic symptoms including developmental delays, motor disturbances and brain atrophy (5). A mild deficiency in MTHFR, due to the 677C > T (A222V) polymorphism, is present in the homozygous state in 10–15% of many Caucasian populations and encodes a thermolabile enzyme with ∼30% residual activity (2).…”