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S-adenosylmethionine treatment in methionine adenosyltransferase deficiency, a case report
Molecular Genetics and Metabolism 105 (2012) 516–518
Contents lists available at SciVerse ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Brief Communication
S-adenosylmethionine treatment in methionine adenosyltransferase deficiency, a case report Mahoko Furujo a,⁎, Masako Kinoshita b, Masayoshi Nagao c, Toshihide Kubo a a b c
Department of Pediatrics, National Hospital Organization, Okayama Medical Center, Okayama, Japan Department of Neurology, National Hospital Organization, Utano National Hospital, Kyoto, Japan Department of Pediatrics, National Hospital Organization, Hokkaido Medical Center, Hokkaido, Japan
a r t i c l e
i n f o
Article history: Received 13 October 2011 Received in revised form 18 November 2011 Accepted 18 November 2011 Available online 2 December 2011 Keywords: Methionine adenosyltransferase deficiency Supplementary treatment S-adenosylmethionine
a b s t r a c t Reported is a female patient with methionine adenosyltransferase I/III (MAT I/III) deficiency, who was found to have pronounced hypermethioninemia on newborn mass spectroscopy screening, and had two compound heterozygous missense mutations in the gene encoding human MAT1A protein. Hypermethioninemia persisted and her mental development was deficient. At 4 years and 8 months, we started with the supplementary treatment of S-adenosylmethionine, the metabolic product of methionine catalyzed by MAT, which was effective in her neurological development. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Methionine adenosyltransferase I/III (MAT I/III) deficiency, caused by mutations in the MAT1A gene, is an inherited metabolic disorder characterized by persistent hypermethioninemia without elevated tyrosine [1]. There is a wide range of clinical manifestations in individuals with mutations in MAT1A, from completely asymptomatic to neurological problems associated with brain demyelination [1–9], and in severe cases plasma total homocysteine level can be elevated [9]. The metabolism of methionine and homocysteine co-activating methyl-transfer pathway is as follows; single carbon units enter the pathway, mostly as methenyl groups derived from the oxidation of serine, bind to tetrahydrofolate, and are reduced to 5,10-methylenetetrahydrofolate then 5-methyltetrahydrofolate. This compound transfers its methyl group to homocysteine, forming methionine, in a complex reaction catalyzed by cobalamin-dependent methionine synthase. Methionine is then activated to form S-adenosylmethionine (SAM), catalyzed by MAT I/III. S-adenosylhomocysteine is formed after transmethylation and then broken down to regenerate homocysteine, which can re-enter the cycle. In inborn errors of methyl-transfer pathway, demyelination is associated with deficiency of cerebrospinal-fluid S-adenosylmethionine [5]. Treatment with SAM in MAT I/III deficient patients can directly bypass the metabolic block and is associated with remyelination and improvement in neurologic symptoms [1, 5].
⁎ Corresponding author at: Department of Pediatrics, National Hospital Organization, Okayama Medical Center, 1711–1 Tamasu, Kitaku, Okayama, 701–1192, Japan. Fax: +81 86 294 9255. E-mail address: [email protected] (M. Furujo). 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.11.192
Brain MRI has been widely used to evaluate the degree of abnormal myelination in patients with metabolic disorders. However, EEG findings have not been fully investigated in spite of their value to investigate the functional status and epileptogenesis. Here we report a MAT I/III deficiency patient who manifested with neurological abnormalities and seizures, successfully treated with SAM and evaluated by MRI and EEG. Part of this manuscript was presented in the 11th International Congress of Inborn Errors of Metabolism, 2009, and appeared in an abstract form [10]. 2. Patient presentation The patient is a girl, born at 41 weeks of gestation with a weight of 3.1 kg, who is the second child of nonconsanguineous parents. At 5 days she was found to have hypermethioninemia (395 μmol/L, normal range, less than 40 μmol/L) on newborn mass spectroscopy screening. She had a boiled-cabbage odor. At 1 year of age delay of language development became apparent whereas motor function was within normal limits, and she had the first febrile convulsion. At 2 years and 11 months she had a series of complex febrile seizures consisting of clonic jerks of the right arm and bilateral clonic seizures twice per day, which were successfully suppressed by diazepam. Subsequent antiepileptic medication was not started. At that time brain MRI (GE Signa 1 T, GE Healthcare Japan, Tokyo) showed a myelination arrest in the central white matter, putamen and globus pallidus (Fig. 1, left column), and EEG (EEG1518, Nihon Kohden, Tokyo) showed central spikes with disorganized and slow posterior dominant rhythm (Fig. 2, left). Her serum methionine level ranged between 1005 and 1676 μmol/L, and folate level between 34 and 45 nmol/L (normal range, 3.6-8.2 nmol/L). Homocysteine and homocystine levels in
M. Furujo et al. / Molecular Genetics and Metabolism 105 (2012) 516–518
2y11m
4y8m
517
6y5m
T1
T2
Fig. 1. Brain MRI of a patient with MAT deficiency. A myelination arrest in the central white matter (black arrow), putamen (white arrow), and globus pallidus (left and middle columns) at 2 years and 11 months and at 4 years and 5 months. After SAM treatment, MRI showed a normal myelination at 6 years and 5 months, (right column).
plasma or urine were not elevated (plasma total homocysteine, less than 3.7 μmol/L, normal range, 3.7-13.5 μmol/L: plasma free homocysteine, undetectable, less than 0.9 μmol/L: plasma homocystine, undetectable, less than 0.9 μmol/L: urine homocystine, undetectable, less than 0.9 μmol/g⋅creatinine), and serum tyrosine concentration and other amino acids were within normal limit. Her liver function was normal. Gene analysis showed an abnormality in MAT1A gene (compound heterozygous of R292C and R356L). Methylenetetrahydrofolate reductase gene, whose abnormality also known to provoke hypermethioninemia and myelination disorder [5], was normal. The methionine level of her father was slightly elevated but that of her mother was normal (father; 54 μmol/L, mother; 27 μmol/L). The older sister of this patient is diagnosed as having partial epilepsy, which was well-controlled by clonazepam. Her development is normal, her plasma methionine was within normal limit (27 μmol/L), and her MRI shows no myelination abnormalities. At 3 years and 9 months we started high-dose pyridoxine therapy (1500–1750 mg/day), in order to activate the catabolism of methionine via the trans-sulfuration pathway to produce SAM [11]. However,
2y11m F2 – A2 T2 – A2 C2 – A2 P2 – A2 O2 – A2 F1 – A1 T1 – A1 C1 – A1 P1 – A1 O1 – A1 Cz – T2 T2 – T1 T1 – Cz Cz – T4 T4 – T3 T3 – Cz ECG
1 sec
100 µV
her mental development remained deficient especially in language function. Developmental quotients evaluated by Tsumori-Isobe Development Diagnostic Questionnaire, which has been standardized and widely used in Japan [12], remained 49 (factors; motor skills 47, exploration 51, social skills 53, daily habits 54, language ability 40: normal range, higher than 70). At 4 years and 8 months, her brain MRI still showed delayed myelination (Fig. 1, middle column), therefore, we started with the treatment of SAM by using S-adenosyl-L-methionine disulfate tosylate (Source Naturals Company, USA) 400–800 mg twice daily, based on a written informed consent by her parents. Dietary methionine intake was not limited. There was no side effect of the therapy. At 5 years and 5 months, her Intelligence Quotients evaluated by Tanaka Binet Intelligence Test V, which has been also widely used in Japan [13], improved to 69 (normal range, higher than 69). Her serum methionine level was still high (1528 μmol/L). Awake EEG showed marked improvement (Fig. 2, right) although residual high voltage spike and slow wave patterns in bilateral centrotemporal regions occurred during sleep. MRI at 6 years and 5 months showed a normal myelination (Fig. 1, right column).
5y8m
1 sec
100 µV
Fp2 - A2 F8 - A2 F4 - A2 C4 - A2 T4 - A2 P4 - A2 T6 - A2 O2 - A2 Fp1 – A1 F7 - A1 F3 - A1 C3 - A1 T3 - A1 P3 - A1 T5 - A1 O1 - A1 ECG
Fig. 2. EEG of a patient with MAT deficiency, before (left) and after (right) SAM treatment. At 2 years and 11 months, EEG showed central spikes with disorganized and slow posterior dominant rhythm (left). At 5 years and 8 months, awake EEG showed marked improvement (right).
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M. Furujo et al. / Molecular Genetics and Metabolism 105 (2012) 516–518
3. Discussion This patient with MAT I/III deficiency, who has MAT1A gene abnormality (compound heterozygous of R292C and R356L), demonstrated intellectual disability especially of language function, and her MRI revealed delayed myelination. We found a novel mutation of R356L; mutation of the same locus R356P has already been identified [14] and the recombinant protein showed impairment of MAT I/III activities [15]. R292C mutation has been reported previously in a methionine MAT deficiency patient [8]. We assumed that these abnormalities were possibly caused by a lack of SAM, the metabolic product catalyzed by MAT I/III. After treatment with SAM, the patient improved in her development without any side effects. The improvement may be associated with increase of neuronal signal frequency, as shown in a study of cultured cortical neurons [16]. Since hypermetionemia alone possibly has neurotoxic effect, methionine reduction can be an additional therapeutic strategy, although the present patient can achieve neurological improvement under remaining hypermetionemia. The present patient restored a normal myelination after SAM treatment. It is extremely rare that a patient spontaneously acquires the myelin after the detection of deficient myelination in older than 2 years [17]. Evaluation of SAM concentration in plasma and in cerebrospinal fluid would reveal its association to myelination process. Seizures and EEG findings of this patient are suggestive of benign childhood epilepsy with centrotemporal spikes (BECTS). Considering relatively high prevalence of epilepsy and history of epileptic seizures of the older sister, seizures of this patient may irrelevant to MAT deficiency. However, similar EEG findings are reported in patients with homocystinuria [18]. Further studies are needed to clarify the correlation between neurological problems and EEG findings in patients with MAT I/III deficiency. In addition, the number of children diagnosed with BECTS who have an underlying metabolic disorder would be interesting to pursue. Acknowledgment This study was partly supported by a Research Grant from the Japan Epilepsy Research Foundation and a Research Grant from Fukuda Foundation for Medical Technology.
References [1] I. Barić, Inherited disorders in the conversion of methionine to homocysteine, J. Inherit. Metab. Dis. 32 (2009) 459–471. [2] M.E. Chamberlin, T. Ubagai, S.H. Mudd, W.G. Wilson, J.V. Leonard, J.Y. Chou, Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency, J. Clin. Invest. 98 (1996) 1021–1027. [3] M.E. Chamberlin, T. Ubagai, S.H. Mudd, J. Thomas, V.Y. Pao, T.K. Nguyen, H.L. Levy, C. Greene, C. Freehauf, J.Y. Chou, Methionine adenosyltransferase I/III deficiency: novel mutations and clinical variations, Am. J. Hum. Genet. 66 (2000) 347–355. [4] S. Hazelwood, I. Bernardini, V. Shotelersuk, A. Tangerman, J. Guo, H. Mudd, W.A. Gahl, Normal brain myelination in a patient homozygous for a mutation that encodes a severely truncated methionine adenosyltransferase I/III, Am. J. Med. Genet. 75 (1998) 395–400. [5] R. Surtees, J. Leonard, S. Austin, Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway, Lancet 338 (1991) 1550–1554. [6] H. Tada, J. Takanashi, A.J. Barkovich, S. Yamamoto, Y. Kohno, Reversible white matter lesion in methionine adenosyltransferase I/III deficiency, AJNR, Am. J. Neuroradiol. 25 (2004) 1843–1845. [7] S.H. Mudd, Hypermethioninemias of genetic and non-genetic origin: A review, Am. J. Med. Genet. C Semin. Med. Genet. 157 (2011) 3–32. [8] M. Ito, Y. Kotani, J. Matsuda, Y. Ichiro, E. Naito, K. Mori, Y. Kuroda, A methionine adenosyltransferase (MAT) deficiency patient treated with diet therapy, J. Inherit. Metab. Dis. 26 (2003) 76. [9] S.P. Stabler, C. Steegborn, M.C. Wahl, J. Oliveriusova, J.P. Kraus, R.H. Allen, C. Wagner, S.H. Mudd, Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency, Metabolism 51 (2002) 981–988. [10] F. Mahoko, K. Toshihide, K. Masako, N. Masayoshi, Supplementary treatment for methionine adenosyltransferase (MAT) deficiency, Mol. Genet. Metab. 98 (2009) 18 (the last names were replaced by the first names). [11] T.T. Nguyen, T. Hayakawa, H. Tsuge, Effect of vitamin B6 deficiency on the synthesis and accumulation of S-adenosylhomocysteine and S-adenosylmethionine in rat tissues, J. Nutr. Sci. Vitaminol. (Tokyo) 47 (2001) 188–194. [12] M. Tsumori, K. Isobe, Early childhood developmental diagnostic scales (from 3 to 7 years of age), first ed. Dainihon Tosho, Tokyo, 1965 (in Japanese). [13] The Institute of Education Tanaka, Tanaka Binet intelligence test V (Five), first ed, Taken Publishing, Tokyo, 2003, (in Japanese). [14] Y.H. Chien, S.C. Chiang, A. Huang, W.L. Hwu, Spectrum of hypermethioninemia in neonatal screening, Early Hum. Dev. 81 (2005) 529–533. [15] J. Fernández-Irigoyen, E. Santamaría, Y.H. Chien, W.L. Hwu, S.H. Korman, H. Faghfoury, A. Schulze, G.E. Hoganson, S.P. Stabler, R.H. Allen, C. Wagner, S.H. Mudd, F.J. Corrales, Enzymatic activity of methionine adenosyltransferase variants identified in patients with persistent hypermethioninemia, Mol. Genet. Metab. 101 (2010) 172–177. [16] M. Serra, A. Chan, M. Dubey, V. Gilman, T.B. Shea, Folate and S-adenosylmethionine modulate synaptic activity in cultured cortical neurons: acute differential impact on normal and apolipoprotein-deficient mice, Phys. Biol. 5 (2008) 044002. [17] R. Schiffmann, M.S. van der Knaap, Invited Article: An MRI-based approach to the diagnosis of white matter disorders, Neurology 72 (2009) 750–759. [18] S. Buoni, R.M. Di Bartolo, M. Molinelli, S. Palmeri, R. Zannolli, Atypical BECTS and homocystinuria, Neurology 61 (2003) 1129–1131.
Contents lists available at SciVerse ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Brief Communication
S-adenosylmethionine treatment in methionine adenosyltransferase deficiency, a case report Mahoko Furujo a,⁎, Masako Kinoshita b, Masayoshi Nagao c, Toshihide Kubo a a b c
Department of Pediatrics, National Hospital Organization, Okayama Medical Center, Okayama, Japan Department of Neurology, National Hospital Organization, Utano National Hospital, Kyoto, Japan Department of Pediatrics, National Hospital Organization, Hokkaido Medical Center, Hokkaido, Japan
a r t i c l e
i n f o
Article history: Received 13 October 2011 Received in revised form 18 November 2011 Accepted 18 November 2011 Available online 2 December 2011 Keywords: Methionine adenosyltransferase deficiency Supplementary treatment S-adenosylmethionine
a b s t r a c t Reported is a female patient with methionine adenosyltransferase I/III (MAT I/III) deficiency, who was found to have pronounced hypermethioninemia on newborn mass spectroscopy screening, and had two compound heterozygous missense mutations in the gene encoding human MAT1A protein. Hypermethioninemia persisted and her mental development was deficient. At 4 years and 8 months, we started with the supplementary treatment of S-adenosylmethionine, the metabolic product of methionine catalyzed by MAT, which was effective in her neurological development. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Methionine adenosyltransferase I/III (MAT I/III) deficiency, caused by mutations in the MAT1A gene, is an inherited metabolic disorder characterized by persistent hypermethioninemia without elevated tyrosine [1]. There is a wide range of clinical manifestations in individuals with mutations in MAT1A, from completely asymptomatic to neurological problems associated with brain demyelination [1–9], and in severe cases plasma total homocysteine level can be elevated [9]. The metabolism of methionine and homocysteine co-activating methyl-transfer pathway is as follows; single carbon units enter the pathway, mostly as methenyl groups derived from the oxidation of serine, bind to tetrahydrofolate, and are reduced to 5,10-methylenetetrahydrofolate then 5-methyltetrahydrofolate. This compound transfers its methyl group to homocysteine, forming methionine, in a complex reaction catalyzed by cobalamin-dependent methionine synthase. Methionine is then activated to form S-adenosylmethionine (SAM), catalyzed by MAT I/III. S-adenosylhomocysteine is formed after transmethylation and then broken down to regenerate homocysteine, which can re-enter the cycle. In inborn errors of methyl-transfer pathway, demyelination is associated with deficiency of cerebrospinal-fluid S-adenosylmethionine [5]. Treatment with SAM in MAT I/III deficient patients can directly bypass the metabolic block and is associated with remyelination and improvement in neurologic symptoms [1, 5].
⁎ Corresponding author at: Department of Pediatrics, National Hospital Organization, Okayama Medical Center, 1711–1 Tamasu, Kitaku, Okayama, 701–1192, Japan. Fax: +81 86 294 9255. E-mail address: [email protected] (M. Furujo). 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.11.192
Brain MRI has been widely used to evaluate the degree of abnormal myelination in patients with metabolic disorders. However, EEG findings have not been fully investigated in spite of their value to investigate the functional status and epileptogenesis. Here we report a MAT I/III deficiency patient who manifested with neurological abnormalities and seizures, successfully treated with SAM and evaluated by MRI and EEG. Part of this manuscript was presented in the 11th International Congress of Inborn Errors of Metabolism, 2009, and appeared in an abstract form [10]. 2. Patient presentation The patient is a girl, born at 41 weeks of gestation with a weight of 3.1 kg, who is the second child of nonconsanguineous parents. At 5 days she was found to have hypermethioninemia (395 μmol/L, normal range, less than 40 μmol/L) on newborn mass spectroscopy screening. She had a boiled-cabbage odor. At 1 year of age delay of language development became apparent whereas motor function was within normal limits, and she had the first febrile convulsion. At 2 years and 11 months she had a series of complex febrile seizures consisting of clonic jerks of the right arm and bilateral clonic seizures twice per day, which were successfully suppressed by diazepam. Subsequent antiepileptic medication was not started. At that time brain MRI (GE Signa 1 T, GE Healthcare Japan, Tokyo) showed a myelination arrest in the central white matter, putamen and globus pallidus (Fig. 1, left column), and EEG (EEG1518, Nihon Kohden, Tokyo) showed central spikes with disorganized and slow posterior dominant rhythm (Fig. 2, left). Her serum methionine level ranged between 1005 and 1676 μmol/L, and folate level between 34 and 45 nmol/L (normal range, 3.6-8.2 nmol/L). Homocysteine and homocystine levels in
M. Furujo et al. / Molecular Genetics and Metabolism 105 (2012) 516–518
2y11m
4y8m
517
6y5m
T1
T2
Fig. 1. Brain MRI of a patient with MAT deficiency. A myelination arrest in the central white matter (black arrow), putamen (white arrow), and globus pallidus (left and middle columns) at 2 years and 11 months and at 4 years and 5 months. After SAM treatment, MRI showed a normal myelination at 6 years and 5 months, (right column).
plasma or urine were not elevated (plasma total homocysteine, less than 3.7 μmol/L, normal range, 3.7-13.5 μmol/L: plasma free homocysteine, undetectable, less than 0.9 μmol/L: plasma homocystine, undetectable, less than 0.9 μmol/L: urine homocystine, undetectable, less than 0.9 μmol/g⋅creatinine), and serum tyrosine concentration and other amino acids were within normal limit. Her liver function was normal. Gene analysis showed an abnormality in MAT1A gene (compound heterozygous of R292C and R356L). Methylenetetrahydrofolate reductase gene, whose abnormality also known to provoke hypermethioninemia and myelination disorder [5], was normal. The methionine level of her father was slightly elevated but that of her mother was normal (father; 54 μmol/L, mother; 27 μmol/L). The older sister of this patient is diagnosed as having partial epilepsy, which was well-controlled by clonazepam. Her development is normal, her plasma methionine was within normal limit (27 μmol/L), and her MRI shows no myelination abnormalities. At 3 years and 9 months we started high-dose pyridoxine therapy (1500–1750 mg/day), in order to activate the catabolism of methionine via the trans-sulfuration pathway to produce SAM [11]. However,
2y11m F2 – A2 T2 – A2 C2 – A2 P2 – A2 O2 – A2 F1 – A1 T1 – A1 C1 – A1 P1 – A1 O1 – A1 Cz – T2 T2 – T1 T1 – Cz Cz – T4 T4 – T3 T3 – Cz ECG
1 sec
100 µV
her mental development remained deficient especially in language function. Developmental quotients evaluated by Tsumori-Isobe Development Diagnostic Questionnaire, which has been standardized and widely used in Japan [12], remained 49 (factors; motor skills 47, exploration 51, social skills 53, daily habits 54, language ability 40: normal range, higher than 70). At 4 years and 8 months, her brain MRI still showed delayed myelination (Fig. 1, middle column), therefore, we started with the treatment of SAM by using S-adenosyl-L-methionine disulfate tosylate (Source Naturals Company, USA) 400–800 mg twice daily, based on a written informed consent by her parents. Dietary methionine intake was not limited. There was no side effect of the therapy. At 5 years and 5 months, her Intelligence Quotients evaluated by Tanaka Binet Intelligence Test V, which has been also widely used in Japan [13], improved to 69 (normal range, higher than 69). Her serum methionine level was still high (1528 μmol/L). Awake EEG showed marked improvement (Fig. 2, right) although residual high voltage spike and slow wave patterns in bilateral centrotemporal regions occurred during sleep. MRI at 6 years and 5 months showed a normal myelination (Fig. 1, right column).
5y8m
1 sec
100 µV
Fp2 - A2 F8 - A2 F4 - A2 C4 - A2 T4 - A2 P4 - A2 T6 - A2 O2 - A2 Fp1 – A1 F7 - A1 F3 - A1 C3 - A1 T3 - A1 P3 - A1 T5 - A1 O1 - A1 ECG
Fig. 2. EEG of a patient with MAT deficiency, before (left) and after (right) SAM treatment. At 2 years and 11 months, EEG showed central spikes with disorganized and slow posterior dominant rhythm (left). At 5 years and 8 months, awake EEG showed marked improvement (right).
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M. Furujo et al. / Molecular Genetics and Metabolism 105 (2012) 516–518
3. Discussion This patient with MAT I/III deficiency, who has MAT1A gene abnormality (compound heterozygous of R292C and R356L), demonstrated intellectual disability especially of language function, and her MRI revealed delayed myelination. We found a novel mutation of R356L; mutation of the same locus R356P has already been identified [14] and the recombinant protein showed impairment of MAT I/III activities [15]. R292C mutation has been reported previously in a methionine MAT deficiency patient [8]. We assumed that these abnormalities were possibly caused by a lack of SAM, the metabolic product catalyzed by MAT I/III. After treatment with SAM, the patient improved in her development without any side effects. The improvement may be associated with increase of neuronal signal frequency, as shown in a study of cultured cortical neurons [16]. Since hypermetionemia alone possibly has neurotoxic effect, methionine reduction can be an additional therapeutic strategy, although the present patient can achieve neurological improvement under remaining hypermetionemia. The present patient restored a normal myelination after SAM treatment. It is extremely rare that a patient spontaneously acquires the myelin after the detection of deficient myelination in older than 2 years [17]. Evaluation of SAM concentration in plasma and in cerebrospinal fluid would reveal its association to myelination process. Seizures and EEG findings of this patient are suggestive of benign childhood epilepsy with centrotemporal spikes (BECTS). Considering relatively high prevalence of epilepsy and history of epileptic seizures of the older sister, seizures of this patient may irrelevant to MAT deficiency. However, similar EEG findings are reported in patients with homocystinuria [18]. Further studies are needed to clarify the correlation between neurological problems and EEG findings in patients with MAT I/III deficiency. In addition, the number of children diagnosed with BECTS who have an underlying metabolic disorder would be interesting to pursue. Acknowledgment This study was partly supported by a Research Grant from the Japan Epilepsy Research Foundation and a Research Grant from Fukuda Foundation for Medical Technology.
References [1] I. Barić, Inherited disorders in the conversion of methionine to homocysteine, J. Inherit. Metab. Dis. 32 (2009) 459–471. [2] M.E. Chamberlin, T. Ubagai, S.H. Mudd, W.G. Wilson, J.V. Leonard, J.Y. Chou, Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency, J. Clin. Invest. 98 (1996) 1021–1027. [3] M.E. Chamberlin, T. Ubagai, S.H. Mudd, J. Thomas, V.Y. Pao, T.K. Nguyen, H.L. Levy, C. Greene, C. Freehauf, J.Y. Chou, Methionine adenosyltransferase I/III deficiency: novel mutations and clinical variations, Am. J. Hum. Genet. 66 (2000) 347–355. [4] S. Hazelwood, I. Bernardini, V. Shotelersuk, A. Tangerman, J. Guo, H. Mudd, W.A. Gahl, Normal brain myelination in a patient homozygous for a mutation that encodes a severely truncated methionine adenosyltransferase I/III, Am. J. Med. Genet. 75 (1998) 395–400. [5] R. Surtees, J. Leonard, S. Austin, Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway, Lancet 338 (1991) 1550–1554. [6] H. Tada, J. Takanashi, A.J. Barkovich, S. Yamamoto, Y. Kohno, Reversible white matter lesion in methionine adenosyltransferase I/III deficiency, AJNR, Am. J. Neuroradiol. 25 (2004) 1843–1845. [7] S.H. Mudd, Hypermethioninemias of genetic and non-genetic origin: A review, Am. J. Med. Genet. C Semin. Med. Genet. 157 (2011) 3–32. [8] M. Ito, Y. Kotani, J. Matsuda, Y. Ichiro, E. Naito, K. Mori, Y. Kuroda, A methionine adenosyltransferase (MAT) deficiency patient treated with diet therapy, J. Inherit. Metab. Dis. 26 (2003) 76. [9] S.P. Stabler, C. Steegborn, M.C. Wahl, J. Oliveriusova, J.P. Kraus, R.H. Allen, C. Wagner, S.H. Mudd, Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency, Metabolism 51 (2002) 981–988. [10] F. Mahoko, K. Toshihide, K. Masako, N. Masayoshi, Supplementary treatment for methionine adenosyltransferase (MAT) deficiency, Mol. Genet. Metab. 98 (2009) 18 (the last names were replaced by the first names). [11] T.T. Nguyen, T. Hayakawa, H. Tsuge, Effect of vitamin B6 deficiency on the synthesis and accumulation of S-adenosylhomocysteine and S-adenosylmethionine in rat tissues, J. Nutr. Sci. Vitaminol. (Tokyo) 47 (2001) 188–194. [12] M. Tsumori, K. Isobe, Early childhood developmental diagnostic scales (from 3 to 7 years of age), first ed. Dainihon Tosho, Tokyo, 1965 (in Japanese). [13] The Institute of Education Tanaka, Tanaka Binet intelligence test V (Five), first ed, Taken Publishing, Tokyo, 2003, (in Japanese). [14] Y.H. Chien, S.C. Chiang, A. Huang, W.L. Hwu, Spectrum of hypermethioninemia in neonatal screening, Early Hum. Dev. 81 (2005) 529–533. [15] J. Fernández-Irigoyen, E. Santamaría, Y.H. Chien, W.L. Hwu, S.H. Korman, H. Faghfoury, A. Schulze, G.E. Hoganson, S.P. Stabler, R.H. Allen, C. Wagner, S.H. Mudd, F.J. Corrales, Enzymatic activity of methionine adenosyltransferase variants identified in patients with persistent hypermethioninemia, Mol. Genet. Metab. 101 (2010) 172–177. [16] M. Serra, A. Chan, M. Dubey, V. Gilman, T.B. Shea, Folate and S-adenosylmethionine modulate synaptic activity in cultured cortical neurons: acute differential impact on normal and apolipoprotein-deficient mice, Phys. Biol. 5 (2008) 044002. [17] R. Schiffmann, M.S. van der Knaap, Invited Article: An MRI-based approach to the diagnosis of white matter disorders, Neurology 72 (2009) 750–759. [18] S. Buoni, R.M. Di Bartolo, M. Molinelli, S. Palmeri, R. Zannolli, Atypical BECTS and homocystinuria, Neurology 61 (2003) 1129–1131.