Studies on a young ataxia patient could guide treatment for a novel condition

A highly collaborative study published in PLoS Genetics has already helped physicians determine a unique treatment plan for an ataxia patient carrying a novel, toxic, gain-of function mutation in a calcium channel gene.  This exciting discovery could potentially become a standard paradigm for treating such patients in the future.

The research surrounding this gene, which is the cause of premature neurodegeneration and muscular incoordination in a young ataxia patients, was conducted in the laboratory ofDr. Michael Wangler at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Baylor College of Medicine.

In this study, physicians and scientists studied a group of five patients with severe early-onset motor incoordination, global developmental and speech delays. Previously, it had been reported that patients with missense variations in the calcium channel gene,CACNA1A, also exhibited similar symptoms. Studies in animal models showed that loss-of-function of cacophony (cac), a gene that encodes for a voltage-gated calcium channel, which transports calcium ions into cells, could be the cause of these clinical symptoms.

Interestingly, in addition to motor and speech deficits, one of the five patients in this study (referred as Patient 1), also exhibited progressive degeneration of the cerebellum, which was not present in the other four patients. Whole exome sequencing of all the five patients and their parents showed that Patient 1 carried a completely different kind of mutation inCACNA1A gene.

To study the functional consequences of this unique variant to neuronal function, researchers in the Wangler lab generated transgenic fruit flies that carried this missense human variant instead of the normal fruit fly version of CACNA1A.

They showed that this toxic gain-of-function mutation was responsible for the massive influx of calcium ions into the neurons of fruit flies, causing damage and destruction. The authors concluded that this mutation is likely also the cause of progressive degeneration of cerebellar neurons observed in Patient 1. 

Responsiveness to a treatment or medication depends on the specific nature of the genetic defect that is being corrected. Typically, patients with loss of calcium channel function respond to acetazolamide to activate calcium channels. As a result of identifying that Patient 1 carries a novel gain-of-function mutation, physicians were able to switch the medication regimen to a drug that blocks calcium channel function.

Researchers are hopeful this study will equip physicians with the knowledge needed to identify the exact mutation in calcium channel gene responsible for ataxia and other symptoms in patients, which will then allow physicians to offer personalized treatment plans.