Combined Methylmalonic Aciduria and Homocystinuria Cblc Type of a Taiwanese Infant with C.609G>A and C.567Dupt Mutations in the MMACHC Gene

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provided by Elsevier - Publisher Connector Pediatrics and Neonatology (2011) 52, 223e226

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CASE REPORT Combined Methylmalonic Aciduria and Homocystinuria cblC Type of a Taiwanese Infant With c.609G>A and c.567dupT Mutations in the MMACHC Gene

Jenn-Tzong Chang a, Ying-Yao Chen a, Tze-Tze Liu b, Mei-Ying Liu c, Pao-Chin Chiu a,*

a Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan b Genome Research Center, National Yang-Ming University, Taipei, Taiwan c Institute of Genetics, National Yang-Ming University, Taipei, Taiwan

Received Mar 26, 2010; received in revised form Aug 18, 2010; accepted Sep 1, 2010

Key Words Combined methylmalonic aciduria and homocystinuria, cobalamin (cbl)C type (cblC disease),

cobalamin; the most common inborn error of vitamin B12, is a rare disorder of intracellular cbl metabolism homocystinuria; because of mutations in the MMACHC gene located in chromosome region 1p34.1. It has methylmalonic aciduria; become possible to establish phenotypeegenotype correlations and to observe ethnicity- MMACHC; related trends. This article provides detailed clinical manifestations and outcomes of a Taiwa- vitamin B12 nese infant boy with early-onset cblC disease, heterozygous for c.609G>A and c.567dupT mutations, although there is limited information about cases with c.609G>A or c.567dupT mutation in the literature. He had no signiﬁcant clinical abnormality during his neonatal period, whereas elevated C3 level was noted at newborn screening. He presented later with life-threatening manifestations and failure to thrive, which resolved through our treatment, although delayed development was still noted at 6 months of age. To date, all reported cblC patients with the c.609G>A mutation have been East Asians. Therefore, we suggest that c.609G>A should be included in the initial mutation screening tests for a cblC patient in East Asian populations. Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.

* Corresponding author. Department of Pediatrics, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st Road, Kaohsiung, Taiwan. E-mail address: [email protected] (P.-C. Chiu).

1. Introduction appearance, and failure to thrive, such that his weight, height, and head circumference were all less than the third Defects in vitamin B [cobalamin (cbl)] metabolism are percentile. Other laboratory data showed pancytopenia 12 9 inherited as autosomal recessive disorders and are classi- (leukocyte count, 2.3 10 /L; hemoglobin, 4.7 g/dL; and 9 fied into the eight genetic complementation groups (cblA-G platelet count, 15 10 /L); normal ammonia level of m e and mut). Among them, cblC is the most common.1,2 The 35 g/dL (normal range, 20 92); and metabolic acidosis disorder cblC disease (Online Mendelian Inheritance in Man with bicarbonate level of 17.7 mmol/L, lactate level of e 277400) has combined methylmalonic aciduria (MMA) and 34 mg/dL (normal range, 6.3 18.9), and normal anion gap homocystinuria (HCU) because of an early block in the of 9.3 mEq/L. synthesis of methylcobalamin (MeCbl) and 50-deoxy- On admission, cyanocobalamin (CNCbl) and carnitine as adenosylcobalamin (AdoCbl). These are the cofactors of the well as other supportive treatments were started as soon as cytoplasmic enzyme methionine synthase and the mito- possible. However, there was a sudden onset of seizure, chondrial enzyme methylmalonyl-CoA mutase, respec- and respiratory failure occurred 3 days later, requiring tively.1 This rare disorder of intracellular cbl metabolism is intubation with mechanical ventilator support. Meanwhile, because of mutations in the MMACHC gene located in the patient’s metabolic acidosis worsened, and elevated chromosome region 1p34.1.2 To date, only 400 known cases ammonia and lactate levels were noted. CNCbl was worldwide and more than 50 causal mutations have been replaced with hydroxycobalamin (OHCbl), and betaine was reported.3 added to the carnitine treatment a day after intubation. Although some patients develop symptoms in childhood, The metabolic acidosis resolved shortly, and the patient adolescence, or adulthood, most patients are acutely ill in was extubated 1 day later. The elevated ammonia and their infancy, presenting with failure to thrive, acute lactate levels, leukopenia, and thrombocytopenia all neurologic deterioration, mental retardation, retinopathy, resolved gradually within 1 week after the new regimen was multiorgan system dysfunction, and hematologic abnor- started. malities.4 In general, late-onset patients have better At 2 months of age, the patient’s brain magnetic reso- survival and response to treatment, and fewer neurologic nance imaging showed mild to moderate ventriculomegaly sequelae compared with early-onset patients.5 with enlarged cortical sulci, diffuse mild edematous The recognition of phenotypeegenotype correlations change over the bilateral central and subcortical white and the association of mutations with specific ethnicities matter regions, and delayed myelination. Echocardiogram will be useful for the identification of disease-causing and ophthalmology consults revealed neither cardiac nor mutations in cblC patients, for carrier detection and ophthalmologic abnormalities. Finally, two mutations, > prenatal diagnosis in families where mutations are known, c.609G A (p.Trp203X) and c.567dupT (p.Ile190TyrfsX13), and in setting up initial screening programs in molecular were found to be inherited from paternal and maternal diagnostic laboratories.1 This study investigated and MMACHC alleles, respectively (Figure 1). described the clinical manifestations, treatment outcomes, At 6 months of age, the patient’s weight was 7500 g the th th and developmental evaluations of a Taiwanese male infant (15 50 percentile), height was 66 cm (15 percentile), < rd with early-onset cblC disease, heterozygous for c.609G>A and head circumference was 39 cm ( 3 percentile), and c.567dupT, who presented at about 1.5 months of age as well as delayed development (Mental Development Z Z with life-threatening manifestations and failure to thrive, Index 74 and Psychomotor Development Index 55) whereas no significant clinical abnormality during his were noted. Currently, he is managed with OHCbl 1-mg neonatal period except elevated C3 level was noted at intramuscular injections biweekly, carnitine 100 mg/kg/d newborn screening. divided into three doses, betaine 275 mg/kg/d, and folinic acid 1 mg three times a day, as well as rehabilitation programs. 2. Case Report

A full-term, male neonate was born by normal spontaneous 3. Discussion vaginal delivery to a 21-year-old, G1P1 mother with uneventful pregnancy. His birth weight was 2650 g, and With the identification of the MMACHC gene, it has become Apgar scores were 9 and 10 at 1 minute and 5 minutes, possible to establish phenotypeegenotype correlations and respectively. Both his parents were Taiwanese, but the to observe ethnicity-related trends.1 The c.271dupA, mother was of Chinese ancestry. The parents and siblings together with c.394C>T and c.331C>T, is the most common were all alive and well. mutation.1,3,6 Patients homozygous for c.271dupA invari- However, the patient had elevated C3-acylcarnitine ably have early onset, or within 4 years of life,5 with acute level of 7.28 mmol/L (upper limit, 4.74) at first newborn metabolic decompensation. In contrast, individuals homo- screening. Subsequent data showed the following: C3- zygous for c.394C>T reportedly have later onset, with acylcarnitine, 5.7; C3/C2 ratio, 0.63 (upper limit, 0.17); better treatment response and reversal of neurologic methionine, 6.13 mmol/L (normal range, 23e59); homo- manifestations.1,3,5,6 cysteine, 219.4 mmol/L (normal range, 5.9-16); and vitamin The c.271dupA mutation is observed primarily in Euro- B12 level, 1226 pg/mL (normal range, 200e950). Therefore, peans, whereas most individuals with c.394C>T are of presymptomatic combined MMA and HCU was highly Middle Eastern origin.3 Interestingly, patients who are suspected. However, at 1.5 months of age, the patient compound heterozygous for the c.271dupA and c.394C>T presented with feeding difficulty, poor activity, pale can manifest with a disease that is intermediate between CblC disease of a Taiwanese infant 225

Figure 1 Two MMACHC mutations, c.609G>A (p.Trp203X) and c.567dupT (p.Ile190TyrfsX13), were found in the patient (II-1). These were inherited from both paternal (I-1) and maternal (I-2) MMACHC alleles. the severe early-onset form associated with homozygosity allows for early treatment before the onset of irreversible for c.271dupA and late-onset phenotype associated with impairment and, in many cases, prevention of catastrophic homozygosity for c.394C>T. Unfortunately, interpretation health outcomes, including death.13 Therefore, we would of anticipated phenotype based on this genotype may not like to suggest that, after the results of newborn screening, be totally reliable.1 it is important to inform the possibility of poor activity, The newest progress of newborn screening with tandem feeding difficulty, or even pale appearance, so that parents mass spectrometry allows the identification of inborn errors, can be aware of this condition and send the patient to the including MMA and HCU, which cannot be approached by hospital as early as possible; once diagnosed with cblC traditional methods. Elevated C3 and high methionine levels disease, therapeutic and supportive treatments must be are usually detected on screening of MMA and HCU, considered and implemented, even in the presymptomatic respectively.7 However, variable values of methionine levels stage. can be present in patients with HCU, depending on which The genotype of this patient is compound heterozygous defective part of the metabolic pathway takes place. for c.609G>A and c.567dupT, a nonsense mutation and Because MeCbl is required for the activity of methionine a duplication and frameshift mutation, respectively.3 Most synthase, which converts homocysteine to methionine, low patients homozygous for c.609G>A reported in the litera- to normal plasma methionine levels will be detected in ture have been diagnosed before 1 year of age, and all were patients with cblC disease because of impaired MeCbl East Asians.2,3 There has been another male Taiwanese synthesis.8 Moreover, it is thought that the most reliable neonate heterozygous for c.609G>A and c.658_660delAAG screening method for HCU, regardless of severity or cause, is diagnosed with cblC disease by means of newborn the measurement of total homocysteine directly.9 There- screening.3 The present patient is the first Asian and is fore, it is important to check the homocysteine levels in the second case with c.567dupT mutation in literature. The blood and urine to rule out combination with HCU in cases first one was a female Hispanic individual diagnosed at where MMA is highly suspected on the initial newborn 1 month of age with three MMACHC mutations: c.567dupT screening. in cis with one c.328_331delAACC allele.3 This article This patient could be diagnosed with combined MMA and provides detailed clinical manifestations and outcomes of HCU by means of newborn screening and subsequent a cblC patient, heterozygous for c.609G>A and c.567dupT biochemical tests before 1 month of age, who belongs to mutations, although there is limited information about the the early-onset group of cblC disease. We did not treat the clinical features except for the early onset in those patients patient in the beginning until he presented later with life- with c.609G>A or c.567dupT mutation reported in the threatening clinical manifestations, which fortunately literature. responded well to our treatment. Some authors suggested Patients with cblC disease, including this one, are progressive neurologic and visual deterioration in the early- generally unresponsive to treatment with CNCbl but are onset cases still occurred despite early intervention with more responsive to OHCbl.5,14,15 This phenomenon remains OHCbl therapy, even as early as prenatal treatment.10e12 a puzzle unsolved since the 1970s, when cultured skin However, in the era of newborn screening, it is widely fibroblasts from patients with mutations in the MMACHC accepted that early recognition of those rare disorders gene were found unable to use CNCbl for the biosynthesis of 226 J.-T. Chang et al

AdoCbl and MeCbl.16 Recently, Kim et al17 found that the 4. Rosenblatt DS, Fenton WA. Inherited disorders of folate and MMACHC gene product (cblC protein) catalyzes a reductive cobalamin transport and metabolism. In: Scriver CR, decyanation reaction of bound CNCbl to cob(II)alamin, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, editors. The th which is a prerequisite for its conversion to the active metabolic & molecular bases of inherited disease.8 ed. New e cofactor forms used by mammals wherein the cyano ligand York: McGraw-Hill; 2001. p. 3897 933. 5. Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, is replaced by a methyl group (in MeCbl) or a 5’-deoxy- 14 Seashore MR. Clinical heterogeneity and prognosis in combined adenosyl group (in AdoCbl). Froese et al reported that the methylmalonic aciduria and homocystinuria (cblC). J Inherit ability of the mutant MMACHC to respond to vitamin Metab Dis 1997;20:528e38. therapy depends on its ability to bind the vitamin with 6. Nogueira C, Aiello C, Cerone R, et al. Spectrum of MMACHC significant affinity. Mutant MMACHC has decreased ability mutations in Italian and Portuguese patients with combined to reductively decyanate the CNCbl to cob(II)alamin. With methylmalonic aciduria and homocystinuria, cblC type. Mol OHCbl treatment, binding is normal and OHCbl is easily Genet Metab 2008;93:475e80. reduced to cob(II)alamin and passed on to the rest of the 7. Fearing MK, Marsden D. Expanded newborn screening. Pediatr e pathway.14,18 However, even the provision of active Ann 2003;32:509 15. cofactors MeCbl and AdoCbl, the major alkylcobalamin 8. Rosenblatt DS, Fowler B. Disorders of cobalamin and folate transport and metabolism. In: Fernandes J, Saudubray JM, forms found in mammalian tissues, plasma, and milk, Berghe G, Walter JH, editors. Inborn metabolic diseases, demands their conversion to give cob(I)alamin, which is diagnosis and treatment.4th revised ed. Berlin, Germany: oxidized to cob(II)alamin and is subsequently converted to Springer; 2006. p. 341e56. 19 MeCbl and AdoCbl ; that is, the removal of the alkyl 9. Fowler B, Jakobs C. Post- and prenatal diagnostic methods for group of alkylcobalamins entering from circulation intra- the homocystinurias. Eur J Pediatr 1998;157:S88e93. cellularly is necessary, and patient fibroblasts with mutated 10. Enns GM, Barkovich AJ, Rosenblatt DS, et al. Progressive MMACHC (cblC protein) are unable to perform dealkylation neurological deterioration and MRI changes in cblC methyl- reactions.20 malonic acidaemia treated with hydroxocobalamin. J Inherit e In conclusion, we have described a Taiwanese infant boy Metab Dis 1999;22:599 607. with early-onset cblC disease, heterozygous for c.609G>A 11. Smith SE, Kinney HC, Swoboda KJ, Levy HL. Subacute combined degeneration of the spinal cord in cblC disorder despite and c.567dupT, who was presymptomatic at newborn treatment with B12. Mol Genet Metab 2006;88:138e45. screening but later showed life-threatening manifestations. 12. Huemer M, Simma B, Fowler B, Suormala T, Bodamer OA, He is the first Asian and is the second case with c.567dupT Sass JO. Prenatal and postnatal treatment in cobalamin C mutation in the literature. Moreover, all reported cblC defect. J Pediatr 2005;147:469e72. patients with the c.609G>A mutation have been East Asians 13. Marsden D, Levy H. Newborn screening of lysosomal storage so far; thus, we suggest that c.609G>A should be included disorders. Clin Chem 2010;56:1071e9. in the initial mutation screening tests for a cblC patient in 14. Froese DS, Zhang J, Healy S, Gravel RA. Mechanism of vitamin East Asian populations. B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Mol Genet Metab 2009;98:338e43. 15. Andersson HC, Shapira E. Biochemical and clinical response to Acknowledgments hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic aciduria and homocystinuria (cblC). The authors sincerely thank Dr Wuh-Liang Hwu and Dr J Pediatr 1998;132:121e4. Yin-Hsiu Chien for their expert assistance in newborn 16. Rosenberg LE, Patel L, Lilljeqvist AC. Absence of an intracellular screening. cobalamin-binding protein in cultured fibroblasts from patients with defective synthesis of 5’-deoxyadenosylcobalamin and methylcobalamin. Proc Natl Acad Sci USA 1975;72:4617e21.

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