Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1 | Genetics and Genomics | JAMA Neurology | JAMA Network
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Patient 72

The patient was homozygous for the Ala198Val mutation in the APTX gene at 28 years of age. Dysmetria during the finger-nose test and oculocephalic dissociation (dissociation of eyes-head when looking toward a lateral target) with hypometric saccades during the head movement task were noted.

Patient 76

The patient was heterozygous for the Trp279* and Lys197Gln mutation in the APTX gene at 28 years of age. Cerebellar ataxia at gait and dysmetria during the finger-nose test were noted.

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Original Investigation
April 2018

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1

Author Affiliations
  • 1Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  • 2Institut 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
  • 3Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
  • 4Faculté de Médecine et Ecole de Santé Publique, Université de Lubumbashi, Lubumbashi, République Démocratique du Congo
  • 5Service de Neuropédiatrie, Hôpital d’Enfants Armand-Trousseau, Paris, France
  • 6Centre de Référence de Neurogénétique, Hôpital Armand-Trousseau, Hôpitaux Universitaires Est Parisien, Assistance Publique–Hôpitaux de Paris, Paris, France
  • 7Groupe de Recherch Clinique ConCer-LD, Sorbonne Universités, l’Université Pierre-et-Marie-Curie, Université Paris 06, Paris, France
  • 8Neuroprotection du Cerveau en Développement, INSERM U1141, Paris, France
  • 9Département de Génétique, Hôpital de La Pitié–Salpétrière, Paris, France
  • 10Service de Neurologie, Etablissement Hospitalier Spécialisé, Algers, Algeria
  • 11Service de Neurologie, Etablissement Hospitalier Spécialisé de Ben Aknoun, Algers, Algeria
  • 12Service de Neurologie C, Hopital Neurologique, Hospices Civils de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
  • 13CNRS, Institut des Sciences Cognitives, UMR 5229, Bron, France
  • 14Exploration Fonctionnelle du Système Nerveux, Pôle de Psychiatrie, Neurologie et Rééducation Neurologique, Centre Hospitalier Universitaire (CHU) Grenoble, Grenoble, France
  • 15INSERM U836, Grenoble Institut des Neurosciences, Bâtiment Edmond J. Safra, Chemin Fortuné Ferrini, La Tronche, France
  • 16Service de Neurologie, CHU Constantine, Constantine, Algeria
  • 17Service de Neurologie, CHU Mustapha, Algers, Algeria
  • 18Service de Neuro-ophtalmologie, Hôpital Neurologique, CHU Lyon, Bron, France
  • 19Service de Génétique et Neurogénétique, CHU Lyon, Lyon, France
  • 20Service de Neurologie, CHU Lausanne, Lausanne, Suisse
  • 21Department of Neurology, University Hospital Zurich, Zurich, Switzerland
  • 22Institut Régional de Médecine Physique et de Réadaptation, Centre de Lay-Saint-Christophe, France
  • 23Service de Pédiatrie, Centre Hospitalier de Bigorre, Tarbes, France
  • 24Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
  • 25Department of Neurology, University of Minnesota Health, Minneapolis, Minnesota
  • 26Service de Génétique, Hôpitaux Universitaires de Genève, Genève, Suisse
  • 27Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland
  • 28National Ataxia Clinic, Adelaide and Meath Hospital Dublin, National Children’s Hospital, Dublin, Ireland
  • 29Department of Public Health and Environment, Greeley, Colorado
  • 30Service de Génétique Médicale, Hopital Purpan, Toulouse, France
  • 31Pediatric Neurology, AZ Delta, Roeselare, Belgium
  • 32Pediatric Neurology, Emma Children’s Hospital, University of Amsterdam, Amsterdam, the Netherlands
  • 33Neurogenetics Unit, School of Medicine of Ribeirao Preto, University of São Paulo, São Paulo, Brazil
  • 34Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
  • 35Neurogenetics Clinic, Department of Child Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
  • 36Sackler School of Medicine Tel Aviv University, Ramat Aviv, Israel
  • 37Service de Neurologie Pédiatrique, Hôpital Bicêtre, Paris, France
  • 38Service de Neurologie, Hôpital de la Timone, Marseille, France
  • 39Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, CHU Montpellier, Montpellier, France
  • 40Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France
  • 41INSERM U1211, Laboratoire Maladies Rares Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
JAMA Neurol. 2018;75(4):495-502. doi:10.1001/jamaneurol.2017.4373
Key Points

Questions  What are the clinical, biomarker, and molecular delineations and genotype-phenotype correlations of ataxia with oculomotor apraxia type 1?

Findings  In this analysis of 80 patients with ataxia with oculomotor apraxia type 1, levels of α-fetoprotein were slightly elevated. The p.Trp279* mutation was the most frequent APTX mutation in the white population.

Meaning  Increased α-fetoprotein levels may constitute a new biomarker of ataxia with oculomotor apraxia type 1, and oculomotor apraxia may be correlated with more severe disease.


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 < .01). Decreased albumin levels (ρ = −0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).

Conclusions and Relevance  The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.