Submission Details

ATXN2 was first reported in relation to autosomal dominant spinocerebellar ataxia type 2 (SCA2) in 1971 (PMID:5571047). SCA2, due to polyglutamine expansions in ATXN2, is characterized by the onset of gait ataxia often along with muscle cramps. Symptoms frequently are reflective of cerebellar neurodegeneration including appendicular ataxia, stance instability and dysarthria (Scoles and Pulst, PMID: 29427103). However, patients often present with symptoms reflective of neurodegneration to other brain areas including the oculomotor brainstem, such as slow or absent saccades, and can present with frontal-executive dysfunction. Polyglutamine expansions in ATXN2 are also a risk factor for the development of autosomal dominant ALS and late onset autosomal dominant Parkinsons disease. ALS is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, while Parkinsons disease is a neurodegenerative disorder characterized by shaking, stiffness, and difficulty with balance and coordination, brought about by the loss of dopaminergic neruons in the substantia nigra. The size of the expansion and whether the expansion is interrupted may impact disease presentation and onset. Full expansion of the CAG repeat (>33) is a known cause of SCA2, while an intermediate expansion (between 27 and 33) has been associated with risk for ALS, though full CAG repeat expansions in ATXN2 can also occur in rare cases of ALS. Furthermore, co-existence of SCA2 and ALS with full CAG repeat expansions in ATXN2 has been observed within a family. Given the overlap in genetic variation and the co-occurrence of ALS in individuals and in families, the ALS GCEP determined that ALS, due to CAG repeats >33, would be considered as part of the SCA2 disease spectrum. These ALS cases have been lumped into the curation for SCA2, contributing 3 points to genetic evidence. A total of 12.5 points of genetic evidence were scored through 25 probands from 12 publications (PMIDs: 21307863, 18499737, 20235484, 22700602, 33284045, 17715286, 21537950, 21562247, 21610160, 21670397, 23959108, 24718895) and a summed LOD score of 6.81, although many more probands exist in the literature. Experimentally, this gene-disease relationship is supported by biochemical function including evidence that polyglutamine expansions cause protein misfolding and purkinje cell death in patients with SCA2 (PMID: 29427103). Additionally, experimental evidence is supported by two mouse models with mice expressing separate length repeat expansions. Both mouse models recapitulated core features of SCA2 including severe motor deficits and neuron degeneration and death (PMID: 31376479, PMID: 10973246). Finally, this gene-disease relationship is supported by protein interaction with FUS, and functional alteration showing increased binding to TDP-43 with larger repeat expansion size more robustly associating with TDP-43 (PMIDs: 20740007, 23172909). In summary, ATXN2 is definitively related to autosomal dominant spinocerebellar ataxia 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. A classification of definitive was approved on 02/16/2024 by the ALS GCEP (SOP version 9).