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

Mathilde Renaud 1 Maria-Ceu Moreira 2 Bondo Ben Monga Diana Rodriguez 3 Rabab Debs 4 Perrine Charles 5 Malika Chaouch 6 Farida Ferrat 6 Chloé Laurencin 7 Laurent Vercueil 8 Martial Mallaret 1 Abderrahim M’zahem Lamia Ali Pacha Meriem Tazir 9 Caroline Tilikete 10 Elisabeth Ollagnon 11 François Ochsner Thierry Kuntzer 12 Hans Jung Jean-Marie Beis 13 Jean-Claude Netter Atbin Djamshidian Mattew Bower Armand Bottani 14 Richard Walsh Sinead Murphy 15 Thomas Reiley Eric Bieth 16 Filip Roelens Bwee Tien Poll-The 17 Charles Marques Lourenço Laura Bannach Jardim Rachel Straussberg Pierre Landrieu 18 Emmanuel Roze 19 Stéphane Thobois 7 Jean Pouget 20 Claire Guissart 21 Cyril Goizet 22 Alexandra Durr 19 Christine Tranchant 23 Michel Koenig 21, 24 Mathieu Anheim 1
18 Equipe Inserm U1163 - Molecular and pathophysiological bases of cognitive disorders
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
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.
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Soumis le : mardi 14 janvier 2020 - 13:32:28
Dernière modification le : mardi 1 septembre 2020 - 03:21:39

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Mathilde Renaud, Maria-Ceu Moreira, Bondo Ben Monga, Diana Rodriguez, Rabab Debs, et al.. Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1. JAMA neurology, American Medical Association (imprimé) / 2018, 75 (4), pp.495. ⟨10.1001/jamaneurol.2017.4373⟩. ⟨hal-02438841⟩



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