Cerebellum and walking
It took David about 6 years to learn how to stand and walk. Even then, he was very unstable. I remember, if he was standing in a room and the lights went out, he would simply fall over. His balance was totally dependent on vision. He had not yet learned to use inner ears and ankle joint position sense to maintain balance. That is what the cerebellum does. It brings together the three senses involved in balance and makes rapid adjustments to our posture. Not many animals are upright walkers and most of the other ones are birds. They have wings! There is no doubt that David has problems with proper functioning of his cerebellum (including seizures associated with the cerebellum), but he did, eventually, learn to walk.
Cerebellar ataxia 10 (SCA10) and the ATXN10 gene
Ataxia is poor coordination, usually associated with walking. Drunken sailors walk with a staggered gait because alcohol affects the cerebellum. There are many different genes that can severely affect the cerebellum and walking. They produce a group of syndromes called “spinocerebellar ataxia” or SCA. Different genes cause different SCAs, each with its own characteristic phenotype. Mutations on the ATXN10 gene leads to SCA10 (Zu et al., 1999). These patients have ataxia (poor gait), dysarthria (poor speech) and nystagmus (poor eye control). These are all cerebellar functions. Many individuals also have seizures. The condition is inherited and found primarily in Latin American families (Teive and Ashizawa, 2014). The disease has a late onset (age 25 to 45) and starts out slowly. Over time, it can be totally incapacitating.
Half of all individuals with 22q13 deletion syndrome have deletions larger than 5 M base (see my posting “Understanding deletion size“), and they are missing the ATXN10 gene. If I did not know more about SCA10, I would be frightened for David. He is currently between the ages of 25 and 45 and SCA10 is a frightening disease. However, it has been shown that SCA10 is not caused by missing the ATXN10 gene. Only mutations of the gene can cause SCA10 (Karen et al., 2010). These mutations create a defective version of the ATXN10 protein. The defective protein has gained a new function (McFarland and Ashizawa, 2012). This is called a “gain-of-function mutation”. Don’t be fooled. In this case, gain-of-function is a bad thing. The new function kills the Purkinje neurons in the cerebellum (Xia et al., 2013).
About 50% of people with 22q13 deletion syndrome are missing the ATXN10 gene. The impact of missing this gene has never been studied on our children, but right now it looks like they are far better off missing the gene than having the special mutation found in families with SCA10.
One interesting related observation comes from the SHANK3 gene. There is a growing body of evidence that SHANK3 mutations may be gain-of-function mutations. Mouse models of SHANK3 mutations suggest that different mutations do very different things. The same is true for humans. There are some normal people walking around with SHANK3 mutations. Other mutations of SHANK3 cause intellectual disability, occasionally with autism. It would be helpful to find a human case where someone is missing all of SHANK3 and no other gene. Then we might know the real impact of missing SHANK3. What we do know is some people with 22q13 deletion syndrome missing SHANK3 are more functional than some people with SHANK3 mutations. That strongly suggests that people with 22q13 deletion syndrome are better off missing the entire SHANK3 gene than having a pathological mutation.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction