出生前診断
Remethylation of homocysteine to methionine by MTR requires the derivative of cobalamin, methylcobalamin. Cobalamin metabolism is initiated by the endocytosis of cobalamin bound to the plasma protein transcobalamin (II). Cleavage of this complex produces free cobalamin, translocating from lysosome to cytoplasm. Conversion can occur to 5’-deoxyadenosylcobalamin (AdoCbl) activating the mitochrondrial enzyme methylmalonly coenzyme A mutase or to methylcobalamin (MeCbl). An error in cobalamin metabolism resulting in decreased MeCbl and unaffected AdoCbl is characteristic of the CblE type of homocystinuria. This complementation is rare with autosomal recessive inheritance. The inherited methionine synthase functional deficiency corresponds to a defect in the reducing system required to activate the MTR enzyme. Symptoms of this condition comprise developmental retardation, megaloblastic anemia, homocystinuria, hypomethioninemia, cerebral atrophy and hyperhomocysteinemia. However, hypomethioninemia remains an inconsistent symptom. Decreased MeCbl alongside normal cobalamin uptake is suggestive of decreased intracellular methionine biosynthesis. Occurring mainly in childhood, 15 pathogenic mutations can be associated with CblE type homocystinuria. Additionally, vascular abnormalities are associated with this defect. Impaired reduction of an oxidised cobalt atom in the active site of MTR is associated with this condition, where enzyme activity can be corrected with reducing agents. Rare polymorphisms related to this disease include (MTRR):c.1459G&gt;A, (MTRR):c.1623-1624insTA and (MTRR):c.903+469T&gt;C. These mutations, excluding (MTRR):c.1459G&gt;A result in a frame shift, producing premature termination codons. As consequent products are distant from normal, mutant mRNA arises and nonsense mediated decay (FMN) is initiated. The large insertion of 903_904ins140 corresponding to 903+469T&gt;C is most prevalent in CblE pathology. The activation of an enhanced splicer within intron 6 is incomplete, producing small quantities of normal spliced MTRR mRNA. Prenatal diagnosis of this condition is possible using [14C] methyltetrahydrofolate. Mutation analysis in native chorionic villi and [14C] formate in amino acids within these villi or cultured amniocytes is indicative of the CblE defect. Additionally, macrocytic anemia is a typical feature of the CblE defect and can be corrected though OH-Cobalamin administration or folate supplementation.