Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.
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Renaud Mathilde, Moreira Maria-Céu, Ben Monga Bondo, Rodriguez Diana, Debs Rabab, Charles Perrine, Chaouch Malika, Ferrat Farida, Laurencin Chloé, Vercueil Laurent, Mallaret Martial, M'Zahem Abderrahim, Pacha Lamia Ali, Tazir Meriem, Tilikete Caroline, Ollagnon Elisabeth, Ochsner François, Kuntzer Thierry, Jung Hans H, Beis Jean-Marie, Netter Jean-Claude, Djamshidian Atbin, Bower Mattew, Bottani Armand, Walsh Richard, Murphy Sinead, Reiley Thomas, Bieth Éric, Roelens Filip, Poll-The Bwee Tien, Lourenço Charles Marques, Jardim Laura Bannach, Straussberg Rachel, Landrieu Pierre, Roze Emmanuel, Thobois Stéphane, Pouget Jean, Guissart Claire, Goizet Cyril, Dürr Alexandra, Tranchant Christine, Koenig Michel, Anheim Mathieu
Аннотация
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.