title: Carbamoyl phosphate synthetase 1 deficiency in Italy: clinical and genetic findings in a heterogeneous cohort.
abstract: Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder, potentially leading to lethal hyperammonemia. Based on the age of onset, there are two distinct phenotypes: neonatal and late form. The CPS1 enzyme, located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa, is encoded by the CPS1 gene. At present more than 220 clear-cut genetic lesions leading to CPS1D have been reported. As most of them are private mutations diagnosis is complicated. Here we report an overview of the main clinical findings and biochemical and molecular data of 13 CPS1D Italian patients. In two of them, one with the neonatal form and one with the late form, cadaveric auxiliary liver transplant was performed. Mutation analysis in these patients identified 17 genetic lesions, 9 of which were new confirming their "private" nature. Seven of the newly identified mutations were missense/nonsense changes. In order to study their protein level effects, we performed an in silico analysis whose results indicate that the amino acid substitutions occur at evolutionary conserved positions and affect residues necessary for enzyme stability or function.
authors.affiliation: Metabolic and Muscular Unit, Clinic of Paediatric Neurology, Meyer Children's Hospital, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Funghini
authors.forename: J
authors.initials: J
authors.lastname: Thusberg
authors.forename: M
authors.initials: M
authors.lastname: Spada
authors.forename: S
authors.initials: S
authors.lastname: Gasperini
authors.forename: R
authors.initials: R
authors.lastname: Parini
authors.forename: L
authors.initials: L
authors.lastname: Ventura
authors.forename: C
authors.initials: C
authors.lastname: Meli
authors.forename: L
authors.initials: L
authors.lastname: De Cosmo
authors.forename: M
authors.initials: M
authors.lastname: Sibilio
authors.forename: S D
authors.initials: SD
authors.lastname: Mooney
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: M A
authors.initials: MA
authors.lastname: Donati
authors.forename: A
authors.initials: A
authors.lastname: Morrone
mesh_terms: D000293:Adolescent; D000328:Adult; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D020165:Carbamoyl-Phosphate Synthase I Deficiency Disease / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D009154:Mutation
chemical_list: D002222:Carbamoyl-Phosphate Synthase (Ammonia)