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Double trouble: coexistence of fully penetrant CAG repeat expansions in the ATXN3 and ATXN7 genes

RESUMO

Report of Case: A 16-year-old young man presented with a 5-year history of slowly progressive imbalance and visual impairment. On neurological examination there was cerebellar ataxia, loss of visual acuity, macular degeneration, slow saccades, ophthalmoparesis, upper motor neuron signs and mild cognitive impairment. Interestingly, there was a positive medical history of an ataxic disease with male-to-male transmission on both paternal and maternal sides in up to six consecutive generations. 
Brain MRI demonstrated mild cerebellar atrophy. Target analysis for CAG expansions through PCR with fragment analysis detected 59 repeats in the SCA3 gene and 57 repeats in the SCA7 gene.
Discussion: The Spinocerebellar Ataxias are heterogeneous group of autosomal dominant neurodegenerative diseases characterized by progressive cerebellar ataxia, different genetic mutations and frequently associated a further signs and symptoms.
SCA3 is caused by a monoallelic CAG trinucleotide repeat expansion in the gene coding for the cytoplasmic protein ataxin-3 (ATXN3) located on chromosome 14. Normal individuals have up to 44 glutamine repeats and complete penetrance of the disease is commonly seen in individuals with more than 52 repeats. Age of onset usually occurs in the 4th decade of life, and correlated with the CAG repeat size. 
SCA7 is caused by a heterozygous CAG repeat expansion in the gene encoding ataxin-7 (ATXN7) located on chromosome 3. Pathogenic fully penetrant expansions have 37-460 repeats. Disease spectrum may vary from an aggressive early-childhood ataxia with failure to thrive, rapidly deterioration and early death or as a progressive adolescent/adult form. Both forms have visual impairment. As observed in SCA3 there is a correlation between CAG repeat size and disease severity and age of onset. 
Final Comments: The presence of more than one SCA mutation in a single individual is rare. The age of onset, the presence of macular degeneration with visual impairment suggests SCA7 is contributing to his clinical picture. This patient and his family also may provide unique opportunities to study the interactions of two genetic mutations and their effect on clinical expression of disease. Furthermore, finding two genetic mutations in a patient may have important implications regarding counseling on genetic risk, genetic testing, and disease prognosis.

Palavras Chave

SCA3; SCA7; Spinocerebellar Ataxia; cerebellar ataxia; macular degeneration