FXTAS is a very common tremor/ataxia syndrome, which is newly described (as of 2001). It is a late-onset disorder, typically beginning in the 60's or 70's, with involvement of multiple systems -- gait ataxia, intention tremor, peripheral neuropathy, autonomic dysturbance, and sometimes dementia. It seems to be more of a diffuse neurological degeneration rather than a specific cerebellar ataxia.
FXTAS may affect as many as 1/3000 men over the age of 50. (Hall et al, 2005). About 3% of persons being tested for hereditary cerebellar disorders are positive for FXTAS. Some say it is the most common inherited ataxia, others say Friedreich's ataxia (1/50,000) is the most common (Wallace and Bird, 2018). It seems to us that if you half the frequency to account for women to 1/6000, from these #'s it should still be 10 times more common than Friedreichs.
Robinson et al (2020) recently described pathology in a single case. They state that "Microscopically, typical p62-postive intranuclear inclusions were present in all the regions examined. ". And "The molecular, Purkinje's cell, and granule cell layers of the cerebellar folia demonstrated mild gliosis, and cerebellar white matter was mildly affected. ". This patient seemed to have a diffuse injury to the brain, rather than a focal injury to the cerebellum.
This is a diagnosis to consider in men with ataxia and tremor. MRI shows atrophy, white matter changes in the corpus callosum, and distinctive T2 hyperintensities in the middle cerebellar peduncles. There are three phenotypes -- essential tremor like (35%), cerebellar (29%), and parkinsonian (12%)
There are almost no reports about oculomotor findings (i.e. nystagmus), suggesting that this disease causes ataxia without most of the expected signs of cerebellar damage. As the saying goes, everything with feathers and that quacks is not necessarily a duck.
Very few people are tested because there is no treatment. This is similar to the situation with all other inherited ataxias. According to Wallace and Bird (2018), specific treatments are available for only a few of the hereditary ataxias, including vit-E deficiency, Refsum disease, cerebrotendinous xanthomatosis, and CoQ10. This is not much considering the 100-300 ataxia disorders that these authors discuss as of 2018.
FXTAS is an X-linked disorder. There are 55-200 CGG repeat expansions in the FMR1 gene. Full mutations cause the Fragile X syndrome, which is much more severe.
Males transmit this gene to all of their daughters. Thus the inheritance pattern of the disease itself goes from father->daughter->male children. Female carriers (the daughters) have a 50% chance of transmitting the gene to each child (male or female).
Proposed criteria for genetic testing for (FMR1) are:
|High signal seen in both middle cerebellar peduncles in person with Fragile X associated tremor ataxia.|
Practically, very few people pay out of pocket for genetic testing, because there is no direct benefit to them for doing this. Insurance companies also seem to be reluctant to pay for academic activities.
There is no treatment, but genetic counseling may be helpful. For example, daughters of a man with FXTAS may benefit from the knowledge that they are a carrier, and that 50% of their male offspring may have FXTAS. Similarly, 50% of their female offspring may be carriers.
We expect that in the future, gene editing technology may evolve to the extent that these FXTAS can be treated.