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.
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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Renaud M, Moreira M, Ben Monga B, et al. Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1. JAMA Neurol. 2018;75(4):495–502. doi:10.1001/jamaneurol.2017.4373
What are the clinical, biomarker, and molecular delineations and genotype-phenotype correlations of ataxia with oculomotor apraxia type 1?
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.
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.
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.
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.
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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