6533b861fe1ef96bd12c4440
RESEARCH PRODUCT
PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation
Viorica ChelbanMatthew P. WilsonJodi Warman ChardonJana VandrovcovaM. Natalia ZanettiEleni Zamba‐papanicolaouStephanie EfthymiouSimon PopeMaria R. ConteGiancarlo AbisYo‐tsen LiuEloise TribolletNourelhoda A. HaridyJuan A. BotíaMina RytenPaschalis NicolaouAnna MinaidouKyproula ChristodoulouKristin D. KernohanAlison EatonMatthew OsmondYoko ItoPierre BourqueJames E. C. JepsonOscar BelloFion BremnerCarla CordivariMary M. ReillyMartha FoianiAmanda HeslegraveHenrik ZetterbergSimon J. R. HealesNicholas W. WoodJames E. RothmanKym M. BoycottPhilippa B. MillsPeter T. ClaytonHenry HouldenYamna KriouileMohamed El KhorassaniMhammed AguennouzStanislav GroppaBlagovesta Marinova KarashovaLionel Van MaldergemWolfgang NachbauerSylvia BoeschLarissa ArningDagmar TimmannBru CormandBelen Pérez‐dueñasGabriella Di RosaJatinder S. GorayaTipu SultanJun MineDaniela AvdjievaHadil KathomRadka TinchevaSelina BanuMercedes Pineda‐marfaPierangelo VeggiottiMichel D. FerrariArn M J M Van Den MaagdenbergAlberto VerrottiGiangluigi MarsegliaSalvatore SavastaMayte García‐silvaAlfons Macaya RuizBarbara GaravagliaEugenia BorgioneSimona PortaroBenigno Monteagudo SanchezRichard BolesSavvas PapacostasMichail VikelisJames RothmanPaola GiuntiHenry HouldenViorica ChelbanVincenzo SalpietroEmer OconnorStephanie EfthymiouDimitri KullmannRauan KaiyrzhanovRoisin SullivanAlaa Matooq KhanWai Yan YauIsabel HostettlerEleni Zamba PapanicolaouEfthymios DardiotisShazia MaqboolShahnaz IbrahimSalman KirmaniNuzhat Noureen RanaOsama AtawnehShen‐yang LimFarooq ShaikhGeorge KoutsisMarianthi BrezaSalvatore ManganoCarmela ScuderiEugenia BorgioneGiovanna MorelloTanya StojkovicErin TortiMassimi ZolloGali HeimerYves A. DauvilliersPasquale StrianoIssam Al‐khawajaFuad Al‐mutairiFowzan S AlkurayaHamed SherifaMie RizigNjideka U. OkubadejoOluwadamilola O. OjoOlajumoke O. OshinaikeKolawole WahabAbiodun H. BelloSanni AbubakarYahaya ObiaboErnest NwazorOluchi EkenzeUduak WilliamsAlagoma IyagbaLolade TaiwoMorenikeji KomolafeOlapeju OguntundeSofya PchelinaKonstantin SenkevichNourelhoda HaridyChingiz ShashkinNazira ZharkynbekovaKairgali KoneyevGanieva ManizhaMaksud IsrofilovUlviyya GuliyevaKamran SalayevSamson KhachatryanSalvatore RossiGabriella SilvestriThomas BourinarisGeorgia XiromerisiouLiana FidaniCleanthe SpanakiArianna Tuccisubject
0301 basic medicineMale[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/NeurobiologyLOCAL TRANSLATIONMedizinmedicine.disease_causeDISEASEchemistry.chemical_compound0302 clinical medicinepolineuropathyCinètica enzimàticaGene Regulatory NetworksPyridoxal phosphateChildPyridoxal KinaseAdenosine triphosphate (ATP)Research ArticlesAged 80 and overMutationGene Regulatory NetworkPLASMAAutosomal recessive axonal polyneuropathyDisease gene identificationPyridoxal kinase3. Good healthSettore MED/26 - NEUROLOGIANeuropaties perifèriquesTreatment OutcomePolyneuropathieNeurologyChild PreschoolPyridoxal PhosphateRELIABILITYVitamin B ComplexFemaleLife Sciences & BiomedicinePolyneuropathyHumanResearch ArticleAdultAdolescentPDXKClinical NeurologyCHARCOT-MARIE-TOOTHCHARCOT-MARIE-TOOTH CMT NEUROPATHY SCORE LOCAL TRANSLATION DISEASE RELIABILITY; MECHANISMS DISCOVERY FRAMEWORK KINASE PLASMAMECHANISMS03 medical and health sciencesPolyneuropathiesAtrophy[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN]KINASEmedicineHumansCMT NEUROPATHY SCOREPDXK mutationsPyridoxalDietary SupplementAgedPeripheral neuropathiesScience & Technology[SCCO.NEUR]Cognitive science/NeuroscienceEnzyme kineticsNeurosciencesFRAMEWORKmedicine.diseaseMolecular biology030104 developmental biologychemistryDISCOVERYDietary SupplementsMutationNeurosciences & NeurologyNeurology (clinical)Adenosine triphosphate030217 neurology & neurosurgerydescription
OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240. ispartof: ANNALS OF NEUROLOGY vol:86 issue:2 pages:225-240 ispartof: location:United States status: published
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-07-01 | Annals of Neurology |