Precision Neuromedicine

We focus on restless legs syndrome (RLS), one of the most common neurological disorders with an age-dependent prevalence of up to 10% in Europe and North America. RLS is characterized by an irresistible urge to move the legs accompanied by disagreeable, painful sensations in the lower limbs at night. As a consequence, patients suffer from severe insomnia resulting in an impairment of quality of life, physical, mental and social health. It is a lifelong disorder with progressive symptoms. RLS can occur as a comorbidity of specific environmental triggers including uremia and pregnancy, and can completely disappear after these environmental conditions resolve (e.g. via kidney transplantation or parturition). However, the causative mechanisms linking genome, environment, and disease manifestation remain to be discovered.

By identifying genetic risk variants for RLS and studying their interactions with environmental risk factors, we aim to deliver starting points for new diagnostic, therapeutic and preventive approaches.

Our research starts directly with the patient in our outpatient clinic at the TUM university hospital Klinikum rechts der Isar, which allows building a well-characterized clinical cohort as well as transfer of new knowledge to affected individuals.

We use genome-wide association studies (GWAS) to identify common genetic risk variants as well as next-generation sequencing (NGS) to search for rare risk variants. We then perform functional follow-up in post-mortem tissue of patients, cellular assays, and animal models in order to decipher the biological basis of disease causation and progression. To achieve our goal of precision medicine for RLS patients, we apply statistical modelling and deep learning algorithms in an attempt to integrate genetic risk scores, environmental factors, and their interactions.

Dystonia:

Dystonia is a hyperkinetic movement disorder characterized by involuntary twisting postures and repetitive movements. By using next-generation sequencing technologies, we aim to uncover the genetic factors contributing to the development of dystonia.

We have characterized novel genetic etiologies for dystonia including KMT2B-, VPS16-, and AOPEP-related syndromes. Moreover, we have established wide international collaborations to assess the monogenic contributions to the disease at scale, elucidating the spectrum of rare disorders underlying dystonia in the pediatric and adult population. We develop prediction tools and scores to provide clinicians with the ability to prioritize affected individuals who will be most likely to benefit from next-generation sequencing-based testing. Currently, we are conducting large-scale whole-genome analyses combined with RNA studies to discover further novel genetic contributors and illuminate the genetic landscape of this debilitating disorder. 

NBIA and NBIA-related metabolic disorders:

Neurodegeneration with brain iron accumulation (NBIA) indicates a group of 15 genetically distinct rare disorders sharing abnormal accumulation of iron in the basal ganglia.

The proteins encoded by these 15 genes take part into various metabolic pathways including lipid metabolism, coenzyme A (CoA) biosynthesis, mitochondrial function, and autophagy. The exact relationship between mutations in these genes, iron accumulation and clinical symptoms is not fully understood. Therefore, there is no specific treatment to slow down or halt disease progression in any of the NBIA subtypes.

We identified pathogenic variants in two NBIA genes, C19orf12 and WDR45, and one NBIA-related gene, PPCS, and established cellular and animal models of the disorders. Currently, we are conducting functional studies to gain insight into the functional consequences of C19orf12, WDR45 and PPCS deficiency and testing therapeutic approaches to produce preclinical data useful for clinical trial readiness

Understanding the mechanisms underlying disease at the levels of molecules, cells, and neuronal circuits is essential for developing more effective therapies for neurological disorders. In particular, neurodevelopmental alterations may already establish disease risk at early life stages. We use molecular and cellular assays to gain insight into disease mechanisms. RNAseq, ATACseq, and ChIPseq on bulk tissue and single cell level are the most relevant functional genomics approaches in our lab. We also generate human organoid and animal models carrying disease-associated genetic variants using CRISPR/Cas9 genome engineering. Moreover, the gene-environment interaction is crucial for disease manifestation and represents a potentially fruitful avenue for prevention strategies. We have a particular focus on modeling changes in internal environment. We also explore lifestyle and nutritional factors which can exacerbate neurological disorders.

Restless legs syndrome and many other neurological disorders are linked to sleep and circadian rhythms. Therefore, we closely collaborate with Dr. Eva Winnebeck, who studies biological rhythms in and around sleep, how these rhythms are influenced by genetics, age and societal timing and to what extent this affects health and well-being. Her current research questions are

· What happens to sleep structure in everyday life when it is challenged by work times, daylight saving time or social jetlag?

· Is a delay in school start times an effective countermeasure to teenage sleep deprivation?
· Why do some travellers suffer from jetlag and others don’t?