Article

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 alpha-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 (rho = -0.532) and
elevated AFP levels (rho = 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.

Langue : ANGLAIS