Remethylation defect

A large elevation of Hey in body fluids and tissues is found in several genetic enzyme deficiencies, the homocystinurias. These include cystathionine /3-synlhase deficiency [9], the remethylation defects due to deficiency of MTHF reductase [10], methionine synthase and methionine synthase reductase deficiencies, as well as defects of intracellular cobalamin metabolism [11], namely the cblF, cblC and cblD defects. It is noteworthy that low levels of total Hey (tHcy) have been described in sulphite oxidase deficiency [12]. 

Patients with this most common form of homocystinuria show evidence of involvement of the eye, the skeletal system, the vascular system, and the brain. It is important to note that individuals with cystathionine P-synthase deficiency do not manifest any abnormalities at birth and that the affected pregnancies are uneventful. Thus, this disorder, as opposed to the more rare remethylation defect variants of homocystinuria (described below), is not usually part of the differential diagnosis of the catastrophically ill newborn. Ectopia lentis does not usually appear before the age of 3 years, but most patients have some manifestations by the age of 10. The initial recognition of ocular abnormahties may be an observation by parent or physician that the iris shakes, when the head is moved rapidly. While a predilection for... 

As the name implies, renal clearance of abnormal levels of homocystine in the plasma causes excessive excretion of the amino acid in the urine. In cystathionine P-synthase deficiency, plasma methionine concentrations are elevated as well -this serves as a point of distinction from the remethylation defects. At present, it appears that the pyridoxal phosphate response may be explained by the fact that this vitamin increases the steady-state concentration of the active enzymes by decreasing the rate of apoenzyme degradation and possibly by increasing the rate of holoenzyme formation. The explanation is not entirely satisfactory, however, since in vitro studies have shown detectable levels of enzyme activity in mutant fibroblasts that have no response, while in other mutant lines without detectable enzyme activity, response has occurred. Once again, a distressing lack of correspondence between in vivo observations and in vitro experiments forces investigators to probe the secrets of these diseases more deeply. 

Variability of presentation characterizes this homocysteine remethylation defect as well. Several patients have been reported from one family one with seizures and muscle weakness, a second with schizophrenia and retardation, and a third who was asymptomatic. Subsequently, patients with a more malignant neonatal presentation were reported, and hence both variants should be part of the differential diagnosis of sepsis neonatorum . 

Fibroblasts from each patient had markedly reduced levels of the above enzyme. The defect results in an inability to synthesize 5-methyltetrahydrofolate in amounts sufficient for the remethylation of homocystine to methionine. Homocystine accumulates in plasma, and the plasma methionine is decreased. As in the other remethylation defect, there is accumulation of cystathionine. Treatment with high doses of folic acid has been beneficial in several patients (Mudd et al., 1989). 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine 677... 

Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12. In the absence of normal B12 activation, homocystinuria results from a failure of normal vitamin B12 metabolism. Complementation analysis classifies defects in vitamin B12 metabolism into three groups cblC (most common), cblD and cblF. Most individuals become ill in the first few months or weeks of life with hypotonia, lethargy and growth failure. Optic atrophy and retinal changes can occur. Methylmalonate excretion is excessive, but less than in methylmalonyl-CoA mutase deficiency, and without ketoaciduria or metabolic acidosis. 

CBS deficiency is inherited as an autosomal recessive trait. Homozygous individuals (I in 200,000 births) have classical homocystinuria with extremely high plasma tHcy. The 677 C > T polymorphism in MTHFR is believed to be one of the most common causes of mildly elevated plasma tHcy, The frequency of the homozygous genotype is I 1% to 15% in North Americans, 5% to 23% in Europeans, I I % in healthy Japanese populations, and only 2,5% in the Indian population in New Delhi (12-14). The polymorphism induces thermolability in the enzyme, resulting in defect remethylation of... 

An alternative reaction for the remethylation of homocysteine to methionine can be accomplished by betaine homocysteine methyltrans-ferase, which uses betaine instead of 5-MTHF as the methyl donor. Unlike the MS reaction, which is believed to be ubiquitously present in all tissues, the betaine homocysteine methyl-transferase reaction occurs only in the liver and kidney. Betaine is not a required nutrient since the liver can synthesize betaine from choline. Betaine supplements, however, have been shown to lower plasma total homocysteine concentrations successfully in subjects with deficient homocysteine remethylation due to defects in MTHFR or MTRR and in those with deficient CBS activity. 

In 1969, McCully made an important observation when he noticed severe vascular pathology caused by defects in homocysteine remethylation in children with homocystinuria (McCully, 1969). Like patients with CBS deficiency, these children had markedly elevated levels of tHcy in their blood and urine, but their blood levels of methionine were lower than... 

Homocysteine lies at a metabolic crossroad it may condense with serine to form cystathionine, or it may undergo remethylation, thereby conserving methionine. There are two pathways for remethylation in humans. In one, betaine provides the methyl groups, while in the other 5-methyltetrahydrofolate is the methyl donor. This latter reaction is catalyzed by a Bj -containing enzyme, 5-methyltetrahydrofolate homocysteine methyltransferase. Two defects in this latter mechanism may account for the inability to carry out remethylation. In one of them, patients are unable to synthesize or accumulate methylcobalamin, while others cannot produce the second cofactor, 5 -methyltetrahydrofolate, because of adefect in 5,10-methylenetrahydrofolate reductase. 

Patients have been described with this defect in remethylation of homocysteine. The initial patient presented a catastrophically ill newborn who died when 7 weeks old. While homocystine levels were elevated in blood and urine, the level of methionine in blood was quite low. Of great interest was the presence of large amounts of methylmalonic add in urine. Three other patients presented later in childhood, two of whom were retarded mentally. One of these patients also had severe megaloblastic anemia (Doscherholmen and Hagen, 1957). 

Since the coenzyme from vitamin is required in two distinct enzyme reactions, i.e., remethylation of homocystine and catabolism of methylmalonic acid, the fundamental defect must involve a step in converting to its coenzymes. Formation of both deoxyadenosyl B and methyl B requires a prior reductive step catalyzed by cobalamin reductase, which appears to be the defective enzyme in this variant (Hogervorst et al., 2002) (Fig. 20.4). 

Fig. 10.1. Defects of transmethylation (methioninehomocysteine), transsulfuration (methionine sulfate), and remethylation (homocysteine - methionine) enzymes of sulfur amino acid metabolism 10.1, methionine adenosyltransferase 10.2, cystathionine ) -synthase 10.3, y-cystathionase 10.4, sulfite oxidase 10.5, molybdenum cofactor 10.6, methylenetetrahydrofolate reductase 10.7 and 10.8, methionine synthase.

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