Exploring hereditary ataxia and spasticity in the era of whole exome sequencing
25 October 2016
UAntwerpen - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof P. De Jonghe & Prof J. Baets
NEW DATE - PhD defence Katrien Smets - Faculty of Medicine and Health Sciences
Hereditary cerebellar ataxias (HCAs) are a group of neurodegenerative disorders with highly variable phenotypes, characterized by imbalance, progressive gait and limb ataxia, dysarthria and eye disturbances. Autosomal dominant forms are also called spinocerebellar ataxias (SCAs). Hereditary spastic paraparesis (HSP) or spastic paraplegia (SPG) compromises a heterogeneous group of neurodegenerative disorders with spasticity in the lower limbs. Both diseases overlap genetically and clinically. Curative approaches are still lacking.
The general aim of the study is to improve our understanding of the genetic etiology in both disorders. For this purpose we searched for novel genes and strived to delineate the spectrum of HSP and SCA. With the results of the study we want to improve the diagnostic phase in clinical practice and aim to gain a better understanding of the pathways involved. This will be the basis for the development of new treatments.
Part 1 of the thesis, is performed in the pre-genomics era. We unraveled a partial deletion of AFG3L2 in two large Belgian SCA28 families by Linkage analysis and Multiplex Amplicon Quantification. Functional cell-based assays confirmed haploinsufficiency as the disease-causing mechanism.
In part 2, next generation sequencing technology, whole exome sequencing (WES) was introduced, along with a collaborative, web-based software tool, GEnomes Management application, to analyze large genomic datasets. This strategy improved and accelerated largely our genetic diagnosis. We discovered a new glycosphingolipid metabolism gene GBA2 in SPG46 families, this links SPG46 to Gaucher’s disease and its treatment options. Next we reported the first de novo KCND3 mutation, causing severe ion channel dysfunction, in a SCA19/22 patient with a severe and unique early-onset ataxia phenotype. We further demonstrated a neuropathological link between SPG11 and amyotrophic lateral sclerosis and showed existence of abnormal neuronal aggregations in SPG11 brain and spinal cord autopsy. Finally, a clinic-pathophysiologic overlap between SPG48 and lysosomal storage disorders is seen: AP5Z1 patients have parkinsonism on top of the ataxia and exhibit abnormal lysosomal multilamellar storage on skin fibroblasts.
With the explosion of new discoveries in HSP and SCA, by the use of WES, we understand now that the genetic and phenotypic spectrum of HSP and SCA is one broad continuum with other neurodegenerative diseases. In the light of these findings we have a door open to more genetic diagnoses and new treatments based on the shared physiopathology and biology itself.