Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene

Abstract

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…Cells lacking Aprataxin show increased levels of DNA breaks and the human disease characterized by Aprataxin deficiency is associated with progressive cerebellar degeneration, ataxia and oculomotor apraxia. This condition resembles other human diseases caused by deficiency in NHEJ pathway proteins but so far, immune deficiency was not described in these patients 74, 75, 76…”

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

“…For example, the neurologic disorder ataxiatelangiectasia is caused by mutations in ATM, the serine-threonine kinase responsible for coordinating the double-strand break response (51). Similarly, mutations in the single-strand break repair gene aprataxin (APTX) cause one of the most common forms of spinocerebellar ataxia, ataxia with oculomotor apraxia 1 (52,53). Notably, despite being germline mutations in ubiquitous DNA damage response genes, both diseases display primarily neurologic deficits, suggesting a particular sensitivity of the nervous system to defects in the DNA damage response.…”

CoQ10 deficiency diseases in adults

“…In addition, seizures in the affected sister disappeared on CoQ 10 therapy and her anti-convulsant medication was discontinued (Musumeci et al, 2001). In these 3 patients, we demonstrated that CoQ 10 deficiency was secondary to a stop codon mutation in the APTX gene, which is known to cause ataxia-oculomotor-aprataxia 1 (AOA1) (Quinzii et al, 2005,Date et al, 2001Moreira et al, 2001). Results from measuring CoQ 10 concentration in skeletal muscle from 12 additional patients from 6 different families with AOA1 confirmed this data (data not published).…”