AssessmentsSpinocerebellar ataxia (NORD)
Spinocerebellar ataxia (NORD)
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 36-year-old carpenter comes to his primary care physician for an evaluation of progressive loss of coordination. The patient states that his hands have been increasingly unsteady lately, which causes problems at work. In addition he states that he has been feeling extremely fidgety and overall weak. The patient denies drug or alcohol use. Physical examination shows abnormal eye movements, hyperreflexia and an unsteady gait in addition to irregular spontaneous hand movements. There are no cognitive deficits and physical examination was otherwise normal. Which of the following is the most likely diagnosis?
Spinocerebellar ataxia or SCA refers to a group of rare genetically inherited conditions, caused by mutations in several types of SCA genes.
The cerebellum sits at 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 mutations in the SCA genes, the cerebellum, along with the spinal cord, slowly degenerate.
In fact, many different gene mutations have been identified, each of which is known to cause different types of spinocerebellar ataxia.
The types are described using "SCA" followed by a number, according to their order of identification, so there’s SCA1 through SCA48, with SCA3 being the most common type.
However, in about 40% to 25% of the cases, the causative genes are still unknown.
Now, most of these gene mutations are inherited in an autosomal dominant pattern, meaning that one copy of an altered SCA gene is enough to cause the disease.
Affected individuals have a 50% chance of passing on the altered gene to their 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 in a row.
The specific way in which extra glutamines causes 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 mutated gene, DNA polymerase can basically lose track of which CAG it’s on and accidently add extra CAGs.