title: Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant.
abstract: The causative variant in a consanguineous family in which the three patients (two siblings and a cousin) presented with intellectual disability, Marfanoid habitus, craniofacial dysmorphisms, chronic diarrhea and progressive kyphoscoliosis, has been identified through whole exome sequencing (WES) analysis. WES study identified a homozygous DDC variant in the patients, c.1123C>T, resulting in p.Arg375Cys missense substitution. Mutations in DDC cause a recessive metabolic disorder (aromatic amino acid decarboxylase, AADC, deficiency, OMIM #608643) characterized by hypotonia, oculogyric crises, excessive sweating, temperature instability, dystonia, severe neurologic dysfunction in infancy, and specific abnormalities of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF). In our family, analysis of neurotransmitters and their metabolites in patient's CSF shows a pattern compatible with AADC deficiency, although the clinical signs are different from the classic form. Our work expands the phenotypic spectrum associated with DDC variants, which therefore can cause an additional novel syndrome without typical movement abnormalities.
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Graziano
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Clinical Genetics Unit, Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Wischmeijer
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Unit of Child Neurology and Psychiatry, Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Fusco
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Diquigiovanni
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Margit
authors.initials: M
authors.lastname: Nõukas
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Martin
authors.initials: M
authors.lastname: Sauk
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Ants
authors.initials: A
authors.lastname: Kurg
authors.affiliation: Clinical Genetics Unit, Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia, Italy; Medical Genetic Service, Department of Laboratory, S. Chiara Hospital, Trento, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rivieri
authors.affiliation: Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.affiliation: Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Greenwood Genetic Center, 113 Gregor Mendel Circle, Greenwood, SC 29646, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Chaubey
authors.affiliation: Greenwood Genetic Center, 113 Gregor Mendel Circle, Greenwood, SC 29646, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. Electronic address: elena.bonora6@unibo.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.affiliation: Clinical Genetics Unit, Arcispedale S. Maria Nuova, IRCCS, Reggio Emilia, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.affiliation: Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics*; D001483:Base Sequence; D003241:Consanguinity; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D055815:Young Adult
chemical_list: D001142:Aromatic-L-Amino-Acid Decarboxylases; C000595218:DDC protein, human
keywords: DDC; Intellectual disability; Whole exome sequencing