28 Disorders of Cobalamin and Folate Transport and Metabolism

28 Disorders of Cobalamin and Folate Transport and Metabolism David S. Rosenblatt, Brian Fowler 28.1 Disorders of Absorption and Transport of Cobalamin – 343 28.1.1 Hereditary Intrinsic Factor Deficiency – 343 28.1.2 Defective Transport of Cobalamin by Enterocytes (Imerslund-Gräsbeck Syndrome) – 343 28.1.3 Haptocorrin (R Binder) Deficiency – 344 28.1.4 Transcobalamin Deficiency – 344 28.2 Disorders of Intracellular Utilization of Cobalamin – 345 28.2.1 Combined Deficiencies of Adenosyl cobalamin and Methylcobalamin – 345 28.2.2 Adenosylcobalamin Deficiency – 347 28.2.3 Methylcobalamin Deficiency – 348 28.3 Disorders of Absorption and Metabolism of Folate – 351 28.3.1 Hereditary Folate Malabsorption – 351 28.3.2 Glutamate-Formiminotransferase Deficiency – 351 28.3.3 Methylenetetrahydrofolate Reductase Deficiency – 352 References – 353 342 Chapter 28 · Disorders of Cobalamin and Folate Transport and Metabolism Cobalamin Transport and Metabolism Cobalamin (cbl or vitamin B12) is a cobalt-containing multiple intracellular conversions. As methylcobalamin, water-soluble vitamin that is synthesized by lower it is a cofactor of the cytoplasmic enzyme methionine organisms but not by higher plants and animals. In the synthase. As adenosylcobalamin, it is a cofactor of human diet, its only source is animal products in which the mitochondrial enzyme methylmalonyl-coenzyme it has accumulated by microbial synthesis. Cbl is needed A mutase, which is involved in the catabolism of valine, for only two reactions in man, but its metabolism in- threonine and odd-chain fatty acids into succinyl-CoA, volves complex absorption and transport systems and an intermediate of the Krebs cycle. V . Fig. 28.1. Cobalamin (Cbl) endocytosis and intracellular me- TC, transcobalamin (previously TCII); V1, variant 1; V2, variant 2; tabolism. The cytoplasmic, lysosomal, and mitochondrial com- 1+,2+,3+ refer to the oxidation state of the central cobalt of Cbl. partments are indicated. AdoCbl, adenosylcobalamin; CoA, co- Letters A-H refer to the sites of blocks. Enzyme defects are indicat- enzyme A; MeCbl, methylcobalamin; OHCbl, hydroxycobalamin; ed by solid bars 343 28 28.1 · Disorders of Absorption and Transport of Cobalamin affinity for Cbl, receptor or increased susceptibility to pro- For patients with inherited disorders affecting cobala- teolysis [7–9]. min (Cbl) absorption, the main clinical finding is megaloblastic anemia. Except for transcobalamin (TC) defi- Genetics ciency, the serum Cbl level will usually be low. Patients At least 45 patients of both sexes have been reported, and with disorders of intracellular Cbl metabolism show inheritance is autosomal recessive. A cDNA has been cha- elevations of homocysteine or methylmalonic acid, racterized, and the gene is localized on chromosome 11q13 either alone or in combination. The serum Cbl level is [10]. A recently described variant of the gastric IF (GIF) not usually low. For those disorders that affect methyl- gene, 68AoG, is probably not a disease causing mutation cobalamin (MeCbl) formation, the major manifestations but could serve as a marker for inheritance of the disorder include megaloblastic anemia secondary to folate [11]. A 4-bp deletion (c183_186delGAAT) in the coding deficiency and neurological abnormalities presumably region of the GIF gene was identified as the cause of intrinsic secondary to methionine deficiency or homocysteine factor deficiency in an 11 year-old girl with severe anemia elevation. The main findings in those disorders that and Cbl deficiency [12]. affect adenosylcobalamin (AdoCbl) formation, are secondary to elevated methylmalonic acid and resultant Diagnostic Tests acidosis. The hematological abnormalities in the defects of Cbl absorption and transport should be detected by measurement of red blood cell indices, complete blood count and bone Inherited disorders of cobalamin (Cbl) metabolism are di- marrow examination. Low serum Cbl levels are present. vided into those involving absorption and transport and A deoxyuridine suppression test on marrow cells is useful those involving intracellular utilization [1–5]. but is not easily available in most clinical laboratories. In hereditary IF deficiency, in contrast to acquired forms of pernicious anemia, there is normal gastric acidity and 28.1 Disorders of Absorption normal gastric cytology. Cbl absorption, as measured by and Transport of Cobalamin the Schilling test, is abnormal but is normalized when the labeled Cbl is mixed with a source of normal IF, such as Absorption of dietary Cbl involves first binding to a glyco- gastric juice from an unaffected individual. protein (R binder, haptocorrin) in the saliva. In the intes- tine, haptocorrin is digested by proteases, allowing the Cbl Treatment and Prognosis to bind to intrinsic factor (IF), which is produced in the IF deficiency can be treated initially with hydroxycoba- stomach by parietal cells. Using a specific receptor, the IFCbl lamin (OHCbl, 1 mg/day intramuscularly) to replete body complex enters the enterocyte. Following release from this stores until biochemical and hematological values nor- complex Cbl binds to transcobalamin (TC), the physiologi- malize. The subsequent dose of OHCbl required to main- cally important circulating Cbl-binding protein, forming tain normal values may be as low as 0.25 mg every 3 months. TC-Cbl, which is then slowly released into the portal vein. If treatment is delayed, some neurological abnormalities Inherited defects of several of these steps are known. may persist in spite of complete reversal of the hematological and biochemical findings. 28.1.1 Hereditary Intrinsic Factor Deficiency 28.1.2 Defective Transport of Cobalamin by Enterocytes Clinical Presentation (Imerslund-Gräsbeck Syndrome) Presentation is usually from one to 5 years of age but in cases of partial deficiency, can be delayed until adolescence Clinical Presentation or adulthood. Patients present with megaloblastic anemia Defective transport of Cbl by enterocytes, also known as as the main finding, together with failure to thrive, often Imerslund-Gräsbeck syndrome or megaloblastic anemia 1 with vomiting, alternating diarrhea and constipation, ano- (MGA1), is characterized by prominent megaloblastic rexia and irritability [6–8]. Hepatosplenomegaly, stomatitis anemia manifesting once fetal hepatic Cbl stores have been or atrophic glossitis, developmental delay, and myelopathy depleted. The disease usually appears between the ages of or peripheral neuropathy may also be found. 1 year and 5 years, but onset may be even later [13–19]. Most patients have proteinuria and, in a few cases, this is Metabolic Derangement of the tubular type, with all species of proteins represented IF is either absent or immunologically detectable but non- rather than albumin alone. The literature on the renal functional. There have been reports of IF with reduced pathology has been reviewed [20]. Although patients who 344 Chapter 28 · Disorders of Cobalamin and Folate Transport and Metabolism excreted protein during childhood continued to excrete 28.1.3 Haptocorrin (R Binder) Deficiency protein in adulthood, the renal lesions were not progressive [14]. Neurological abnormalities, such as spasticity, trun- Clinical Presentation cal ataxia and cerebral atrophy, may be present as a con- Very few cases have been described and it is not clear sequence of the Cbl deficiency. whether this entity has a distinct phenotype. Hematological findings are absent and neurological findings such as sub- Metabolic Derangement acute combined degeneration of the spinal cord in one man This disorder is caused by defects of the IF-Cbl receptor, in the fifth decade of life [29] and optic atrophy, ataxia, which has been recently shown to comprise two compo- long-tract signs and dementia in another, may be coinci- nents. Cubilin was first purified as the IF-Cbl receptor from dental. the proximal renal tubule [21–23]. Fyfe et al. demonstrated that a second component, amnionless, co-localizes with Metabolic Derangement V cubilin in the endocytic apparatus of polarized epithelial The role of haptocorrin is uncertain but it could be involved cells, forming a tightly bound complex that is essential for in the scavenging of toxic Cbl analogs or in protecting endocytic function [24]. Thus defective function of either methylcobalamin from photolysis [30]. Deficiency of hapto- protein may cause this disorder. corrin has been described in isolation and in association with deficiency of other specific granule proteins such as Genetics lactoferrin [31]. About 250 cases have been reported and inheritance is autosomal recessive [19], with environmental factors affecting Genetics expression [22, 25]. Most patients are found in Finland, The haptocorrin gene has been cloned and mapped to Norway, Saudi Arabia, Turkey, and among Sephardic Jews. chromosome 11q11-q12 [32, 33]. No mutations have been The cubilin gene (CUBN) has been mapped to 10p12.1. A described in any patient with haptocorrin deficiency. P1297L mutation was found in 31 of 34 disease chromo- Heterozygosity for haptocorrin deficiency appears to be somes from 16 of 17 Finnish families segregating megalo- associated with low serum cobalamin [34]. blastic anemia [26]. Linkage studies in families from Nor- way, without mutations of the CUBN gene, led to the Diagnostic Tests discovery of the amnionless gene (AMN). A study of 42 Serum Cbl levels are low, because most circulating Cbl is MGA1 sibships confirmed CUBN mutations in Finnish bound to haptocorrin. TC-Cbl levels

Load more