Research focus

​Many neurodegenerative disorders have a genetic etiology or are complex disorders caused by an interaction between environmental and inherited factors. In our research group we focus on the clinical and genetic aspects of inherited peripheral neuropathies and inherited epilepsy syndromes. The clinical, electrophysiological and neuropathological characterization of patients affected by these disorders forms the starting point for molecular genetic studies. Classical genetic approaches, such as linkage analysis and homozygosity mapping, are performed in extended pedigrees or cohorts of nuclear inbred families, resulting in the mapping of genetic loci and the identification of novel genes. Based on genotype-phenotype studies in homogeneous patient populations, we delineate the range of clinical variables. These observations often provide preliminary insights into the disease mechanisms and help to select specific mutations for additional functional studies. These findings also help to develop algorithms for diagnostic DNA analysis in these disorders, and provide rationales for therapeutic interventions.

Our main research topics are the molecular genetics of peripheral neuropathies, idiopathic epilepsy syndromes, progressive external ophthalmoplegia (PEO) and spastic paraplegias. In the epilepsy project, we demonstrated that de novo mutations in the sodium-channel gene SCN1A are the major cause of severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome), a devastating form of childhood epilepsy. We reported that dominant mutations in the GLUT1, representing the main glucose transported in the human brain, can cause Paroxysmal Exercise-induced Dyskinesia (PED) and early-onset absence epilepsy, thus expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for these clinical syndromes. We identified mutations in GABRG2 and SCN1B in families with generalized epilepsy and febrile seizures plus (GEFS+), and mutations in KCNQ2 in benign familial neonatal convulsions. We mapped novel loci for GEFS+, temporal lobe epilepsy and temporal-occipital lobe epilepsy with migraine. We identified mutations in the ATP1A2 gene in families with migraine and epilepsy. We performed extensive genotype-phenotype correlations in families with known and novel mutations in the dynamin 2 gene, causing Dominant Intermediate Charcot-Marie-Tooth disease type B (DI-CMTB). We identified mutations in the mitochondrial DNA polymerase gamma (POLG) gene as the major cause of PEO. We described additional mutations in Spastin, the gene involved in SPG4, and made genotype-phenotype correlations in a large group of patients with SPG3a. In addition, we are curating the Inherited Peripheral Neuropathies Mutation Database for the European CMT consortium.

Our current focus is on mapping additional loci for inherited peripheral neuropathies and inherited epilepsy syndromes, and on identifying the genes in the newly mapped loci.