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

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.

Figure 1.. Position of the Mutations With Respect to the Aprataxin (APTX) Protein Domains

The histidine triad (HIT) motif (HxHxH) is highlighted in green. The deletion, insertion, and splice site mutations are translated into estimated protein consequences. Correspondence for novel mutations (red) is indicated in Table 3; c.544-2A>G (acceptor) and c.770 + 1G>A (donor) exon 5 splice site mutations are estimated to result in frameshift exon 5 skipping p.Val182Profs*12; c.875-1G>A (last) exon 7 acceptor splice site mutation is estimated to result in use of a minor alternative exon 7’ (isoform coded by transcript NM_175069) Ala292Glufs*2. The position of the in-frame exon 4 deletion (Glu162_Gln181del20) is indicated by a double arrow that represents the extent of internal peptide deletion. The large deletion of exons 1 to 4 is not represented because it is estimated to result in complete absence of APTX transcription.

Figure 2.. Levels of α-Fetoprotein (AFP)

Distribution of AFP levels in 102 control individuals (no ataxia), 76 patients with sporadic late-onset cerebellar ataxia (SLOCA), 74 patients with ataxia with oculomotor apraxia type 2 (AOA2) described previously, and 80 patients with AOA1 in our study. The density of points is presented as log of the AFP serum level.