Inborn Errors of Metabolism (IEM) are monogenic disorders disrupting biochemical pathways, causing diseases of hormones and metabolism. The brain is particularly sensitive, but any organ can be affected. Many thousand monogenic disease genes remain to be identified, and IEM are ideal targets gene discovery by high-throughput DNA sequencing, as their biochemical nature facilitates identification and validation of functionally relevant gene variants. Many IEM are treatable provided that treatment is initiated before the onset of irreversible damage. We have built a clinical grade system for diagnosis of all known IEM in one step, using exome and genome sequencing and an in-house developed pipeline for coverage calculations, filtering and ranking according to e.g., inheritance model and predicted pathogenicity, gene selection based on clinical presentation, and visualization enabling rapid translation of data into clinically actionable results. Using this system, we are currently transforming clinical diagnostics, with huge gains for affected patients who can now receive correct treatment in earlier disease stages. In patients who remain unexplained, we are discovering novel disease mechanisms by exploring whole exome and genome data.
We characterize novel putative disease genes in detail using three complementary model systems: Drosophila, mouse and reprogrammed patient cells. This is done in collaboration with groups Wredenberg, Larsson and Falk. The aim is to clarify pathogenetic mechanisms, discover biomarkers, and develop novel treatment modalities. We have discovered several novel monogenic diseases that have shed light on normal as well as abnormal brain metabolism. In one case we have been able to translate this knowledge into individualized treatment, reversing the biochemical abnormality and compensating for the genetic defect in a girl with severe brain damage. We have a strong focus on mitochondrial disease. As disturbed mitochondrial function is implicated in many common neurodegenerative diseases, our results have potential implications for larger groups of patients with common disorders.
Henrik Stranneheim, PhD, researcher
Nicole Lesko, PhD, researcher
Michela Barbaro, PhD, researcher
Anna Nordenström, MD, PhD, clinician/researcher
Svetlana Lajic, MD, PhD, clinician/researcher
Martin Engvall, MD, PhD student
Tommy Stödberg, MD, PhD student
Måns Magnusson, PhD student
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