Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.
JAMA Neurol. 2018-04-01; 75(4): 495
DOI: 10.1001/jamaneurol.2017.4373
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1. JAMA Neurol. 2018 Apr 1;75(4):495-502. doi: 10.1001/jamaneurol.2017.4373.
Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype
Correlations of Ataxia With Oculomotor Apraxia Type 1.
Renaud M(1)(2)(3), Moreira MC(2), Ben Monga B(4), Rodriguez D(5)(6)(7)(8), Debs
R(9), Charles P(9), Chaouch M(10), Ferrat F(11), Laurencin C(12)(13), Vercueil
L(14)(15), Mallaret M(14), M’Zahem A(16), Pacha LA(17), Tazir M(17), Tilikete
C(18), Ollagnon E(19), Ochsner F(20), Kuntzer T(20), Jung HH(21), Beis JM(22),
Netter JC(23), Djamshidian A(24), Bower M(25), Bottani A(26), Walsh R(27)(28),
Murphy S(28), Reiley T(29), Bieth É(30), Roelens F(31), Poll-The BT(32), Lourenço
CM(33), Jardim LB(34), Straussberg R(35)(36), Landrieu P(37), Roze E(9), Thobois
S(12)(13), Pouget J(38), Guissart C(39), Goizet C(40)(41), Dürr A(9), Tranchant
C(1)(2)(3), Koenig M(39), Anheim M(1)(2)(3).
Author information:
(1)Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg,
France.
(2)Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut
National de la Santé et de la Recherche Medicale (INSERM)-U964, Centre National
de la Recherche Scientifique (CNRS)-Unité Mixte de Recherché (UMR) 7104,
Université de Strasbourg, Illkirch, France.
(3)Fédération de Médecine Translationnelle de Strasbourg, Université de
Strasbourg, Strasbourg, France.
(4)Faculté de Médecine et Ecole de Santé Publique, Université de Lubumbashi,
Lubumbashi, République Démocratique du Congo.
(5)Service de Neuropédiatrie, Hôpital d’Enfants Armand-Trousseau, Paris, France.
(6)Centre de Référence de Neurogénétique, Hôpital Armand-Trousseau, Hôpitaux
Universitaires Est Parisien, Assistance Publique-Hôpitaux de Paris, Paris,
France.
(7)Groupe de Recherch Clinique ConCer-LD, Sorbonne Universités, l’Université
Pierre-et-Marie-Curie, Université Paris 06, Paris, France.
(8)Neuroprotection du Cerveau en Développement, INSERM U1141, Paris, France.
(9)Département de Génétique, Hôpital de La Pitié-Salpétrière, Paris, France.
(10)Service de Neurologie, Etablissement Hospitalier Spécialisé, Algers, Algeria.
(11)Service de Neurologie, Etablissement Hospitalier Spécialisé de Ben Aknoun,
Algers, Algeria.
(12)Service de Neurologie C, Hopital Neurologique, Hospices Civils de Lyon,
Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
(13)CNRS, Institut des Sciences Cognitives, UMR 5229, Bron, France.
(14)Exploration Fonctionnelle du Système Nerveux, Pôle de Psychiatrie, Neurologie
et Rééducation Neurologique, Centre Hospitalier Universitaire (CHU) Grenoble,
Grenoble, France.
(15)INSERM U836, Grenoble Institut des Neurosciences, Bâtiment Edmond J. Safra,
Chemin Fortuné Ferrini, La Tronche, France.
(16)Service de Neurologie, CHU Constantine, Constantine, Algeria.
(17)Service de Neurologie, CHU Mustapha, Algers, Algeria.
(18)Service de Neuro-ophtalmologie, Hôpital Neurologique, CHU Lyon, Bron, France.
(19)Service de Génétique et Neurogénétique, CHU Lyon, Lyon, France.
(20)Service de Neurologie, CHU Lausanne, Lausanne, Suisse.
(21)Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
(22)Institut Régional de Médecine Physique et de Réadaptation, Centre de
Lay-Saint-Christophe, France.
(23)Service de Pédiatrie, Centre Hospitalier de Bigorre, Tarbes, France.
(24)Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
(25)Department of Neurology, University of Minnesota Health, Minneapolis,
Minnesota.
(26)Service de Génétique, Hôpitaux Universitaires de Genève, Genève, Suisse.
(27)Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland.
(28)National Ataxia Clinic, Adelaide and Meath Hospital Dublin, National
Children’s Hospital, Dublin, Ireland.
(29)Department of Public Health and Environment, Greeley, Colorado.
(30)Service de Génétique Médicale, Hopital Purpan, Toulouse, France.
(31)Pediatric Neurology, AZ Delta, Roeselare, Belgium.
(32)Pediatric Neurology, Emma Children’s Hospital, University of Amsterdam,
Amsterdam, the Netherlands.
(33)Neurogenetics Unit, School of Medicine of Ribeirao Preto, University of São
Paulo, São Paulo, Brazil.
(34)Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Universidade
Federal do Rio Grande do Sul, Porto Alegre, Brazil.
(35)Neurogenetics Clinic, Department of Child Neurology, Schneider Children’s
Medical Center of Israel, Petach Tikva, Israel.
(36)Sackler School of Medicine Tel Aviv University, Ramat Aviv, Israel.
(37)Service de Neurologie Pédiatrique, Hôpital Bicêtre, Paris, France.
(38)Service de Neurologie, Hôpital de la Timone, Marseille, France.
(39)Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de
Recherche Clinique, Université de Montpellier, CHU Montpellier, Montpellier,
France.
(40)Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
(41)INSERM U1211, Laboratoire Maladies Rares Génétique et Métabolisme, Université
de Bordeaux, Bordeaux, France.
Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal
recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is
characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor
neuropathy, and eventual decrease of albumin serum levels.
Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1
and provide genotype-phenotype correlations.
Design, Setting, and Participants: This retrospective analysis included the
clinical, biological (especially regarding biomarkers of the disease),
electrophysiologic, imaging, and molecular data of all patients consecutively
diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through
December 31, 2014. Data were analyzed from January 1, 2015, through January 31,
2016.
Main Outcomes and Measures: The clinical, biological, and molecular spectrum of
AOA1 and genotype-phenotype correlations.
Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34
women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including
57 new (with 8 new mutations) and 23 previously described patients. Elevated
levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia,
in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range,
1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2
ng/mL; P