The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and <i>APTX</i> human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1).
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).
Mutations in TDP1 and APTX have been linked to Spinocerebellar ataxia with axonal neuropathy (SCAN1) and Ataxia-ocular motor apraxia 1 (AOA1), respectively, while mutations in PNKP are considered to be responsible for Microcephaly with seizures (MCSZ) and Ataxia-ocular motor apraxia 4 (AOA4).
Early onset ataxia with ocular motor apraxia and hypoalbuminaemia/ataxia-oculomotor apraxia 1 is a recessively inherited ataxia caused by mutations in the aprataxin gene.
A molecular diagnosis could be established for 57 patients; 36 were affected with FRDA, seven with ataxia plus oculomotor apraxia type 2 (AOA2), four with AT, three with ataxia plus oculomotor apraxia type 1 (AOA1), three with Marinesco-Sjögren syndrome, two with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), one with ataxia with vitamin E deficiency (AVED) and one with autosomal recessive cerebellar ataxia type 2 (ARCA2).
In the present study, we sought to determine possible causative mutations in aprataxin gene (all exons and flanking intronic sequences) in 14 Greek patients with sporadic cerebellar ataxia all but one without GAA expansion in frataxin gene (1 patient was heterozygous).
We genetically screened patients with ataxia with ocular motor apraxia type 1 (AOA1)/early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), with a Japanese variant form of Friedreich's ataxia.
We recently discovered that the pathogenesis involved impaired nuclear import of DNA repair proteins, including DNA ligase I and the cerebellar ataxia causative protein aprataxin.
APTX gene mutations responsible for ataxia-oculomotor apraxia 1 (AOA1) were identified in a family previously reported with ataxia and coenzyme Q10 (CoQ10) deficiency.
In a family with ataxia and CoQ10 deficiency, analysis of genome-wide microsatellite markers suggested linkage of the disease to chromosome 9p13 and led to identification of an aprataxin gene (APTX) mutation that causes ataxia oculomotor apraxia (AOA1 [MIM606350]).
Ataxia and oculomotor apraxia are seen in ataxia-telangiectasia, type 1 ataxia with oculomotor apraxia, and type 2 ataxia with oculomotor apraxia; however, only type 1 ataxia with oculomotor apraxia is associated with aprataxin gene mutation.
The mild presentation allele, APTX-K197Q, associated with ataxia but not oculomotor apraxia, encodes a protein with a mild defect in stability and activity, while enzyme encoded by the atypical presentation allele, APTX-R199H, retained substantial function, consistent with altered and not loss of activity.
It is concluded that autosomal recessive inheritance seems the most likely explanation here, as recent studies have found insertion and missense mutations of the aprataxin gene which have been related to an early onset form of ataxia with ocular motor apraxia and hypoalbuminaemia.
Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia.
Early-onset ataxia with hypoalbuminemia and ataxia with ocular motor apraxia have been considered as the same clinical entity because of the recent identification of a common mutation in the aprataxin gene.
The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal.
We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia.