The Expanding Spectrum of Ataxia Genetics
Abstracts & Commentary
Sources: Date H, et al. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet. 2001;29:184-188; Moreira MC, et al. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet. 2001;29:189-193.
The genetics of inherited ataxias are a complex and intimidating topic for neurologists. Much attention has been paid in the last 5 years to the autosomal dominant spinocerebellar ataxias (SCAs). At last count, more than 16 different loci have been identified for autosomal dominant SCAs. These disorders are united by several common themes: patients usually present after age 20, and almost all autosomal dominant SCAs occur due to expanded CAG repeats which result in large poly-glutamine insertions in the target protein. In contrast, the autosomal recessive spinocerebellar ataxias are clinically and genetically heterogeneous. They usually present within the first 2 decades of life, although neurologists may encounter patients who present in adulthood.
There are 5 major autosomal recessive SCAs: Friedreich’s ataxia, ataxia with isolated vitamin E deficiency, Unverricht-Lundborg disease, ataxia telangiectasia, and ataxia with oculomotor apraxia. The genes responsible for the first 4 are known: frataxin (Friedrich’s ataxia, chromosome 9), alpha-tocopherol protein (inherited vitamin E deficiency, chromosome 8), cystatin B (Unverricht-Lundborg, chromosome 21), and ATM protein (ataxia telangiectasia, chromosome 11). In the papers to be discussed, 2 scientific groups report their simultaneous discovery of the gene responsible for the fifth autosomal recessive SCA, aprataxin (ataxia with oculomotor apraxia).
Date and colleagues characterized 7 families remarkably similar in their clinical phenotype. Affected patients presented in the first or second decade of life with ataxia, absent deep-tendon reflexes, distal proprioceptive loss, pyramidal leg weakness, and hypoalbuminemia. A lod score of 7.71 (extremely high for genetic recombination) at D9S1845 eventually led to the isolation of the causative gene, named aprataxin. The patients described by Date et al did not have oculomotor apraxia, however, they demonstrated that mutations in aprataxin were responsible for their patients’ phenotype and also 2 families with ataxia with oculomotor apraxia. Insertion or deletion mutations in aprataxin produce more severe phenotypes with earlier age of onset, while missense mutations (which preserve part of the protein’s function) have milder phenotypes.
Simultaneously, Moreira and colleagues isolated the gene for aprataxin and showed that mutations in this gene were responsible for ataxia with oculomotor apraxia in Portugese and Japanese families. They investigated the biology of aprataxin, a novel and intriguing protein. Aprataxin is widely expressed in both neural and non-neural tissues, and it is widely expressed within the brain and spinal cord. Aprataxin’s amino acid sequence suggests that it may be involved in DNA single-strand break repair, reminiscent of another autosomal recessive ataxia, ataxia telangiectasia. The ATM protein (of ataxia telangiectasia) senses DNA double-strand breaks, and patients with ataxia telangiectasia are prone to develop neoplasias. Thus, 2 of the autosomal recessive ataxias have been linked to defects in DNA repair. This suggests that cerebellar neurons are particularly prone to DNA damage.
Commentary
How will these discoveries affect practicing neurologists? Commercial tests are already available for 4 of the autosomal recessive ataxias, and a commercial test for aprataxin mutations will soon follow. Patients with these disorders can now receive a definitive diagnosis, obviating the need for further diagnostic studies. More important, the discovery of these genes allows researchers to design transgenic animal models, which will allow them to test agents that may affect the natural history of these disorders. —Steven Frucht
Dr. Frucht, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, is Assistant Editor of Neurology Alert.
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