Spinocerebellar ataxia (NORD)

Spinocerebellar ataxia or SCA refers to a group of rare genetically inherited conditions, caused by variants in several different genes. These variants result in degenerative changes in the cerebellum and often, the spinal cord, which causes progressive problems with coordination and balance, known as ataxia. 

The cerebellum sits in the back of the skull, posterior to the brainstem. Neurons send their axons carrying input from the spinal cord, the brain and the internal ear through the brainstem into the cerebellum. Once there, the cerebellum uses this information to coordinate and plan movement as well as maintain balance. 

So, with variants in the SCA genes, the cerebellum, along with the spinal cord, slowly degenerate. In fact, variants in over 50 different genes have been identified, each of which is known to cause a different type of spinocerebellar ataxia. The types are described using "SCA" followed by a number, according to their order of identification, so there’s SCA1 through SCA51, with SCA1, SCA2, SCA3 and SCA6 being the most common types worldwide. However, in about 25% to 40% of the cases, the causative genes are still unknown. 
 
Now, most of these gene variants are inherited in an autosomal dominant pattern, meaning that one copy of a disease-causing SCA gene variant is enough to cause the disease. Affected individuals have a 50% chance of passing the gene variant to each child, causing that child to have the disease. 
 
In some cases, the involved gene contains a triplet repeat, where the nucleotides C, A, and G are repeated multiple times in a row. And since CAG codes for the amino acid glutamine, the encoded protein will have multiple extra glutamines, or “polyglutamine”, in a row. The specific way in which extra glutamines cause the disease’s symptoms isn’t fully understood, but the abnormal protein seems to aggregate within the neurons of the cerebellum and spinal cord, causing them to die. 

The expanded CAG repeats also affect DNA replication itself. When copying the gene variant, DNA polymerase can basically lose track of which CAG it’s on and accidentally add extra CAGs. This expansion of the originally inherited gene means a child of a parent with the disease can inherit even more CAG repeats than the parent. The higher the number of repeats in the protein, the earlier the age of onset and the more severe the symptoms. 
 
Symptoms vary depending on the type of spinocerebellar ataxia, but usually include poor coordination of hands, speech, walking and eye movements. These symptoms may develop anytime from childhood to late adulthood.