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Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes
N. Himmelreich, M. Bertoldi, M. Alfadhel, MA. Alghamdi, Y. Anikster, X. Bao, FA. Bashiri, BB. Zeev, G. Bisello, AC. Ceylan, YH. Chien, YS. Choy, SH. Elsea, L. Flint, À. García-Cazorla, C. Gijavanekar, EY. Gümüş, MH. Hamad, B. Hişmi, T. Honzik,...
Language English Country United States
Document type Journal Article
- MeSH
- Amino Acids genetics MeSH
- Aromatic-L-Amino-Acid Decarboxylases * MeSH
- Dopamine metabolism MeSH
- Genotype MeSH
- Humans MeSH
- Prevalence MeSH
- Amino Acid Metabolism, Inborn Errors * epidemiology genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
1st Department of Pediatrics Aghia Sophia Children's Hospital University of Athens Athens Greece
Boston Children's Hospital Harvard Medical School Boston MA USA
Department of Genetics Hospital Kuala Lumpur Ministry of Health Malaysia
Department of Medical Genetics and Pediatrics National Taiwan University Hospital Taipei Taiwan
Department of Neurosciences Biomedicine and Movement Sciences University of Verona Verona Italy
Department of Pediatrics Peking University 1st Hospital Beijing China
Department of Screening and Metabolic Diagnostics Institute of Mother and Child Warsaw Poland
Dept of Molecular and Human Genetics Baylor College of Medicine Houston TX USA
Divisions of Metabolism University Children's Hospital Zürich Switzerland
Genetics Service Department of Paediatrics KK Women's and Children's Hospital Singapore
Neurology Division Pediatric Department King Saud University Medical City Riyadh SA Saudi Arabia
Neurometabolic Unit Department of Neurology Hospital Sant Joan de Déu CIBERER Barcelona Spain
Pediatric Neurology Unit Arrixaca Universitary Hospital 30120 Murcia Spain
References provided by Crossref.org
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- $a Himmelreich, Nastassja $u Dietmar-Hopp Metabolic Center and Centre for Pediatrics and Adolescent Medicine, University Children's Hospital, Heidelberg, Germany
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- $a Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes / $c N. Himmelreich, M. Bertoldi, M. Alfadhel, MA. Alghamdi, Y. Anikster, X. Bao, FA. Bashiri, BB. Zeev, G. Bisello, AC. Ceylan, YH. Chien, YS. Choy, SH. Elsea, L. Flint, À. García-Cazorla, C. Gijavanekar, EY. Gümüş, MH. Hamad, B. Hişmi, T. Honzik, OK. Hübschmann, WL. Hwu, S. Ibáñez-Micó, K. Jeltsch, N. Juliá-Palacios, ÇS. Kasapkara, MA. Kurian, K. Kusmierska, N. Liu, LH. Ngu, JD. Odom, WP. Ong, T. Opladen, M. Oppeboen, PL. Pearl, B. Pérez, R. Pons, AM. Rygiel, TE. Shien, R. Spaull, J. Sykut-Cegielska, B. Tabarki, T. Tangeraas, B. Thöny, T. Wassenberg, Y. Wen, Y. Yakob, JGC. Yin, J. Zeman, N. Blau
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- $a Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
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