Abstract
Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare neurotransmitter metabolic disorder caused by DDC gene mutations, which leads to the metabolic disturbance of dopamine and serotonin. Most of the reported cases came from Taiwan China, but patients from mainland China were seldomly reported. The current study was the largest AADCD patient cohort from mainland China. Twenty-three patients with clinical features of AADCD and DDC gene variants were recruited. A total of 16 DDC variants were identified in this study, of which four variants (c.2T>C, c.277A>G, c.1021+1G>A, c.565G>T) were never reported previously. The intronic variant c.714+4A>T was the most common one, with an allele frequency of 45.7%. And patients carried this intronic variant presented with severe clinical manifestations, all of whom were bedridden. In this study, the average onset age was 3.61 ± 1.28 months and the average age of diagnosis was 12.91 ± 5.62 months. Early onset hypotonia, oculogyric crises, and autonomic symptoms such as excessive sweating, nasal congestion and profuse nasal, and oropharyngeal secretions, were common in our patients. Eighteen patients (78.3%) got various degree of improvement after using pyridoxine monotherapy or different combination of pyridoxine, dopamine agonists, and monoamine oxidase (MAO) inhibitors.
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References
Brun L, Ngu LH, Keng WT, Ch’ng GS, Choy YS, Hwu WL, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010;75:64–71.
Himmelreich N, Montioli R, Bertoldi M, Carducci C, Leuzzi V, Gemperle C, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019;127:12–22.
Montioli R, Cellini B, Borri Voltattorni C. Molecular insights into the pathogenicity of variants associated with the aromatic amino acid decarboxylase deficiency. J Inherit Metab Dis. 2011;34:1213–24.
Guenter J, Lenartowski R. Molecular characteristic and physiological role of DOPA-decarboxylase. Postepy Hig Med Dosw. 2016;70:1424–40.
Montioli R, Dindo M, Giorgetti A, Piccoli S, Cellini B, Voltattorni CB. A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications. Hum Mol Genet. 2014;23:5429–40.
Wassenberg T, Molero-Luis M, Jeltsch K, Hoffmann GF, Assmann B, Blau N, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12:12.
Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J Inherit Metab Dis. 1990;13:301–4.
Chien YH, Chen PW, Lee NC, Hsieh WS, Chiu PC, Hwu WL, et al. 3-O-methyldopa levels in newborns: result of newborn screening for aromatic l-amino-acid decarboxylase deficiency. Mol Genet Metab. 2016;118:259–63.
Chen X, Xu J, Chen L. Aromatic L-amino acid decarboxylase deficiency: a report of two cases and literature review. Linchuang Er Ke Za Zhi. 2019;37:365–8.
Dai L, Ding C, Fang F. A novel DDC gene deletion mutation in two Chinese mainland siblings with aromatic l-amino acid decarboxylase deficiency. Brain Dev. 2019;41:205–9.
Zhu J, Yu F. Feeding difficulty and developmental delay for 8 months and nystagmus for 4 months in an infant. Zhongguo Dang Dai Er Ke Za Zhi. 2017;19:68–72.
Lee NC, Chien YH, Hwu WL. A review of aromatic l-amino acid decarboxylase (AADC) deficiency in Taiwan. Am J Med Genet C Semin Med Genet. 2019;181:226–9.
Hwu WL, Chien YH, Lee NC, Li MH. Natural history of aromatic L-amino acid decarboxylase deficiency in Taiwan. JIMD Rep. 2018;40:1–6.
Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol. 2009;13:135–40.
Verbeek MM, Geurtz PB, Willemsen MA, Wevers RA. Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes. Mol Genet Metab. 2007;90:363–9.
Arnoux JB, Damaj L, Napuri S, Serre V, Hubert L, Cadoudal M, et al. Aromatic L-amino acid decarboxylase deficiency is a cause of long-fasting hypoglycemia. J Clin Endocrinol Metab. 2013;98:4279–84.
Helman G, Pappa MB, Pearl PL. Widening phenotypic spectrum of AADC deficiency, a disorder of dopamine and serotonin synthesis. JIMD Rep. 2014;17:23–27.
Tay SK, Poh KS, Hyland K, Pang YW, Ong HT, Low PS, et al. Unusually mild phenotype of AADC deficiency in 2 siblings. Mol Genet Metab. 2007;91:374–8.
Kojima K, Anzai R, Ohba C, Goto T, Miyauchi A, Thony B, et al. A female case of aromatic l-amino acid decarboxylase deficiency responsive to MAO-B inhibition. Brain Dev. 2016;38:959–63.
Manegold C, Hoffmann GF, Degen I, Ikonomidou H, Knust A, Laass MW, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis. 2009;32:371–80.
Chang YT, Sharma R, Marsh JL, McPherson JD, Bedell JA, Knust A, et al. Levodopa-responsive aromatic L-amino acid decarboxylase deficiency. Ann Neurol. 2004;55:435–8.
Brautigam C, Wevers RA, Hyland K, Sharma RK, Knust A, Hoffman GF. The influence of L-dopa on methylation capacity in aromatic L-amino acid decarboxylase deficiency: biochemical findings in two patients. J Inherit Metab Dis. 2000;23:321–4.
Barth M, Serre V, Hubert L, Chaabouni Y, Bahi-Buisson N, Cadoudal M, et al. Kinetic analyses guide the therapeutic decision in a novel form of moderate aromatic acid decarboxylase deficiency. JIMD Rep. 2012;3:25–32.
Chien YH, Lee NC, Tseng SH, Tai CH, Muramatsu SI, Byrne BJ, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017;1:265–73.
Kojima K, Nakajima T, Taga N, Miyauchi A, Kato M, Matsumoto A, et al. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain. 2019;142:322–33.
Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4:134ra161.
Acknowledgements
We would like to thank the reported families for their cooperation in this study. Financial support has been provided by clinical research special fund of Wu Jieping Medical Foundation (grant No. 320.6750.17091, receiptor: Xinhua Bao), the Youth foundation of the National Natural Science Foundation of China (grant No. 81801128, receiptor: Qingping Zhang), and the Peking University First Hospital Scientific Research Seed Fund (grant No. 2018SF013, receiptor: Qingping Zhang).
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Wen, Y., Wang, J., Zhang, Q. et al. The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China. J Hum Genet 65, 759–769 (2020). https://doi.org/10.1038/s10038-020-0770-6
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DOI: https://doi.org/10.1038/s10038-020-0770-6
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