Inborn Metabolic Diseases Diagnosis and Treatment - part 7 docx

27 333 Two inherited defects in biotin metabolism are known: holocarboxylase synthetase (HCS) deficiency and biotinidase deficiency. Both lead to deficiency of all biotin- dependent carboxylases, i.e. to multiple carboxylase deficiency (MCD). In HCS deficiency, the binding of biotin to apocarboxylases is impaired. In biotinidase deficiency, biotin depletion ensues from the inability to recycle endogenous biotin and to utilize protein-bound biotin from the diet. As the carboxylases play an essential role in the catabolism of several amino acids, in glu- coneogenesis and in fatty-acid synthesis, their deficiency provokes multiple, life-threatening metabolic derangements, eliciting characteristic organic aciduria and neurological symptoms. The clinical presentation is extremely variable in both disorders. Characteristic symptoms include metabolic acidosis, hypotonia, seizures, ataxia, impaired consciousness and cutaneous symptoms, such as skin rash and alopecia. All patients with biotinidase and a majority of patients with HCS deficiency respond dramatically to oral therapy with pharmacological doses of biotin. Delayed diagnosis and treatment in biotinidase deficiency may result in irreversible neurological damage. A few patients with HCS deficiency show a partial or even no response to biotin and seem to have an impaired long-term outcome. Acquired biotin deficiency, which also causes MCD, is extremely rare. A defect in biotin transport has been reported in a single child; however the genetic defect remains unresolved to date. Biotin-Responsive Basal Ganglia Disease (BRBGD) is a recently described subacute encephalopathy which disappears within a few days without neurological sequelae if biotin is administered early. 27.1 Clinical Presentation The characteristic manifestation of multiple carboxylase deficiency (MCD) is metabolic acidosis associated with neurological abnormalities and skin disease. The expression of the clinical and biochemical features is variable in both inherited disorders [1]. While patients with holocarboxylase synthetase (HCS) deficiency commonly present with the typical symptoms of MCD, those with biotinidase deficiency show a less consistent clinical picture, particularly during the early stage of the disease. The onset in biotinidase deficiency may be insidious, and the manifestation is usually very variable, neurological symptoms often being prominent without markedly abnormal organic-acid excretion or metabolic acidosis. Later-onset forms of HCS deficiency cannot be clinically distinguished from biotinidase deficiency, necessitating confirmation of the diagnosis by enzyme assay. 27.1.1 Holocarboxylase Synthetase Deficiency Although HCS deficiency was initially termed early-onset MCD, recent experience shows that the age of onset varies widely, from a few hours after birth to 8 years of age [2, 3]. Nevertheless, about half of the patients have presented acutely in the first days of life with symptoms very similar to those observed in other severe organic acidurias, i.e., lethargy, hypotonia, vomiting, seizures and hypothermia. The most common initial clinical features consist of respiratory difficulties, such as tachypnea or Kussmaul breathing. Severe metabolic acidosis, ketosis and hyperammonaemia may lead to coma and early death. Patients with a less severe defect and later onset may also present with recurrent life- threatening attacks of metabolic acidosis and typical organic aciduria [4, 5]. Early-onset patients that recover without biotin therapy and untreated patients with a less severe defect may additionally develop psychomotor retardation, hair loss and skin lesions. The latter include an erythematous, scaly skin rash that spreads over the whole body but is particularly prominent in the diaper and intertriginous areas; alternatively, the rash may resemble seborrheic der- matitis or ichthyosis [6]. Superinfection with Candida may occur. Disorders of immune function have been observed with decreased T cell count and impaired in vitro and in vivo response to Candida antigen. Episodes of acute illness are often precipitated by catabolism during intercurrent infections or by a higher protein intake. 27.1.2 Biotinidase Deficiency Important features are the gradual development of symptoms and episodes of remission, which may be related to increased free biotin in the diet. The full clinical picture has been reported as early as 7 weeks, but discrete neurological symptoms may occur much earlier, even in the neonatal period [7]. Neurological manifestations (lethargy, muscular hypotonia, grand mal and myoclonic seizures, ataxia) are the most frequent initial symptoms. In addition, respiratory abnormalities, such as stridor, episodes of hyperventilation and apnoea occur frequently; these may be of neurological origin [8]. Skin rash and/or alopecia are hallmarks of the disease; however, they may develop late or not at all [9, 10]. Skin lesions are usually patchy, erythematous/exudative and typically localized periorificially. Eczematoid dermati- tis or an erythematous rash covering large parts of the body has also been observed, as has keratoconjunctivitis. Hair loss is usually discrete but may, in severe cases, become complete, including the eyelashes and eyebrows. Immuno- logical dysfunction may occur in acutely ill patients. Some children with profound biotinidase deficiency may not develop symptoms until later in childhood or during adolescence [11]. Their symptoms usually are less characteristic 27.1 · Clinical Presentation Chapter 27 · Biotin-Responsive Disorders V 334 and may include motor limb weakness, spastic paraparesis and eye problems such as loss of visual acuity and scotomata [11]. Two asymptomatic adults with profound biotinidase deficiency were ascertained after identification of their affected children by newborn screening [12]. Similarly, in two asymptomatic adolescent girls and in an asymptomatic adult male, residual plasma biotinidase activity, assessed by a sensitive assay, was between 1.2–3.1% of the mean control value, indicating that the threshold level of biotinidase activity needed for normal development is low [13, 14]. Alternatively, other factors such as modifying genes or environmental factors may protect some enzyme-deficient individuals from developing symptoms. Because of the variability and nonspecificity of clinical manifestations, there is a great risk of a delay in diagnosis [8, 15, 16]. Late-diagnosed patients often have psychomotor retardation and neurological symptoms, such as leukoencephalopathy, hearing loss and optic atrophy, which may be irreversible [9, 10, 15–18]. The outcome may even be fatal. One patient died at the age of 22 months, with features of Leigh syndrome proven by histopathology [8]. Metabolic acidosis and the characteristic organic aciduria of MCD are frequently lacking in the early stages of the disease. Plasma lactate and 3-hydroxyisovalerate may be only slightly elevated, whereas cerebrospinal fluid levels may be significantly higher [19]. This fact and the finding of severely decreased carboxylase activities in brain but moderately deficient activity in liver and kidney in a patient with lethal outcome [8] are in accordance with the pre- dominance of neurological symptoms and show that, in biotinidase deficiency, the brain is affected earlier and more severely than other organs. The threat of irreversible brain damage demands that biotinidase deficiency should be considered in all children with neurological problems, even if obvious organic aciduria and/or cutaneous findings are not present. Sadly, there seems to have been little improvement in the diagnostic delay over the last 10 years [15, 17]. Therefore, neonatal screening provides the best chance of improving outcome in biotinidase deficiency. Impor- tantly, treatment should be instituted without delay, since patients may become biotin depleted within a few days after birth [7]. 27.1.3 Biotin-Responsive Basal Ganglia Disease Biotin-responsive basal ganglia disease (BRBGD) is an autosomal recessive disorder with childhood onset that presents as a subacute encephalopathy with confusion, dys- arthria and dysphagia, that progresses to severe cogwheel rigidity, dystonia, quadriparesis and, if left untreated, to death [19a]. On brain magnetic resonance imaging (MRI) examination patients display central bilateral necrosis in the head of the caudate nucleus with complete or partial involvement of the putamen. All patients diagnosed to date are of Saudi, Syrian, or Yemeni ancestry. 27.2 Metabolic Derangement In HCS deficiency, a decreased affinity of the enzyme for biotin and/or a decreased maximal velocity lead to reduced formation of the four holocarboxylases from their corresponding inactive apocarboxylases at physiological biotin concentrations ( . Fig. 27.2) [20–22]. In biotinidase deficiency, biotin cannot be released from biocytin and short biotinyl peptides. Thus, patients with biotinidase deficiency are unable to either recycle endogenous biotin or to use protein-bound dietary biotin ( . Fig. 27.2) [1]. Consequently, biotin is lost in the urine, mainly in the form of biocytin [7, 23], and progressive biotin depletion occurs. Depending on the amount of free biotin in the diet and the severity of the enzyme defect, the disease becomes clinically manifest during the first months of life or later in infancy or childhood. Deficient activity of carboxylases in both HCS and biotinidase deficiencies ( . Fig. 27.1) results in accumulation of lactic acid and derivatives of 3-methylcrotonyl-coenzyme A (CoA) and propionyl-CoA ( 7 Sect. 27.4). Isolated inherited deficiencies of each of the three mitochondrial carboxylases, propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC); (for both, 7 Chap.19), and pyruvate carboxylase (PC; 7 Chap.12), are also known. A single patient with an isolated defect of acetyl-CoA carboxylase (ACC, cyto solic) has been reported [24]. These isolated deficiencies are due to absence or abnormal structure of the apoenzyme and usually do not respond to biotin therapy. A patient with isolated partial MCC-deficiency and partial responsiveness to biotin therapy has recently been reported [25]. In BRBGD there is a defective cerebral transport of biotin [25a]. Acquired biotin deficiency is rare but may result from excessive consumption of raw egg white, malabsorption, long-term parenteral nutrition, hemodialysis, and long- term anticonvulsant therapy. Biotin dependency due to a defect in biotin transport has been suggested in a 3-year-old boy with normal biotinidase and nutritional biotin intake [26], but the genetic defect remains unresolved to date. 27.3 Genetics Both HCS and biotinidase deficiency are inherited as autosomal recessive traits. HCS deficiency seems to be rarer than biotinidase deficiency. The incidences of profound (<10% residual activity) and partial (10–30% residual activity) biotinidase deficiencies are, on average, 1:112 000 and 1:129 000, respectively [27]. The incidence of combined 27 335 profound and partial deficiency is about 1 in 60 000. The cDNAs for human HCS [28, 29] and biotinidase [30] have been cloned, and the corresponding genes have been mapped to human chromosomes 21q22.1 [29] and 3p25 [31], respectively. In both genes, multiple disease causing mutations have been identified. 27.3.1 Holocarboxylase Synthetase Deficiency More than 20 different disease causing mutations have been reported [32–35]. About 2/3 of them are within the putative biotin-binding region of HCS and result in decreased affinity of the enzyme for biotin [20, 22, 32, 34, 36]; this probably accounts for the in vivo responsiveness to biotin therapy of these patients. The degree of abnormality of the K m values of HCS for biotin correlates well with the time of onset and severity of illness, i.e. highest K m with early onset and severe disease [21]. Other mutations, located outside the biotin-binding site in the N-terminal region, are associated with normal K m but decreased V max [22]. Most patients with this type of mutation also respond to biotin, although higher doses may be required and residual biochemical and clinical abnormalities may persist. Biotin responsiveness in such patients may derive from a positive effect of biotin on HCS mRNA transcription and thus on HCS protein, which has recently been suggested [37]. However, since this mechanism involves HCS protein itself, it requires the presence of residual HCS activity in order to work. Only one mutant allele, L216R, when present in the homozygous state, has been associated with a biotin- unresponsive, severe clinical phenotype [32]. This mutation seems to be highly prevalent in Polynesian patients of Samoan origin (David Thorburn and Callum Wilson, per- sonal communication). 27.3.2 Biotinidase Deficiency At least 79 different mutations have been identified in patients with profound or partial biotinidase deficiency [35, 38, 39]. The two most common mutations detected in symptomatic patients with profound deficiency in the U.S.A., accounting for about one third of the alleles, are 98-104del7ins3 and R538C [38, 40]. In contrast, in patients with profound biotinidase deficiency detected by newborn screening, three mutations – Q456H, the double-mutant allele A171T + D444H, and D252G – accounted for about half of the mutant alleles detected [38]. Strikingly, these mutations were not detected in any of the symptomatic patients [38, 40]. Furthermore, none of the symptomatic children had detectable serum biotinidase biotinyl-transferase activity while two thirds of the children identified by screening had detectable activity [41]. A comparison of mutations in children detected by newborn screening with mutations in symptomatic children revealed four mutations comprising 59% of the mutant alleles studied [42]. Only two of these mutations occurred in both populations [42]. Thus it is possible that individuals with certain mutations in the newborn screening group may have a decreased risk of developing symptoms. Almost all individuals with partial biotinidase deficiency have the D444H mutation in combination with a mutation causing profound biotinidase deficiency on the second allele [39]. 27.3.3 Biotin-Responsive Basal Ganglia Disease BRBGD is due to mutations in SLC19A3, a gene coding for a cerebral biotin transporter related to the reduced folate and thiamine transporters [25a]. Different missense mutations have been identified. 27.4 Diagnostic Tests A characteristic organic aciduria due to systemic deficiency of the carboxylases is the key feature of MCD. In severe cases, an unpleasant urine odour (cat’s urine) may even be suggestive of the defect. MCD is reflected in elevated urinary and plasma concentrations of organic acids as follows: 4 Deficiency of MCC: 3-hydroxyisovaleric acid in high concentrations, 3-methylcrotonylglycine in smaller amounts; 4 Deficiency of PCC: methylcitrate, 3-hydroxypro pionate , propionylglycine, tiglylglycine, propionic acid in small to moderate amounts; 4 Deficiency of PC: lactate in high concentrations, pyruvate in smaller amounts. There is no metabolic marker in BRBGD. The majority of HCS-deficient patients excrete all of the typical organic acids in elevated concentrations, provided that the urine sample has been taken during an episode of acute illness. In contrast, in biotinidase deficiency elevated excretion of only 3-hydroxyisovalerate may be found, especially in early stages of the disease. 20 % of untreated biotinidase-deficient children had normal urinary organic acid excretion when symptomatic [10]. The measurement of carboxylase activities in lymphocytes provides direct evidence of MCD. These activities are low in HCS deficiency but may be normal in biotinidase deficiency, depending on the degree of biotin deficiency [3, 14]. The two inherited disorders can easily be distinguished by assay of biotinidase activity in serum. Today, this assay is included in the neonatal screening programs in many countries worldwide. 27.4 · Diagnostic Tests Chapter 27 · Biotin-Responsive Disorders V 336 27.4.1 Holocarboxylase Synthetase Deficiency 4 Biotin concentrations in plasma and urine are normal; 4 Carboxylase activities in lymphocytes are deficient and cannot be activated by in vitro preincubation with biotin [1]; 4 Direct measurement of HCS activity requires a protein, e.g. an apocarboxylase or an apocarboxyl carrier protein of ACC as one of the substrates [21, 43]; therefore, it is not routinely performed; 4 HCS deficiency can be diagnosed indirectly by de- monstrating severely decreased carboxylase activities in fibroblasts cultured in a medium with low biotin concentration (10 –10 mol/l) and by normalization (or, at least an increase) of the activities in cells cultured in media supplemented with high biotin concentrations (10 –6 –10 –5 mol/l) [3, 21]. It must be noted that fibroblasts of some late-onset patients may exhibit normal levels of carboxylase activities when cultured in standard media supplemented with 10% fetal calf serum, which results in a final biotin concentration of about 10 –8 mol/l [3, 5]. 27.4.2 Biotinidase Deficiency 4 Biotinidase activity in plasma is absent or decreased [14, 27]. Many patients have measurable residual activity and should be evaluated for the presence of a K m defect ( 7 below); 4 Symptomatic patients usually have decreased biotin concentrations in plasma and urine [7, 14], provided that an assay method that does not detect biocytin is used [44]. In addition, carboxylase activities in lymphocytes are usually decreased but are normalized within hours after either a single dose of oral biotin [7] or in vitro preincubation with biotin [1, 14]; 4 Patients excrete biocytin in urine [23], the concentration being dependent on the level of residual biotinidase activity [14]; 4 Carboxylase activities in fibroblasts cultured in low- biotin medium are similar to those in control fibroblasts, and are always normal in fibroblasts cultured in standard medium. 27.4.3 Acquired Biotin Deficiency 4 Biotinidase activity is normal in plasma; 4 Biotin concentrations are low in plasma and urine; 4 Carboxylase activities in lymphocytes are decreased and are promptly normalized after a single dose of oral biotin or after preincubation with biotin in vitro [1]. 27.4.4 Prenatal Diagnosis Prenatal diagnosis of HCS deficiency is possible by enzymatic studies in cultured chorionic villi or amniotic fluid cells or by demonstration of elevated concentrations of metabolites by stable isotope dilution techniques in amniotic fluid. Organic acid analysis in milder forms of HCS deficiency may fail to show an affected fetus, necessitating enzymatic investigation in these cases [5]. Prenatal diagnosis allows rational prenatal therapy, preventing severe metabolic derangement in the early neonatal period [5, 45]. Biotinidase can be measured in chorionic villi or cultured amniotic fluid cells but, in our opinion, this is not warranted, because prenatal treatment is not necessary. 27.5 Treatment and Prognosis With the exception of some cases of HCS deficiency, both inherited disorders can be treated effectively with oral biotin in pharmacologic doses. No adverse effects have been observed from such therapy over a more than 20-year experience of treating biotinidase deficiency [39] and, importantly, there is no accumulation of biocytin in body fluids [23], which was previously suspected to be a possible risk. Restriction of protein intake is not necessary except in very severe cases of HCS deficiency. Acutely ill patients with metabolic decompensation require general emergency treatment in addition to biotin therapy ( 7 Chap. 4). 27.5.1 Holocarboxylase Synthetase Deficiency The required dose of biotin is dependent on the severity of the enzyme defect and has to be assessed individually [1]. Most patients have shown a good clinical response to 10– 20 mg/day, although some may require higher doses, i.e. 40-200 mg/day [1, 3, 45–47]. In spite of apparently complete clinical recovery, some patients continue to excrete abnormal metabolites (particularly 3-hydroxyisovalerate), a finding that correlates inversely with the actual level of carboxylase activity in lymphocytes. Exceptionally, per- sistent clinical and biochemical abnormalities have been observed despite treatment with very high doses of biotin [1, 32, 45–47]. All patients with HCS deficiency have at least partially responded to pharmacological doses of biotin with the exception of those homozygous for the missense mutation L216R [32]. To date, the prognosis for most surviving, well-treated patients with HCS deficiency seems to be good, with the exception of those who show only a partial or no response to biotin [1, 32, 45–47]. Careful follow-up studies are needed to judge the long-term outcome. In one patient, followed for 27 337 9 years and treated prenatally and from the age of 3.5 months with 6 mg biotin/day, some difficulties in fine motor tasks were obvious at the age of 9 years [48]. In five Japanese patients (four families), the intelligence quotient (IQ) at the age of 5–10 years varied between 64 and 80 [45]. Four of these patients had a severe neonatal onset form, and one of them (IQ=64) was treated prenatally. Three of these patients showed recurrent respiratory infections, metabolic acidosis and organic aciduria despite high-dose (20–60 mg/day) biotin therapy. However, irreversible neurological auditory- visual deficits, as described for biotinidase deficiency, have not been reported. Prenatal biotin treatment (10 mg/day) has been reported in a few pregnancies [5, 45]. It is unclear whether prenatal treatment is essential; treatment of at-risk children immediately after birth may be sufficient. 27.5.2 Biotinidase Deficiency Introduction of neonatal screening programs has resulted in the detection of asymptomatic patients with residual biotinidase activity [27]. Based on measurement of plasma biotinidase activity, the patients are classified into three main groups. 1. Patients with profound biotinidase deficiency, with less than 10% of mean normal serum biotinidase activity. Using a sensitive method with the natural substrate biocytin, we classify these patients further into those with complete deficiency (undetectable activity, limit of detection a0.05% of the mean normal value) and those with residual biotinidase activity up to 10% [14]. 2. Patients with partial biotinidase deficiency, with 10– 30% residual activity. 3. Patients with decreased affinity of biotinidase for biocytin, i.e. Km variants [49]. Group 1 In early-diagnosed children with complete biotinidase deficiency, 5–10 mg of oral biotin per day promptly reverse or prevent all clinical and biochemical abnormalities. For chronic treatment, the same dose is recommended. Under careful clinical and biochemical control, it may be possible to reduce the daily dose of biotin to 2.5 mg. However, biotin has to be given throughout life and regularly each day, since biotin depletion develops rapidly [7]. Neonatal screening for biotinidase deficiency [27] allows early diagnosis and effective treatment. In such patients, the diagnosis must be confirmed by quantitative measurement of biotinidase activity. Treatment should be instituted without delay, since patients may become biotin deficient within a few days after birth [7]. In patients who are diagnosed late, irreversible brain damage may have occurred before the commencement of treatment. In particular, auditory and visual deficits often persist in spite of biotin therapy [9, 10, 17–19], and intel- lectual impairment and ataxia have been observed as long- term complications [9, 15, 17, 18]. Patients with residual activity up to 10%, usually detected by neonatal screening or family studies, may remain asymptomatic for several years or even until adulthood [12–14]. According to our experience with 61 such patients (52 families), however, they show a great risk of becoming biotin deficient and should be treated with, e.g., 2.5 mg of biotin per day [14, 27, 39]. Group 2 Patients with partial biotinidase deficiency (10–30% residual activity) are mostly detected by neonatal screening and in family studies and usually remain asymptomatic. One infant with about 30% enzyme activity developed hypotonia, skin rash and hair loss during an episode of gastroenteritis at 6 months of age. This was reversed by biotin therapy [50]. We showed that among 24 patients with 14–25% serum biotinidase activity studied at the age of 8 months to 8 years, 16 patients had a subnormal biotin concentration in at least one plasma sample, with a ten- dency toward lower values with increasing age [51]. There- fore, it seems necessary to regularly control patients with 10-30% of residual activity and to supplement patients with borderline abnormalities with small doses of biotin, e.g., 2.5–5 mg/week. Group 3 Among 201 patients (176 families), we found ten patients (eight families) with a K m defect. In the routine colorimetric biotinidase assay with 0.15 mmol/l biotinyl-p-amino- benzoate as substrate, six of these patients (five families) showed profound deficiency (0.94–3% residual activity), whereas four patients (three families) showed partial deficiency (18–20% residual activity). The index patient in all five families with profound deficiency presented with a severe clinical illness [16, 49], and one of the patients with partial deficiency, although apparently asymptomatic, had marginal biotin deficiency at the age of 2 years [49]. These results show the importance of testing all patients with residual biotinidase activity for a K m defect. They all seem to have a high risk of becoming biotin deficient and, therefore, must be treated with biotin. 27.5.3 Biotin-Responsive Basal Ganglia Disease All clinical symptoms of BRBGD disappear within a few days with the administration of high doses of biotin (5– 10 mg/kg/day) if the patient is treated early. 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Pomponio RJ, Hymes J, Reynolds TR et al (1997) Mutation in the human biotinidase gene that causes profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res 42:840-848 41. Hymes J, Fleischhauer K, Wolf B (1995) Biotinylation of histones by human serum biotinidase: assessment of biotinyl-transferase activity in sera from normal individuals and children with biotinidase deficiency. Biochem Mol Med 56:76-83 42. Norrgard KJ, Pomponio RJ, Hymes J, Wolf B (1999) Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different fre- quencies than in symptomatic children. Pediatr Res 46:20-27 43. Suzuki Y, Aoki Y, Sakamoto O et al (1996) Enzymatic diagnosis of holocarboxylase synthetase deficiency using apo-carboxyl carrier protein as a substrate. Clin Chim Acta 251:41-52 44. Baur B, Suormala T, Bernoulli C, Baumgartner ER (1998) Biotin determination by three different methods: specificity and application to urine and plasma ultrafiltrates of patients with and without disorders in biotin metabolism. Int J Vit Nutr Res 68:300-308 45. Aoki Y, Suzuki Y, Sakamoto O et al (1995) Molecular analysis of holocarboxylase synthetase deficiency: a missense mutation and a single base deletion are predominant in Japanese patients. Bio- chim Biophys Acta 1272:168-174 46. Santer R, Muhle H, Suormala T et al (2003) Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical, biochemical, and molecular genetic aspects. Mol Genet Metab 79:160-166 47. Wolf B, Hsia YE, Sweetman L et al (1981) Multiple carboxylase deficiency: clinical and biochemical improvement following neonatal biotin treatment. Pediatrics 68:113-118 48. Michalski AJ, Berry GT, Segal S (1989) Holocarboxylase synthetase deficiency: 9-year follow-up of a patient on chronic biotin therapy and a review of the literature. J Inherit Metab Dis 12:312-316 49. Suormala T, Ramaekers VTH, Schweitzer S et al (1995) Biotinidase Km-variants: detection and detailed biochemical investigations. J Inherit Metab Dis 18:689-700 50. Secor McVoy JR, Levy HL, Lawler M et al (1990) Partial biotinidase deficiency: clinical and biochemical features. J Pediatr 116:78-83 51. Bernoulli C, Suormala T, Baur B, Baumgartner ER (1998) A sensitive method for the determination of biotin in plasma and CSF, and application to partial biotinidase deficiency. J Inherit Metab Dis 21[Suppl 2]46:92 References 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 Chapter 28 · Disorders of Cobalamin and Folate Transport and Metabolism V 342 Cobalamin Transport and Metabolism Cobalamin (cbl or vitamin B 12 ) is a cobalt-containing water-soluble vitamin that is synthesized by lower organisms but not by higher plants and animals. In the human diet, its only source is animal products in which it has accumulated by microbial synthesis. Cbl is needed for only two reactions in man, but its metabolism involves complex absorption and transport systems and multiple intracellular conversions. As methylcobalamin, it is a cofactor of the cytoplasmic enzyme methionine synthase. As adenosylcobalamin, it is a cofactor of the mitochondrial enzyme methylmalonyl-coenzyme A mutase, which is involved in the catabolism of valine, threonine and odd-chain fatty acids into succinyl-CoA, an intermediate of the Krebs cycle. . Fig. 28.1. Cobalamin (Cbl) endocytosis and intracellular metabolism. The cytoplasmic, lysosomal, and mitochondrial com- partments are indicated. AdoCbl, adenosylcobalamin; CoA, coenzyme A; MeCbl, methylcobalamin; OHCbl, hydroxycobalamin; TC, transcobalamin (previously TCII); V1 , variant 1; V2, variant 2; 1 + ,2 + ,3 + refer to the oxidation state of the central cobalt of Cbl. Letters A-H refer to the sites of blocks. Enzyme defects are indicated by solid bars 28 343 For patients with inherited disorders affecting cobalamin (Cbl) absorption, the main clinical finding is megaloblastic anemia. Except for transcobalamin (TC) deficiency, the serum Cbl level will usually be low. Patients with disorders of intracellular Cbl metabolism show elevations of homocysteine or methylmalonic acid, either alone or in combination. The serum Cbl level is not usually low. For those disorders that affect methylcobalamin (MeCbl) formation, the major manifestations include megaloblastic anemia secondary to folate deficiency and neurologica l abnormalities presumably secondary to methionine deficiency or homocysteine elevation. The main findings in those disorders that affect adenosylcobalamin (AdoCbl) formation, are secondary to elevated methylmalonic acid and resultant acidosis. Inherited disorders of cobalamin (Cbl) metabolism are di- vided into those involving absorption and transport and those involving intracellular utilization [1–5]. 28.1 Disorders of Absorption and Transport of Cobalamin Absorption of dietary Cbl involves first binding to a glyco- protein (R binder, haptocorrin) in the saliva. In the intes- tine, haptocorrin is digested by proteases, allowing the Cbl to bind to intrinsic factor (IF), which is produced in the stomach by parietal cells. Using a specific receptor, the IFCbl complex enters the enterocyte. Following release from this complex Cbl binds to transcobalamin (TC), the physiologi- cally important circulating Cbl-binding protein, forming TC-Cbl, which is then slowly released into the portal vein. Inherited defects of several of these steps are known. 28.1.1 Hereditary Intrinsic Factor Deficiency Clinical Presentation Presentation is usually from one to 5 years of age but in cases of partial deficiency, can be delayed until adolescence or adulthood. Patients present with megaloblastic anemia as the main finding, together with failure to thrive, often with vomiting, alternating diarrhea and constipation, ano- rexia and irritability [6 –8]. Hepatosplenomegaly, stomatitis or atrophic glossitis, developmental delay, and myelopathy or peripheral neuropathy may also be found. Metabolic Derangement IF is either absent or immunologically detectable but non- functional. There have been reports of IF with reduced affinity for Cbl, receptor or increased susceptibility to pro- teolysis [7–9]. Genetics At least 45 patients of both sexes have been reported, and inheritance is autosomal recessive. A cDNA has been characterized, and the gene is localized on chromosome 11q13 [10]. A recently described variant of the gastric IF (GIF) gene, 68AoG, is probably not a d isease causing mutation but could serve as a marker for inheritance of the disorder [11]. A 4-bp deletion (c183_186delGAAT) in the coding region of the GIF gene was identified as the cause of intrinsic factor deficiency in an 11 year-old girl with severe anemia and Cbl deficiency [12]. Diagnostic Tests 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 marrow examination. Low serum Cbl levels are present. A deoxyuridine suppression test on marrow cells is useful 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 normal gastric cytology. Cbl absorption, as measured by the Schilling test, is abnormal but is normalized when the labeled Cbl is mixed with a source of normal IF, such as gastric juice from an unaffected individual. Treatment and Prognosis IF deficiency can be treated initially with hydroxycobalamin (OHCbl, 1 mg/day intramuscularly) to replete body stores until biochemical and hematological values nor- malize. The subsequent dose of OHCbl required to main- tain normal values may be as low as 0.25 mg every 3 months. If treatment is delayed, some neurological abnormalities may persist in spite of complete reversal of the hematological and biochemical findings. 28.1.2 Defective Transport of Cobalamin by Enterocytes (Imerslund-Gräsbeck Syndrome) Clinical Presentation Defective transport of Cbl by enterocytes, also known as Imerslund-Gräsbeck syndrome or megaloblastic anemia 1 (MGA1), is characterized by prominent megaloblastic anemia manifesting once fetal hepatic Cbl stores have been depleted. The disease usually appears between the ages of 1 year and 5 years, but onset may be even later [13–19]. Most patients have proteinuria and, in a few cases, this is of the tubular type, with all species of proteins represented rather than albumin alone. The literature on the renal pathology has been reviewed [20]. Although patients who 28.1 · Disorders of Absorption and Transport of Cobalamin [...]... 91:359 3-3 600 23 Birn H, Verroust PJ, Nexo E et al (19 97) Characterization of an epithelial ~460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein J Biol Chem 272 :2649 7- 2 6504 24 Fyfe JC, Madsen M, Hojrup P et al (2004) The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless Blood 103:1 57 3-1 579 ... initiated by the rate-limiting GTP cyclohydrolase-1 (GTPCH-I), which forms dihydroneopterin triphosphate (NH2TP) L-dopa and 5-hydroxytryptophan (5-HTP) are metabolized by a common B6-dependent aromatic l-amino acid decarboxylase (AADC) into dopamine (the precursor of the catecholamines, adrenaline and noradrenaline) and serotonin (5-hydroxytryptamine), respectively Adrenaline and noradrenaline are... complete blood count and bone marrow examination may detect megaloblastic anemia Normal to high serum folate levels are found, particularly in the mild form Hyperhistidinemia and histidinuria have been reported Two other metabolites that may be found in the urine are hydantoin-5-propionate, a stable oxidation product of the formiminoglutamate precursor, 4-imidazolone-5-propionate and 4-amino-5-imidazolecarboxamide,... clinical diagnosis and treatment Eur J Pediatr 1 57: S 7 7- S83 49 Traboulsi EI, Silva JC, Geraghty MT et al (1992) Ocular histopathologic characteristics of cobalamin C complementation type vitamin B12 defect with methylmalonic aciduria and homocystinuria Am J Ophthalmol 113:26 9-2 80 50 Rosenblatt DS, Aspler AL, Shevell MI et al (19 97) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and. .. Endocrinology, Bristol, pp 31 5-3 23 56 Pezacka EH (1993) Identification and characterization of two enzymes involved in the intracellular metabolism of cobalamin Cyanocobalamin beta-ligand transferase and microsomal cob(III)alamin reductase Biochim Biophys Acta 11 57: 16 7- 1 77 56a Lerner-Ellis JP, Tirone JC, Pawelek PD et al (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria,... anemia and homocystinuria due to a new defect in methionine biosynthesis J Clin Invest 74 :214 9-2 156 71 Gulati S, Chen Z, Brody LC, Rosenblatt DS, Banerjee R (19 97) Defects in auxillary redox proteins lead to functional methionine synthase deficiency J Biol Chem 272 :19 17 1-1 9 175 72 Schuh S, Rosenblatt DS, Cooper BA et al (1984) Homocystinuria and megaloblastic anemia responsive to vitamin B12 therapy An inborn. .. Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency Blood 103:151 5-1 5 17 28 354 V Chapter 28 ã Disorders of Cobalamin and Folate Transport and Metabolism 13 Grasbeck R (1 972 ) Familial selective vitamin B12 malabsorption N Engl J Med 2 87: 358 14 Broch H, Imerslund O, Monn E et al (1984) Imerslund-Grasbeck anemia: A long-term follow-up study Acta Paediatr Scand 73 :248253 15... apoenzyme itself Genetics There are at least 27 cblE and 27 cblG patients known A cDNA for methionine-synthase reductase has been cloned, and mutations have been detected in cblE patients [77 ] The methionine-synthase-reductase gene has been localized to chromosome 5p15.215.3 Mutations in the methioninesynthase gene have been found in cblG patients following Treatment and Prognosis Both of these disorders are... absorption disorder (Imerslund-Grasbeck syndrome)] syndroma) Orv Hetil 133:331 1-3 313 19 Grasbeck R (19 97) Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor Acta Biochimica Polonica 44 :72 5 -7 33 20 Liang DC, Hsu HC, Huang FY, Wei KN (1991) Imerslund-Grasbeck syndrome in two brothers: renal biopsy and ultrastructure findings Pediatr Hematol Oncol 8:36 1-3 65 21 Moestrup SK, Kozyraki... homocystinuria, cblC type Nat Genet 38:9 2-1 00 56b Morel CF, Watkins D, Scott P et al (2005) Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport Mol Genet Metab 86:16 0-1 71 57 Bartholomew DW, Batshaw ML, Allen RH et al (1988) Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria J Pediatr 112:3 2-3 9 58 Bain MD, Jones MG, Fowler B, . precursor, 4-imidazolone-5-propionate and 4-amino-5-imidazolecarboxamide, an intermediate of purine synthesis. Treatment and Prognosis It is not clear whether reducing formiminoglutamate excretion. late onset. J Pediatr 101:54 6-5 50 5. Suormala T, Fowler B, Jakobs C et al (1998) Late-onset holocarboxylase synthetase-deficiency: pre- and post-natal diagnosis and evaluation of effectiveness. Genet 75 :79 0-8 00 25a. Zeng WQ, Al-Yamani E, Acierno JS Jr et al (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77 :1 6-2 6 26.

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