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Hamdan Medical Journal 2012; 5(Suppl Hamdan Medical Journal 2012; 5(Suppl. 1):39–41 SP15 SP15 Disorders of cobalamin and folate metabolism a!ecting remethylation Bridget Wilcken Sydney Children’s Hospitals Network and University of Sydney, Sydney, Australia Cobalamin and folate de!ciencies and disorders of to diagnose as serum cobalamin concentrations are absorption, transport and metabolism are important low. Transport disorders may be more problematic. to diagnose, as they are treatable.1,2,3 Pathways In haptocorrin (formerly called transcobalamin I) of cobalamin and folate metabolism intersect de!ciency levels of vitamin B12 as usually measured at methionine synthase, and disorders in both are low, as 80% of circulating cobalamin is bound pathways that impact on methionine synthase a#ect to haptocorrin, but levels of the biologically active remethylation. This is shown in Figure 1. transcobalamin–cobalamin compound (previously transcobalamin II-cobalamin) are normal. Haptocorrin Cobalamin de!ciency, from whatever cause, and de!ciency appears benign. The recently described cobalamin intestinal uptake disorders (intrinsic factor transcobalamin receptor de!ciency may also be de!ciency and Imerslund–Gräsbeck disorder) are easy largely benign.2 Transcobalamin (II) de!ciency is FIGURE 1 Pathways of intracellular cobalamin and folate metabolism. Enzymes are shown in boxes, coenzymes in dashed boxes and the metabolic disorders are in italics. 5-MTHF, 5-methyltetrahydrofolate reductase; AdoCbl, adenosylcobalamin; ATP, adenosine triphosphate; Cbl, cobalamin; MetCbl, methylcobalamin; MS, methionine synthase; MTHFR, 5,10-methylenetetrahydrofolate reductase; Mutase, methylmalonyl CoA mutase; OHCbl, hydroxocobalamin; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; THF, tetrahydrofolate. Reprinted with permission from Wilcken B. Leukoencephalopathies associated with disorders of cobalamin and folate metabolism. Semin Neurol 2012; 32:68–74. © 2012 The Author(s) 39 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5(Suppl. 1):39–41 SP15 however symptomatic early, with failure to thrive and have megaloblastic anaemia, and often pancytopenia. megaloblastic anaemia. The level of measured vitamin The serum vitamin B12 and folate levels are normal. B12 may be within the normal range, as only 20% of The occurrence of thromboembolism in the CblC cobalamin is bound to transcobalamin. This disorder defect has been well documented, mainly in late- needs early treatment similar to that in the speci!c onset patients who usually present with neurological remethylating disorders, as described below. or psychiatric symptoms. The other disorders of intracellular cobalamin metabolism with defective Disorders associated with defective remethylation remethylation, CblF, D, E and G are much rarer but of homocysteine to methionine are rare but clinically somewhat similar to patients with a CblC important disorders associated with leukodystrophy. defect. For all these cobalamin defects, treatment Cobalamin is required in humans for two must include high-dose parenteral hydroxocobalamin reactions: remethylation of homocysteine to daily or at least several times per week, and betaine to methionine, with methylcobalamin as a cofactor provide remethylation by a di#erent pathway. for methionine synthase, and the conversion of methylmalonyl-Coenzyme A (CoA) to succinyl CoA by Disorders of folate metabolism are less familiar. methylmalonylCoA mutase, with adenosylcobalamin Intestinal transport is defective in hereditary folate as cofactor. Mutations at various metabolic points malabsorption which presents with mucositis, a#ect the synthesis of adenosylcobalamin (cobalamin diarrhoea, failure to thrive, anaemia and very low defects A, B, and D variant 2) or methylcobalamin levels of circulating folate. Cerebral folate de!ciency (cobalamin defects E, G and D variant1) or of both syndromes are caused by several distinct genetic (cobalamin defects F, D and C). Only the disorders disorders of transport across the blood–brain barrier. of methylcobalamin synthesis a#ect remethylation, Neurological symptoms start in the !rst few months. see Figure 1. Patients with the remethylation Diagnosis is di"cult and depends on demonstration disorders may present acutely or chronically, with of low 5-methyltetrahydrofolate in cerebrospinal $uid signi!cant neurological, haematological, vascular (CSF), but not peripherally. Already described above and other symptoms. The majority of described and within the folate cycle are cobalamin E, G and patients have presented in early infancy, often D1 defects. The most frequent disorder in the folate within the neonatal period, but it is likely that there pathway is 5-methylenetetrahydrofolate reductase is considerable under-diagnosis of late-presenting (5-MTHFR) de!ciency. Severe 5-MTHFR de!ciency patients. Diagnostic di"culties arise because may present from early infancy to adulthood. Infants circulating levels of cobalamin and folate are usually have severe developmental delay, seizures, hypotonia normal, and initial diagnosis requires measurement and microcephaly, and may have apnoeas and of plasma holotranscobalamin, plasma and red coma. Cases with a later onset may have intellectual cell folate, homocysteine, methylmalonic acid, and impairment, gait abnormalities, ataxia, dysarthria, methionine, plus haematological and other tests. First tremors, psychotic symptoms and, commonly, identi!cation is now often by newborn screening. thromboembolism which may be the only feature These disorders have autosomal recessive inheritance, in an otherwise well person. Laboratory !ndings and all are treatable, although with variable outcome. include elevated levels of homocysteine in urine and The most common of the disorders is a cobalamin C plasma, and low or low–normal plasma methionine. (CblC) defect, caused by mutations in the MMACHC There is no megaloblastosis, (an important di#erential gene located on chromosome 1, at 1p34.1. Among feature) and no methylmalonic aciduria. Serum folate the 50 + mutations described is a common frame- levels may be normal or low. Treatment with folic or shift mutation, c.271dupA, associated with a severe folinic acid together with betaine shows the most presentation, and accounting for approximately success. Glutamate formiminotransferase de!ciency 40% mutant alleles in a large series. Newborn is also a disorder of folate metabolism but, despite screening has revealed a birth prevalence of about early reports, current experience suggests that this is 1 : 60–100,000. Early infantile onset is associated probably benign. Additional disorders have recently with lethargy, poor feeding, vomiting and failure to been identi!ed3. thrive, and sometimes acute illness with haemolytic– uraemic syndrome or progressive hydrocephalus. The !rst step in diagnosis is to consider the possibility Later, microcephaly, seizures, hypotonia, and of one of these rare disorders in patients presenting developmental delay are seen, and a pigmentary with symptoms and signs outlined here. Further retinopathy is common. Almost all untreated patients testing is indicated in Table 1. The e#ectiveness 40 © 2012 The Author(s) Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences Hamdan Medical Journal 2012; 5(Suppl. 1):39–41 SP15 of treatment may be greater now that most of References the disorders can be identi!ed with the newborn 1 Wilcken B. Leukoencephalopathies associated with screening tests that are becoming more available. disorders of cobalamin and folate metabolism. Semin Neurol 2012; 32:68–74. 2 Watkins D, Rosenblatt DS. Inborn errors of cobalamin absorption and metabolism. Am J Med Genet C Semin Med Genet 2011; 157:33–4. 3 Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 2012; 35:665–70. http://dx.doi.org/10.1007/s10545-011-9418-1 TABLE 1 Usual !ndings in disorders of cobalamin and folate absorption, transport and metabolism, and comparison with other disorders among the di#erential diagnoses. Reprinted with permission from Wilcken B. Leukoencephalopathies associated with disorders of cobalamin and folate metabolism. Semin Neurol 2012; 32:68–74 Disorder Serum Cbl HoloTC Serum/RBC folate Plasma MMA Plasma Hcy Plasma methionine Other Cbl absorption r r N p p N > r Haem TC II de#ciency N r N p p N Haem CblA, B, D2 N N N p N N Haem CblC, D, F N N N p p r Haem CblE, G, D1 N N N N p r Haem MTHFR(S) N N r> N N p r> N No haem HFM N N r N p r CSF : serum folate ratio r CFD N N N N N N CSF 5-MTHF r DHFR de#ciency N N N (RBC r) N N N Haem FTCD N N p > N N N N Urine FIGLU p Cbl de#ciency r r N p p N > r Haem Folate de#ciency N N r N p N > r FIGLU CBS de#ciency N N N N p p Cysta r 5-MTHF, 5-methyltetrahydrofolate; Cbl, cobalamin; CBS, cystathionine β-synthase de#ciency (homocystinuria); CFD, cerebral folate de#ciency; CSF, cerebrospinal "uid; DHFR, dihydrofolate reductase; FIGLU, formiminoglutamic acid; FTCD, formiminotransferase-cyclodeaminase de#ciency; haem, indicates haematological #ndings, principally megaloblastosis; Hcy, homocyst(e) ine; HFM, hereditary folate malabsorption; holoTC, holotranscobalamin; MMA, methylmalonic acid; MTHFR(S), severe 5,10-methylenetetrahydrofolate reductase de#ciency; N, normal; RBC, erythrocyte; TC II, transcobalamin II. These are usual #ndings, and there are individual exceptions to some. © 2012 The Author(s) 41 Journal Compilation © 2012 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences .
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