Abstract

1. Folate coenzymes participate in a number of critical single-carbon transfer reactions, including those involved in the biosynthesis of pyrimidines, purines, serine, and methionine and in the degradation of histidine and purines.

   
   

2. Five inherited disorders of folate transport and metabolism have been well substantiated: methylene-H₄Folate reductase deficiency (MIM 236250); functional methyltetrahydrofolate (methyl-HFolate):homocysteine methyltransferase (methionine synthase) deficiency caused by mutations in the gene for methionine synthase reductase (cblE) (MIM 236270) or mutations in the gene for methionine synthase itself (cblG) (MIM 250940); glutamate formiminotransferase deficiency (MIM 229100); and hereditary folate malabsorption (MIM 229050).

   
   

3. Four putative inherited disorders in the literature cannot be considered to be well substantiated: dihydrofolate reductase deficiency; methenyl-H₄Folate cyclohydrolase deficiency; cellular uptake defects; and the original description of primary methyl-H4Folate: homocysteine methyltransferase deficiency from Japan.

   
   

4. Methylene-H₄Folate reductase deficiency, the most widely studied of the inherited disorders of folate metabolism, is a condition in which clinical severity correlates with the degree of enzyme deficiency. The clinical symptoms vary, with developmental delay accompanied by motor and gait abnormalities, seizures, and psychiatric manifestations being described. The age of onset has ranged from the neonatal period to adulthood. The major biochemical findings are moderate homocystinuria and hyperhomocystinemia with low or relatively normal levels of plasma methionine. Most severely affected patients have died. Pathologic findings include vascular changes similar to those seen in classical homocystinuria and demyelination presumably due to low levels of neurotransmitters or methionine in the central nervous system. A variant form of methylene-H₄Folate reductase deficiency resulting in “intermediate homocystinuria” is associated with 50 percent residual activity and enzyme thermolability, and is suggested to be an inherited risk factor for coronary heart disease. In the majority of cases, this variant is due to homozygosity for a common polymorphism, 677C→T, in the methylene-H₄Folate reductase gene. Severe methylene-H₄Folate reductase deficiency is resistant to treatment; folates, methionine, pyridoxine, cobalamin, and carnitine have all been used. Betaine has the theoretical advantage of both lowering homocysteine levels and supplementing methionine levels and has been the most promising therapeutic agent to date, particularly if started immediately after birth. Nevertheless, the prognosis is generally poor.

   
   

5. Functional methionine synthase deficiency due to the cblE and cblG mutations is characterized by homocystinuria and defective biosynthesis of methionine. Most patients have presented in the first few months of life with megaloblastic anemia and developmental delay. At least one patient presented in early adulthood with a misdiagnosis of multiple sclerosis. The distribution of cobalamin derivatives was altered in cultured cells, with decreased levels of MeCbl as compared with normal fibroblasts. The cblE mutation is associated with low methionine synthase activity when the assay is performed with low levels of thiol, whereas the cblG mutation is associated with low activity under all assay conditions. cblE and cblG represent distinct complementation classes. Both diseases respond to treatment with hydroxocobalamin (OH-Cbl).

   
   

6. Glutamate formiminotransferase deficiency is a heterogeneous condition associated with elevated excretion of formiminoglutamic acid, 4-amino-5-imidazole-carboxamide, and hydantoin-5-propionate. Clinical findings have varied from mental and physical retardation to massive excretion of formiminoglutamate in the absence of retardation. Therapy with folates and methionine has been described, but given that the correlation between symptoms and formiminoglutamate excretion remains uncertain, the basis for treating these patients is unclear.

   
   

7. Hereditary folate malabsorption is characterized by the early onset of failure to thrive and severe folate-responsive megaloblastic anemia. All patients have been severely restricted in their ability to absorb oral folic acid or oral reduced folates. Severe mental retardation may be a prominent feature if therapy does not succeed in maintaining adequate levels of folate in the cerebrospinal fluid. Two patients have shown increased susceptibility to infection. This disorder provides the best evidence for the existence of a specific carrier for folate both at the level of the intestine and at the choroid plexus. Therapy has been attempted with large doses of oral or systemic folates.

   
   

8. All of the clearly delineated disorders of folate metabolism appear to be inherited as autosomal recessive traits. Heterozygotes for methylene-H₄Folate reductase deficiency show decreased enzyme levels in somatic cells. A difference in folate absorption in the heterozygote has been suggested in at least one family with hereditary folate malabsorption.

   
   

9. Prenatal diagnosis has been successfully performed for methylene-H₄Folate reductase deficiency, methionine synthase reductase deficiency (cblE), and methionine synthase (cblG) deficiency using cultured amniotic cells.

   
   

10. Cobalamins (Cbls) are complex organometallic substances consisting of a corrin ring, a central cobalt atom, and various axial ligands. The basic structure, known as vitamin B₁₂, is synthesized exclusively by microorganisms, but most higher animals are capable of converting the vitamin into the two required coenzyme forms, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl).

    
    

11. Dietary Cbl is acquired mostly from animal sources, including meat and milk, and is absorbed in a series of steps that includes proteolytic release from its associated proteins, binding to a gastric secretory protein known as intrinsic factor (IF), recognition of the IF-Cbl complex by cubilin, a receptor on ileal mucosal cells, transport across those cells, and release into the portal circulation bound to transcobalamin II (TC II), the serum protein that carries newly absorbed Cbl throughout the body.

    
    

12. The cellular metabolism by which the coenzymes are formed involves receptor-mediated binding of the TC II-Cbl complex to the cell surface, adsorptive endocytosis of the complex, intralysosomal degradation of the TC II, release of Cbl into the cytoplasm, enzyme-mediated reduction of the central cobalt atom, and cytosolic methylation to form MeCbl or mitochondrial adenosylation to form AdoCbl.

    
    

13. Only two enzymes in mammalian cells are known to depend on cobalamin coenzymes: methylmalonyl CoA mutase, which requires AdoCbl; and methionine synthase (also known as N ⁵-methyltetrahydrofolate:homocysteine methyltransferase), which requires MeCbl.

    
    

14. Ten different inherited defects are known to impair the pathways of Cbl transport and metabolism in humans (see Fig. 155-12). Three affect absorption and transport; the other seven alter cellular utilization and coenzyme production.

    
    

15. The defects affecting Cbl absorption and transport generally manifest themselves in infancy or early childhood as developmental delay with megaloblastic anemia. Serum Cbl levels may be reduced (in IF (MIM 261000) or cubilin-protein deficiency (MIM 261100)) or near normal (in TC II deficiency (MIM 275350)). Treatment with periodic injections of Cbl, with or without folate therapy, is generally effective in controlling these problems.

    
    

16. The clinical manifestations of deficiencies in cellular Cbl utilization and metabolism vary depending on whether one or both coenzymes are affected. Two abnormalities in AdoCbl synthesis only (designated cblA (MIM 251100) and cblB (MIM 251110) lead to impaired methylmalonyl CoA mutase activity and result in methylmalonic acidemia. In most, but not all, patients with these defects, pharmacologic supplements of Cbl (cyanocobalamin or hydroxocobalamin) produce distinct reductions in methylmalonate accumulation and offer a valuable therapeutic adjunct to dietary protein limitation. Oral antibiotic therapy may be useful to reduce propionate production by gut bacteria. The defect in cblA is unknown, while the defect in cblB patients is in cob(I)alamin adenosyltransferase, the final step of AdoCbl biosynthesis.

    
    

17. Three distinct mutations, designated cblC (MIM 277400), cblD (MIM 277410), and cblF (MIM 277380), lead to impaired synthesis of both AdoCbl and MeCbl and, accordingly, to deficient activity of both methylmalonyl CoA mutase and methionine synthase. Children from these groups have methylmalonic aciduria and homocystinuria. Children with the cblC mutation appear to be more severely affected clinically than the two known sibs in the cblD group or those in the cblF group. Major clinical problems in cblC patients include failure to thrive, developmental retardation, and such hematologic abnormalities as megaloblastic anemia and macrocytosis. Treatment requires a combination of the therapies for the individual coenzyme deficiencies: protein restriction and pharmacologic doses of hydroxocobalamin, possibly in combination with oral antibiotics and betaine supplements. The precise defects in the cblC and cblD patients are not yet known, but they must involve early steps in the intracellular metabolism of cobalamins, possibly cytosolic Cbl reduction. The defect in cblF appears to be in the transport mechanism by which Cbl is released from lysosomes.

    
    

18. The discriminating biochemical features of the inherited defects in Cbl transport and metabolism are shown in Table 155-5.

    
    

19. All the disorders of Cbl metabolism for which there are adequate data are inherited as autosomal recessive traits. Heterozygotes can be detected only for cblB. Genetic complementation analyses with somatic-cell heterokaryons have been particularly useful in demonstrating genetic heterogeneity and in confirming the existence of autosomal recessive inheritance among defects in cellular Cbl utilization and metabolism.

    
    

20. Prenatal detection of fetuses with defects in the complementation groups cblA, cblB, cblC, and cblF has been accomplished using cultured amniotic cells and chemical determinations on amniotic fluid or maternal urine. In several cases, in utero Cbl therapy was done with apparent success.

    
    

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