Ataxia with Oculomotor Apraxia Type 2: Novel Mutations in Six Patients with Juvenile Age of Onset and Elevated Serum α-Fetoprotein

Abstract

Ataxia with oculomotor apraxia type 2 (AOA2), a neurodegenerative disorder with juvenile to adolescent onset is caused by mutations within the senataxin gene (SETX). We performed molecular analyses in six patients showing clinically an AOA2 phenotype and moderate to significant elevated serum α-fetoprotein levels. Sequencing the 24 coding exons and flanking intronic sequences revealed 11 novel DNA variations, including seven unknown missense mutations, a dinucleotide deletion, a four-nucleotide deletion affecting the 5′ splice site of exon 22 and two sequence variations, which are considered to be polymorphisms. By molecular testing the clinical diagnosis has been confirmed in all patients.

ataxia - AOA2 - α-fetoprotein (AFP) - recessive inheritance

References

• 1 Anheim M, Fleury MC, Franques J. et al . Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families.  Arch Neurol. 2008;  65 958-962
• 2 Arning L, Schöls L, Cin H. et al . Identification and characterisation of a large senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2).  Neurogenetics. 2008;  , [Epub ahead of print]
• 3 Asaka T, Yokoji H, Ito J. et al . Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: Novel mutations in SETX.  Neurology. 2006;  66 1580-1581
• 4 Chen YZ, Hashemi SH, Anderson SK. et al . Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease.  Neurobiology of Disease. 2006;  23 97-108
• 5 Criscuolo C, Chessa L, Di Giandomenico S. et al . Ataxia with oculomotor apraxia type 2. A clinical, pathologic, and genetic study.  Neurology. 2006;  66 1207-1210
• 6 Duquette A, Roddier K, MacNabb-Baltar J. et al . Mutations in Senataxin responsible for Quebec Cluster of Ataxia with Neuropathy.  Ann Neurol. 2005;  57 408-414
• 7 Fogel BL, Perlman S. Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.  Neurology. 2006;  67 2083-2084
• 8 Lynch DR, Braastad CD, Nagan N. Ovarian failure in ataxia with oculomotor apraxia type 2.  Am J Med Genet. 2007;  143A 1775-1777
• 9 Moreira MC, Klur S, Watanabe M. et al . Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.  Nat Genet. 2004;  36 225-227
• 10 Nicolaou P, Georghiou, Votsi C. et al . A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia.  BMC Medical Genetics. 2008;  9 28
• 11 Schöls L, Arning L, Schüle R. et al . “Pseudodominant inheritance”of ataxia with ocular apraxia type 2 (AOA2).  J Neurol. 2008;  255 495-501
• 12 Zühlke C, Bernard V, Gillessen-Kaesbach G. Investigation of recessive ataxia loci in patients with young age of onset.  Neuropediatrics. 2007;  38 207-209

Correspondence