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Novel APTX Mutation in a Hispanic Subject Affected by Ataxia with Oculomotor Apraxia Type 1

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Authors:  Martin Paucar MD, Isabel Alonso PhD, Mats Eriksson MD, PhD, Stanislav Beniaminov MD, Paula Coutinho MD, PhD and Per Svenningsson MD, PhD

Article first published online: 10 DEC 2014 | DOI: 10.1002/mdc3.12112

Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive (AR) disorder caused by mutations in the aprataxin (APTX) gene.[1] The phenotype consists of early-onset progressive cerebellar ataxia, oculomotor apraxia (OMA), and polyneuropathy. Cognitive impairment, dystonia, chorea, hypoalbuminemia, and hypercholesterolemia are common features.[2] AOA1 is the most common AR ataxia disorder in Japan and the second-most common AR ataxia disorder in Portugal after Friedreich's ataxia.[2] AOA1 cases have been described in France, Italy, and Tunisia.[2-5] Recent reports indicate that AOA1 is present in a wide range of ethnic populations.[2, 6-8]However, AOA1 has not been described among Hispanic subjects.


Here, we report on an 18-year-old female subject from Colombia born from consanguineous parents and affected by a complex movement disorder. Disease age at onset was at 7 years, and her earlier development was unremarkable. The subject developed progressive ataxia, dysarthria, tongue biting, and involuntary movements (see Video 1). Areflexia, bilateral foot drop, and muscle wasting are also evident. She was diagnosed with an intellectual disability and has attended a special school. The subject is still able to walk shorter distances using a walker. A neuro-ophthalmic examination found saccadic pursuit, abnormal saccades, and absence of optokinetic nystagmus. Video-oculography showed saccadic intrusions. MRI of her brain displayed progressive and marked cerebellar atrophy. Electroneurography detected a sensorimotor polyneuropathy 4 years ago. Laboratory tests revealed hypercholesterolemia and hypoalbuminemia, and alpha-fetoprotein (AFP) and immunoglobulin levels were normal (Table 1). The subject is on a protein-enriched diet, and her hypercholesterolemia is treated with ezetimibe. Multiplex ligation-dependent probe amplification analysis revealed a large deletion of exon 6 of the APTX gene; both parents are carriers for this new mutation (Figs. 1 and 2). Characterization of the APTXintragenic exon 6 deletion revealed an Alu-mediated mechanism as the responsible for this deletion, supported by a 32-base-pair (bp) microhomology region and 92% identity between two Alu elements.

Table 1. Laboratory abnormalities found in the serum of a young female affected by AOA1
Laboratory Test November 2011 May 2014 Normal Reference Interval
  1. Normal AFP also helps to distinguish this condition from AT and AOA2.

  2. a

    Value after introduction of ezetimibe 10 mg once-daily.

Total cholesterol 5.7 4.4a <5.2 mmol/L
Albumin 33 34 36–48 g/L
AFP 4.2 <6.6 μg/L

Pedigree of the family.Figure 1. Pedigree of the family. The proband is homozygous for the APTXexon 6 deletion (2,256 bp), and both parents are single mutation carriers. The normal allele is 3,421 bp.





Characterization of the APTX intragenic exon 6 deletion found in this study and schematic representation of its breakpoints.Figure 2. Characterization of the APTX intragenic exon 6 deletion found in this study and schematic representation of its breakpoints.

This is the first time a Hispanic subject is reported as affected by AOA1; also novel is the underlying APTX mutation. The phenotype is classical for this condition, except for the lack of OMA, which is observed in up to 86% of cases.[2] Genotype-phenotype correlations in AOA1 can be made to some degree, but some reports yielded contradicting results.[2, 5, 7, 9] Even though the aprataxin protein is involved in DNA repair, there is no evidence indicating cancer predisposition in AOA1.[10] Important clues to AOA1 diagnosis are hypoalbuminemia and hypercholesterolemia. Normal AFP levels distinguish it from ataxia telangiectasia (AT) and AOA2.



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