Isolated and Combined Remethylation Disorders: Biochemical and Genetic Diagnosis and Pathophysiology

Abstract Genetic defects affecting the remethylation pathway cause hyperhomocysteinemia. Isolated remethylation defects are caused by mutations of the 5, 10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase(MTRR), methionine synthase(MTR), and MMADHC genes, and combined remethylation defects are the result of mutations in genes involved in the synthesis of either methylcobalamin or adenosylcobalamin, that is, the active cofactors of MTRR and methylmalonyl-CoA mutase. Diagnosis is based on the biochemical analysis of amino acids, homocysteine, propionylcarnitine, methylmalonic acid, S-adenosylmethionine, and 5-methylentetrahydrofolate in physiological fluids. Gene-by-gene Sanger sequencing has long been the gold standard genetic analysis for confirming the disorder and identifying the gene involved, but massive parallel sequencing is now being used to examine all those potentially involved in one go. Early treatment to rescue metabolic homeostasis is based on the following of an appropriate diet, betaine administration, and, in some cases, oral or intramuscular administration of vitamin B12 or folate. Elevated ROS levels, apoptosis, endoplasmic reticulum (ER) stress, the activation of autophagy, and alterations in Ca2+ homeostasis may all contribute toward the pathogenesis of the disease. Pharmacological agents to restore the function of the ER and mitochondria and/or to reduce oxidative stress-induced apoptosis might provide novel ways of treating patients with remethylation disorders.

Diagnóstico y tratamiento de la aciduria metilmalónica: a propósito de un caso / Diagnosis and treatment of methylmalonic aciduria: a case report

La aciduria metilmalónica es una acidemia orgánica, autosómica recesiva, causada por la deficiencia de la metilmalonil CoA-mutasa, o por defectos en la biosíntesis del cofactor adenosilcobalamina. Del defecto enzimático, existen dos formas: mut (o) sin actividad enzimática y mut (-) con actividad reducida. Su presentación clínica puede variar desde una forma neonatal grave con acidosis y muerte, hasta una forma crónica progresiva. A continuación se describe el caso de un niño de 4 años de edad, con deficiencia de metilmalonil-CoA mutasa tipo mut (-), que se presentó en forma aguda. El estudio molecular del gen MUT mostró 2 mutaciones c.607G>A (G203R) y c.2080C > T(R694W), confirmadas posteriormente en los padres. El objetivo de este reporte es destacar la importancia de indicar el análisis de ácidos orgánicos en orina entre los estudios de primera línea, en todo niño con un cuadro clínico de presentación aguda y severamente enfermo, sin etiología definida. Por otra parte, se desea resaltar que el diagnóstico oportuno y definitivo es importante ya que permite iniciar un tratamiento específico, lograr una evolución favorable y prevenir las secuelas.