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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.

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.

Abstract

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.

PMID:
29356829
PMCID:
PMC5933354
DOI:
10.1001/jamaneurol.2017.4373
[Indexed for MEDLINE]
Free PMC Article

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