Successful teamwork between Neurology and Human Genetics leads to identification of two new ataxia genes

19 September 2018

Thanks to close cooperation between Bart van de Warrenburg (Neurology) and Erik-Jan Kamsteeg (Genetics) two new genes involved in movement disorders were identified. The genes are relevant for autosomal recessive cerebellar ataxia. They published their findings with their co-workers in Brain and Annals of Neurology.

The genes, previously not associated with human disease, were identified via clinical exome sequencing in patients that visited the Radboudumc expert centre for genetic movement disorders. Mutations in VPS13D were identified in 4 patients and an additional 8 patients were tracked by US and German collaborators.
This gene, which acts within the mitochondrial pathway, is probably a relevant gene for patients with movement disorders. While the Nijmegen patients showed features within the ataxia and spasticity spectrum, a back-to-back publication reported on a series of patients with hyperkinetic movement disorders caused by VPS13D mutations.

Cellular stress

Mutations in the second gene, GDAP2, were identified in a patient with a new ataxia phenotype. A second patient with this rare form of ataxia was found by Belgian partners in the E-rare/H2020 consortium PREPARE. Ilse Eidhof, PhD student in the Drosophila models of brain disorders group led by Annette Schenck, demonstrated that GDAP2 mutations lead to motor defects and reduced lifespan in Drosophila, resembling hallmarks of the human disorder. This work further suggested that GDAP2 pathology may result from altered responses to cellular stress.

Link to full publications:
Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects, Annals of neurology.
GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia, Brain.
 

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