Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias
Por:
D. MARTINEZ-RUBIO, I. HINAREJOS, P. SANCHO, N. GORRIA-REDONDO, R. BERNADO-FONZ, C. TELLO, C. MARCO-MARIN, I. MARTI-CARRERA, M. MARTINEZ-GONZALEZ, A. GARCIA-RIBES, R. BAVIERA-MUNOZ, I. SASTRE-BATALLER, I. MARTINEZ-TORRES, A. DUAT-RODRIGUEZ, P. JANEIRO, E. MORENO, L. PIAS-PELETEIRO, M. GORDO, A. RUIZ-GOMEZ, E. MUNOZ, M. MARTI, A. SANCHEZ-MONTEAGUDO, C. FUSTER, A. ANDRES-BORDERIA, R. PONS, S. JESUS-MAESTRE, P. MIR, V. LUPO, B. PEREZ-DUENAS, A. DARLING, S. AGUILERA-ALBESA and C. ESPINOS
Publicada:
1 oct 2022
Resumen:
Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.
Filiaciones:
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Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
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Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
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Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
N. GORRIA-REDONDO:
Hosp Univ Navarra, Dept Paediat, Paediat Neurol Unit, Navarrabiomed, Pamplona 31008, Spain
R. BERNADO-FONZ:
Hosp Univ Navarra, Dept Paediat, Paediat Neurol Unit, Navarrabiomed, Pamplona 31008, Spain
:
Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
C. MARCO-MARIN:
Ctr Invest Biomed Enfermedades Raras CIBERER ISCI, Inst Biomed Valencia IBV, Struct Enzymopathol Unit, Consejo Super Invest Cient CSIC, Valencia 46010, Spain
I. MARTI-CARRERA:
Univ Basque Country UPV EHU, Donostia Univ Hosp, Biodonostia Hlth Res Inst, Dept Paediat,Paediat Grp, San Sebastian 20014, Spain
M. MARTINEZ-GONZALEZ:
Hosp Univ Cruces, Paediat Neurol Unit, Baracaldo 48903, Pais Vasco, Spain
A. GARCIA-RIBES:
Hosp Univ Cruces, Paediat Neurol Unit, Baracaldo 48903, Pais Vasco, Spain
R. BAVIERA-MUNOZ:
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
Hosp Univ & Politecn La Fe, Hlth Res Inst, Valencia 46026, Spain
Hosp Univ & Politecn La Fe, Neurol Dept, Movement Disorders Unit, Valencia 46026, Spain
I. SASTRE-BATALLER:
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
Hosp Univ & Politecn La Fe, Neurol Dept, Movement Disorders Unit, Valencia 46026, Spain
I. MARTINEZ-TORRES:
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
Hosp Univ & Politecn La Fe, Neurol Dept, Movement Disorders Unit, Valencia 46026, Spain
A. DUAT-RODRIGUEZ:
Hosp Infantil Univ Nino Jesus, Paediat Neurol Unit, Madrid 28009, Spain
P. JANEIRO:
Hosp Santa Maria, Ctr Referencia Doencas Hereditarias Metab, CHULN, P-1649035 Lisbon, Portugal
E. MORENO:
Hosp Reg Univ, Dept Paediat, Malaga 29010, Spain
L. PIAS-PELETEIRO:
Hosp St Joan de Deu, Paediat Neurol Unit, Barcelona 08950, Spain
M. GORDO:
Hosp St Joan de Deu, Paediat Neurol Unit, Barcelona 08950, Spain
A. RUIZ-GOMEZ:
Hosp Univ Son Espases, Dept Paediat, Palma De Mallorca 07120, Spain
E. MUNOZ:
Hosp Univ Clin, Dept Neurol, Unit Parkinson & Movement Disorders, Barcelona 08036, Spain
M. MARTI:
Hosp Univ Clin, Dept Neurol, Unit Parkinson & Movement Disorders, Barcelona 08036, Spain
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Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
C. FUSTER:
Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
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Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
R. PONS:
Hosp Agia Sofia, Paediat Neurol, Athens 11527, Greece
S. JESUS-MAESTRE:
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla,CSIC, Movement Disorders Unit,Dept Neurol & Clin Neurop, Seville 41013, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Seville 41013, Spain
P. MIR:
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla,CSIC, Movement Disorders Unit,Dept Neurol & Clin Neurop, Seville 41013, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Seville 41013, Spain
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Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
B. PEREZ-DUENAS:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Dept Paediat Neurol, Barcelona 08035, Spain
A. DARLING:
Hosp St Joan de Deu, Paediat Neurol Unit, Barcelona 08950, Spain
S. AGUILERA-ALBESA:
Hosp Univ Navarra, Dept Paediat, Paediat Neurol Unit, Navarrabiomed, Pamplona 31008, Spain
:
Ctr Invest Principe Felipe CIPF, Rare Neurodegenerat Dis Lab, Valencia 46012, Spain
Joint Unit CIPF IIS La Fe Rare Dis, Valencia 46012, Spain
Univ Catolica Valencia San Vicente Martir, Fac Vet & Expt Sci, Dept Biotechnol, Valencia 46001, Spain
Green Published, gold
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