title: Novel homozygous missense mutation in ALDH7A1 causes neonatal pyridoxine dependent epilepsy.
abstract: Pyridoxine dependent epilepsy (PDE) (OMIM#266100) is a neonatal form of epilepsy, caused by dysfunction of the enzyme α-aminoadipic semialdehyde dehydrogenase (ALDH7A1 or Antiquitin). This enzyme converts α-aminoadipic semialdehyde (α-AASA) into α-aminoadipate (AAA), a critical step in the lysine metabolism of the brain. ALDH7A1 dysfunction causes an accumulation of α-AASA and δ1-piperideine-6-carboxylic acid (P6C), which are in equilibrium with each other. P6C binds and inactivates pyridoxal 5'-phosphate (PLP), the active form of pyridoxine. Individuals affected by ALDH7A1 deficiency show pre-natal and post-natal seizures, which respond to oral pyridoxine but not to other pediatric anti-epileptic drugs. We discovered a novel missense mutation (c.566G > A, p.Gly189Glu) in homozygous state residing in the NAD+ binding domain coding region of exon 6 and affecting an highly conserved amino acid residue. The seizures stopped under post-natal pyridoxine therapy, nevertheless a longer follow-up is needed to evaluate the intellectual development of the child, who is additionally treated with oral l-arginine since the 13th month of life. Developmental delay with or without structural cortex abnormalities were reported in several patients. A brain MRI scan revealed hyperintense white matter in the right cerebellum compatible with cerebellar gliosis. Taken together, our studies enlarge the group of missense pathogenic mutations of ALDH7A1 gene and reveal a novel cerebellar finding within the PDE patients cohort.
authors.affiliation: Center of Social Pediatrics and Pediatric Neurology, General Hospital of Celle, 29221 Celle, Germany; Department of Neuropediatrics, University Children's Hospital, Ruhr-University Bochum, 44791 Bochum, Germany. Electronic address: Emanuele.Coci@akh-celle.de.
authors.forename: Emanuele G
authors.initials: EG
authors.lastname: Coci
authors.affiliation: Institute of Organic Chemistry, Centre of Biomolecular Drug Research (BMWZ), Leibniz University of Hannover, 30167 Hannover, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Codutti
authors.affiliation: Department of Radiology, General Hospital of Celle, 29221 Celle, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Fink
authors.affiliation: Institute of Human Genetics, University Hospital of Jena, 07743 Jena, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bartsch
authors.affiliation: Department of Pediatrics, General Hospital of Celle, 29221 Celle, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Grüning
authors.affiliation: Department of Neuropediatrics, University Children's Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lücke
authors.affiliation: Institute of Human Genetics, University Hospital of Jena, 07743 Jena, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Kurth
authors.affiliation: Center of Social Pediatrics and Pediatric Neurology, General Hospital of Celle, 29221 Celle, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Riedel
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D003241:Consanguinity; D004827:Epilepsy / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree
chemical_list: C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase
keywords: Alpha amino adipic semialdehyde dehydrogenase deficiency; Catalytic domain; Developmental delay; NAD+ binding domain; Pyridoxine dependent epilepsy