Martino L di Salvo1, Mario Mastrangelo2, Isabel Nogués3, Manuela Tolve4, Alessandro Paiardini5, Carla Carducci6, Davide Mei7, Martino Montomoli8, Angela Tramonti9, Renzo Guerrini10, Roberto Contestabile11, Vincenzo Leuzzi12. 1. Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy. Electronic address: martino.disalvo@uniroma1.it. 2. Dipartimento di Pediatria e Neuropsichiatria Infantile, Sapienza Università di Roma, Italy. Electronic address: mario.mastrangelo@uniroma1.it. 3. Istituto di Biologia Ambientale e Forestale, Consiglio Nazionale delle Ricerche, Monterotondo Scalo, Roma, Italy. Electronic address: isabel.nogues@ibaf.cnr.it. 4. Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Italy. 5. Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Italy. Electronic address: alessandro.paiardini@uniroma1.it. 6. Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Italy. Electronic address: carla.carducci@uniroma1.it. 7. Dipartimento di Neuroscienze, Azienda Ospedaliero-Universitaria Meyer, Università di Firenze, Italy. Electronic address: d.mei@meyer.it. 8. Dipartimento di Neuroscienze, Azienda Ospedaliero-Universitaria Meyer, Università di Firenze, Italy. Electronic address: martino.montomoli@meyer.it. 9. Istituto di Biologia e Patologia Molecolari, Consiglio Nazionale delle Ricerche, Roma, Italy. Electronic address: angela.tramonti@uniroma1.it. 10. Dipartimento di Neuroscienze, Azienda Ospedaliero-Universitaria Meyer, Università di Firenze, Italy. Electronic address: renzo.guerrini@meyer.it. 11. Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Italy. Electronic address: roberto.contestabile@uniroma1.it. 12. Dipartimento di Pediatria e Neuropsichiatria Infantile, Sapienza Università di Roma, Italy. Electronic address: vincenzo.leuzzi@uniroma1.it.
Abstract
BACKGROUND: Pyridoxal-5'-phosphate oxidase (PNPO) deficiency presents as a severe neonatal encephalopathy responsive to pyridoxal-5'-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected genetic variants on PNPO gene whose pathogenic role and clinical expression remain to be established. OBJECTIVE: This paper aims to characterize the functional effects of the c.347G>A (p.Arg116Gln) mutation in the PNPO gene in order to define its pathogenicity and describe the clinical features of new patients with epilepsy carrying this mutation. METHODS: Arg116Gln protein variant was expressed as recombinant protein. The mutant protein was characterized with respect to structural and kinetic properties, thermal stability, binding constants of cofactor (FMN) and product (PLP). We also reviewed clinical data of 3 new patients carrying the mutation. RESULTS: The Arg116Gln mutation does not alter the overall enzyme structure and only slightly affects its catalytic efficiency; nevertheless, this mutation affects thermal stability of PNPO, reduces its affinity for FMN and impairs transfer of PLP to PLP-dependent enzymes. Three boys with seizure onset between 8months and 3years of age, carrying the Arg116Gln mutation, are described. These three patients exhibited different seizure types associated with interictal EEG abnormalities and slow background activity. Mild/moderate intellectual disability was observed in 2/3 patients. A dramatic therapeutic response to pyridoxine was observed in the only patient who still had active seizures when starting treatment, while in all three patients interictal EEG discharges and background activity improved after pyridoxine treatment was initiated. CONCLUSIONS: The reported data support a pathogenic role of the c.347G>A (p.Arg116Gln) mutation in PNPO deficiency. The later onset of symptoms and the milder epilepsy phenotype of these expand the disease phenotype.
BACKGROUND:Pyridoxal-5'-phosphate oxidase (PNPO) deficiency presents as a severe neonatal encephalopathy responsive to pyridoxal-5'-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected genetic variants on PNPO gene whose pathogenic role and clinical expression remain to be established. OBJECTIVE: This paper aims to characterize the functional effects of the c.347G>A (p.Arg116Gln) mutation in the PNPO gene in order to define its pathogenicity and describe the clinical features of new patients with epilepsy carrying this mutation. METHODS:Arg116Gln protein variant was expressed as recombinant protein. The mutant protein was characterized with respect to structural and kinetic properties, thermal stability, binding constants of cofactor (FMN) and product (PLP). We also reviewed clinical data of 3 new patients carrying the mutation. RESULTS: The Arg116Gln mutation does not alter the overall enzyme structure and only slightly affects its catalytic efficiency; nevertheless, this mutation affects thermal stability of PNPO, reduces its affinity for FMN and impairs transfer of PLP to PLP-dependent enzymes. Three boys with seizure onset between 8months and 3years of age, carrying the Arg116Gln mutation, are described. These three patients exhibited different seizure types associated with interictal EEG abnormalities and slow background activity. Mild/moderate intellectual disability was observed in 2/3 patients. A dramatic therapeutic response to pyridoxine was observed in the only patient who still had active seizures when starting treatment, while in all three patients interictal EEG discharges and background activity improved after pyridoxine treatment was initiated. CONCLUSIONS: The reported data support a pathogenic role of the c.347G>A (p.Arg116Gln) mutation in PNPO deficiency. The later onset of symptoms and the milder epilepsy phenotype of these expand the disease phenotype.
Authors: Malak Alghamdi; Fahad A Bashiri; Marwa Abdelhakim; Nouran Adly; Dima Z Jamjoom; Khalid M Sumaily; Bandar Alghanem; Stefan T Arold Journal: Clin Genet Date: 2020-09-16 Impact factor: 4.438
Authors: Anna Barile; Philippa Mills; Martino L di Salvo; Claudio Graziani; Victoria Bunik; Peter Clayton; Roberto Contestabile; Angela Tramonti Journal: Int J Mol Sci Date: 2021-11-06 Impact factor: 5.923