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Exome sequencing data screening to identify undiagnosed Aromatic l-amino acid decarboxylase deficiency in neurodevelopmental disorders.
Riva, Antonella; Iacomino, Michele; Piccardo, Chiara; Franceschetti, Laura; Franchini, Rossella; Baroni, Alessandra; Minetti, Carlo; Bisello, Giovanni; Zara, Federico; Scala, Marcello; Striano, Pasquale; Bertoldi, Mariarita.
Afiliação
  • Riva A; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Iacomino M; Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy.
  • Piccardo C; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
  • Franceschetti L; PTC Therapeutics, Roma, RM, Italy.
  • Franchini R; Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
  • Baroni A; PTC Therapeutics, Roma, RM, Italy.
  • Minetti C; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
  • Bisello G; Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
  • Zara F; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Unit of Medical Genetics, IRCCS Giannina Gaslini Institute, Genoa, Italy.
  • Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Electronic address: mscala.md@gmail.com.
  • Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Bertoldi M; Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. Electronic address: mita.bertoldi@univr.it.
Biochem Biophys Res Commun ; 673: 131-136, 2023 09 17.
Article em En | MEDLINE | ID: mdl-37385007
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the DDC gene and mainly characterized by developmental delay, hypotonia, and oculogyric crises. Early diagnosis is crucial for correct patient management; however, many patients remain misdiagnosed or undiagnosed due to the rarity and clinical heterogeneity of the disorder especially in the milder forms. Here, we applied exome sequencing approach by screening 2000 paediatric patients with neurodevelopmental disorders to identify possible new AADC variants and AADC deficiency patients. We identified five distinct DDC variants in two unrelated individuals. Patient #1 harboured two compound heterozygous DDC variants: c.436-12T > C and c.435 + 24A>C and presented with psychomotor delay, tonic spasms, and hyperreactivity. Patient #2 had three homozygous AADC variants: c.1385G > A; p.Arg462Gln, c.234C > T; p.Ala78 = , and c.201 + 37A > G and presented with developmental delay and myoclonic seizures. The variants were classified as benign class I variants and therefore non-causative according to the ACMG/AMP guidelines. Since the AADC protein is a structural and functional obligate homodimer, we evaluated the possible AADC polypeptide chain combinations in the two patients and determined the effects resulting from the amino acid substitution Arg462Gln. Our patients carrying DDC variants presented clinical manifestations not precisely overlapped to the classical symptoms exhibited by the most severe AADC deficiency cases. However, screening data derived from exome sequencing in patients featuring wide-range symptoms related to neurodevelopmental disorders may help to identify AADC deficiency patients, especially when applied to larger cohorts.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos do Neurodesenvolvimento / Erros Inatos do Metabolismo dos Aminoácidos Tipo de estudo: Diagnostic_studies / Guideline / Prognostic_studies / Screening_studies Limite: Child / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos do Neurodesenvolvimento / Erros Inatos do Metabolismo dos Aminoácidos Tipo de estudo: Diagnostic_studies / Guideline / Prognostic_studies / Screening_studies Limite: Child / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article