Disorders of Metabolism

Congenital

The conversion of a vitamin to its active coenzyme and subsequent binding to an apoenzyme producing active holoenzyme are fundamental biochemical processes. Therefore, deficient activity of an enzyme can result not only from a defect of the enzyme protein itself, which may involve interaction of a coenzyme with an apoen-zyme, but also from a defect in the conversion of the vitamin to a coenzyme.

Once vitamin B12 has been taken up into cells, it must be converted to an active coenzyme in order to act as a cocatalyst with vitamin B12-dependent apoenzymes. Two enzymes are known to depend for activity on vitamin B12 derivatives:

• Methylmalonyl coenzyme A (CoA) mutase, which requires adenosylcobalamin. Methylmalonyl CoA mutase catalyzes the conversion of methylmalonyl CoA to succinyl CoA. A decreased activity of methylmalonyl CoA mutase is reflected by the excretion of elevated amounts of methylmalonic acid.

• N5-Methyltetrahydrofolate homocysteine methyltransferase, which requires methylcobalamin. Lack of methylcobalamin leads to deficient activity of N5-methyltetrahydrofolate homocysteine methyltransferase, with reduced ability to methylate homocysteine, resulting in hyperhomocysteinemia and homocystinuria.

Patients with inborn errors of cobalamin utilization present with methylmalonic acidemia and hyperhomocysteinemia, either alone or in combination. Methyl-malonic acidemia occurs as a result of a functional defect in the mitochondrial methyl-malonyl CoA mutase or its cofactor adenosylcobalamin. Hyperhomocysteinemia occurs as a result of a functional defect in the cytoplasmic methionine synthase or its cofactor methylcobalamin. The sites of the defects and their frequency are shown in Figure 4-1. Tables 4-4 and 4-5 list the main features of genetic defects in processing cobalamins.

Severe metabolic acidosis, with the accumulation of large amounts of methyl-malonic acid in blood, urine, and cerebrospinal fluid, characterizes the methylmalonic acidurias. The incidence is estimated at 1:61,000. All the disorders of Cbl metabolism are inherited as autosomal recessive traits and prenatal diagnosis is possible. Classification has relied on somatic cell complementation studies in cultured fibroblasts. Prenatal detection of fetuses with defects in the complementation groups cblA, cblB, cblC, cblE, 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 has been attempted with apparent success.

TCII Cob(III)alamin

TCII Cob(III)alamin

Cobalamin Malonic Acid

Fig. 4-1. Cobalamin metabolism in cultured mammalian cells and the sites of the known inborn errors of cobalamin metabolism. AdoMet, S-adenosylmethionine; cob(III)alamin, cob(II)alamin, cob(II)alamin represent cobalamin with its cobalt in the 3+, 2+, or 1+ oxidation state; methyl-THF is 5-methyltetrahydrofolate. The incidence or minimum numbers of patients with a given disease are shown in parentheses. (From Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 36:1999, with permission.)

Fig. 4-1. Cobalamin metabolism in cultured mammalian cells and the sites of the known inborn errors of cobalamin metabolism. AdoMet, S-adenosylmethionine; cob(III)alamin, cob(II)alamin, cob(II)alamin represent cobalamin with its cobalt in the 3+, 2+, or 1+ oxidation state; methyl-THF is 5-methyltetrahydrofolate. The incidence or minimum numbers of patients with a given disease are shown in parentheses. (From Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 36:1999, with permission.)

Table 4-4. Autosomal Recessive Inborn Errors of Cobalamin Transport and Metabolism

Condition (OMIM No.)

Defect

Typical clinical manifestations

Typical onset

Laboratory findings

Treatment and response

TC II deficiency (OMIM 275350)

Defective/absent TC II

Failure to thrive, megaloblastic anemia, later neurologic features, and immunodeficiency

Early infancy 3-5 weeks

Usually normal serum Cbl; elevated serum MMA, homocysteine; absent/defective TC II

High doses of Cbl by injection; good response to treatment if begun early

TC I (R-binder) deficiency (OMIM 193090)

Deficiency/absence of TC I in plasma, saliva, leukocytes

Neurologic symptoms (myelopathy) reported, but unclear if these are related to condition

Unclear if observed symptoms are related to condition

Low serum Cbl, normal TC II-Cbl levels. No increase in MMA or homocysteine.

Cbl therapy does not appear to be of benefit

Defective synthesis of AdoCbl: cblA (OMIM 251100) cblB (OMIM 251110)

Defective synthesis of AdoCbl

Lethargy, failure to thrive, recurrent vomiting, dehydration, hypotonia, ketoacidosis hypoglycemia

First weeks or months of life

Normal serum Cbl, homocysteine, and methionine; elevated MMA, ketones, glycine, ammonia; leukopenia, thrombocytopenia, anemia

Pharmacologic doses of Cbl, dietary protein restriction, oral antibiotics. Treatment response for cblA better than for cblB

Defective synthesis of MeCbl: cblE (OMIM 236270) cblG (OMIM 250940)

Defective synthesis of MeCbl

Vomiting, poor feeding, lethargy, severe neurologic dysfunction, megaloblastic anemia

Defective synthesis of Impaired synthesis Failure to thrive,

AdoCbl and MeCbl: cblC (OMIM 277400) cblD (OMIM 277410) cblF (OMIM 277380)

of both AdoCbl and MeCbl developmental delay, neurologic dysfunction, megaloblastic anemia, some cases with retinal findings

Most in first 2 years of life

Variable from neonatal period to adolescence; majority with neonatal onset

Normal serum Cbl and folate; homocystinuria, hypomethioninemia

Normal serum Cbl, TC II; methylmalonic aciduria, homocystinuria, hypomethioninemia

Pharmacologic doses of Cbl, betaine; good treatment response in some patients treated early

Pharmacologic doses of hydroxocobalamin, moderate protein restriction, betaine treatment. Response often not optimum

Abbreviations: TC II, transcobalamin II; OMIM, Online Mendelian Inheritance in Man; Cbl, cobalamin; MMA, methylmalonic acid; TC I, transcobalamin I; AdoCbl, adenosylcobalamin; MeCbl, methylcobalamin.

Modified from Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J of Pediatrics 2001;138:10-17.

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Table 4-5. Main Features of Genetic Defects of Processing of Cobalamins

Defect

Serum B12

Clinical/biochemical

Food cobalamin malabsorption

Low

NA ± anemia, mild T MMA/tHcy

Intrinsic factor deficiency

Low

Anemia, delayed development,

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