Fatty acid oxidation disorders: risk stratification, disease modifiers and metabolic networks

Fatty acid oxidation disorders: risk stratification, disease modifiers and metabolic networks2020-12-01T12:19:07+01:00

Project Description

Professor Ute Spiekerkötter, MD

Pediatrician and Metabolic specialist
Medical Director and Chair of Pediatrics

E: ute.spiekerkoetter@uniklinik-freiburg.de

T: +49 (0)761 270-43060
F: +49 (0)761 270-44810

Department of Pediatrics and Adolescent Medicine
Medical Center– University of Freiburg
Mathildenstr. 1
79106 Freiburg
Germany

Fatty acid oxidation defects present with heterogeneous phenotypes. An early risk stratification impacts treatment decisions and life style. However, endogenous and external factors highly modify disease. Deciphering the effects of monogenic diseases on metabolic networks elucidates our understanding of pathophysiology in order to identify new treatment targets.

TEAM

RESEARCH THEMES

Fatty acid oxidation disorders are a group of inborn errors of metabolism that either affect the transport of fatty acids or their mitochondrial β-oxidation. As a consequence, fatty acids cannot be used as an appropriate energetic source during prolonged fasting, exercise or other catabolic states. The clinical phenotype is heterogeneous with different organ involvement and asymptomatic presentations since implementation of newborn screening.

Our research has identified how disease phenotypes are modified by life style, sports and diet. Nevertheless, early risk stratification is essential to implement targeted preventive and treatment measures.

Deciphering the effects of monogenic diseases on metabolic networks elucidates our understanding of disease pathophysiology. In fatty acid oxidation disorders, targeted metabolomics has identified endogenous compensatory mechanisms through activation of other energy producing pathways. Metabolomics (including via our metabolomics core facility, MetaboCF) as well as computational modelling in collaboration with the University of Groningen allow the identification of new treatment targets.

Our working group coordinates the new international guideline on the diagnosis and management of long-chain fatty acid oxidation disorders which will be released soon.

CURRENT PROJECTS

PoLiMeR – Polymers in the liver: metabolism and regulation (EU, Horizon 2020, MARIE SKŁODOWSKA-CURIE ACTIONS)

The focus of the project within the International PoLiMeR consortium is the biopolymer metabolism in monogenetic diseases of energy metabolism. In mouse and cell models, as in humans, targeted metabolomics and computational modeling are applied in parallel to better understand patient variability in disease severity.

This consortium represents also the first research training initiative in Systems Medicine in Europe.

VLCAD-/- mouse

Targeted Metabolomics (Else Kröner research college, NAKSYS)

Within our translational Metabolomics Core Facility at Freiburg University Children’s Hospital we perform metabolomic profiling in genetic kidney diseases in order to identify metabolic fingerprints. This information indicates systemic and secondary effects which determine disease pathology and outcome and points to new treatment targets.

Carnitine transporter deficiency

Carnitine homeostasis in fatty acid oxidation defects is a long-term research topic of our group. Here we investigate carnitine biosynthesis and transport in the CTD mouse with special focus on alternative transporters and alternative energy producing pathways.

Risk stratification

Residual enzyme function and correlation of enzyme function and genotype have the potential to quantify the risk for a symptomatic disease. Our diagnostic algorithms after positive newborn screening for fatty acid oxidation defects serve the purpose of an early clear diagnosis and an early risk assessment to implement a personalized therapy.

d)-In vivo1H MRI: Abdominal fat distribution. From Tucci et al. (2011) AJCN.

 

Body fat composition

Long-term effects of medium-chain triglycerides have been extensively studied in our mouse model of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. In cooperation with the Medical Physics Department at Freiburg University Medical Center we now investigate body fat distribution and composition applying magnetic resonance imaging and spectroscopy in patients with long-chain fatty acid oxidation defects.

SELECTED RECENT PUBLICATIONS

COLLABORATIONS, CO-OPERATIONS AND NETWORKS

Barbara Bakker (PoLiMeR)

Rani Singh (guideline development)

Jerry Vockley (Inform network)

Ronald Wanders (Fatty acid oxidation enzymology and risk stratification)

Silke Wiegand-Grefe, Care-FAM-Net

MetabERN (European Reference Network for Hereditary Metabolic Disorders)

Selbsthilfegruppe für angeborene Fettsäurenoxidationsstörungen Fett-SOS e.V. (Self-help group for people with congenital fatty acid oxidation disorders)

FUNDING

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