Classification and diagnostic approach of IEM affecting the synthesis and remodelling of complex lipids

They involve central and peripheral nervous system, (upper and/or lower motoneuron degeneration, spastic paraplegia, neurodegeneration with brain iron accumulation), heart and muscle (myopathies, recurrent myoglobinuria), eye (retinitis pigmentosa), skin (Ichthyosis), bone (chondrodysplasias), liver, immune system, etc. This course presents a first tentative overview of this new group of IEM and more broadly provides an update on other IEM involving complex lipids, namely very long chain fatty acids, plasmalogens, phosphatidylinositides, dolichol and glycolipids linked to congenital disorders of lipid glycosylation and dystroglycanopathies. Because of the implication of several cellular compartments, this new group of disorders affecting the synthesis and remodelling of complex molecules challenges our current classification of IEM still largely based on cellular organelles – i.e. mitochondrial, lysosomal, peroxisomal disorders. While most of these new disorders have been identified by next generation sequencing, this course emphasizes the promising role of lipidomics in deciphering their pathophysiology and identifying therapeutic targets.

Target audience:

Already trained metabolic physicians and clinical biochemists, geneticists, pediatric and adult neurologists and paediatricians.

LEARNING OBJECTIVES

• To discover a new group of inherited metabolic diseases (IEM) :the Inborn errors of the synthesis and remodelling of complex lipids.
• To learn the biochemical and clinical classification of these disorders : IEM of Glycerolipids (triglycerides), Glycero phospholipids, Ether phospholipids (plasmalogens), Phosphatidylinositides, Sphingolipids, Isoprenoids (oxysterols, dolichol, coenzyme Q), Glycolipids, Complex long chain and very long chain fatty acids and eicosanoids derived from arachidonic acid.
• To learn about the phosphatydyl inositol pathway and the relevance of the different related molecules in cell division, immunity, cancer and signaling.
• To study the synthesis of lipid linked oligosacharides (LLOs) and understand the significance of this complex molecule in glycosylation and how LLOs are used in diagnostics.
• To understand the basis of dystroglycanopathies due to dolichol related defects, review the links between different cell compartments and see how mannose links the different pathways to each other.
• To challenge the current classification of IEM based on cellular organelles.
• To learn the clinical presentations focusing on central and peripheral nervous system (many neurodegenerative disorders), muscular, orthopedic, skin, eye, inflammatory, visceral and multisystemic presentations.
• To diagnose these disorders using biochemical screening tests and molecular technics.
• To discover lipidomics, a new methodology able to identify > 1000 molecules in biological fluids (plasma, urine, CSF, cultured fibroblasts).

Provider organisations: 

LA PITIE-SALPETRIERE HOSPITAL, PIERRE ET MARIE CURIE UNIVERSITY PARIS VI

The Pitié-Salêtrière is the largest hospital in France with over 1600 beds and 171 ambulatory beds. The hospital has a long history which originates from a “bureau of poverty” created in 1544 to keep beggars from the streets of Paris and in 1612, Marie de Medicis created the hospice “Notre Dame de la Pitié” to host the poor. Later, through the eminent Dr. Philippe Pinel, the Salpêtrière became world famous as a psychiatric centre. A century later, Jean-Martin Charcot was credited as the founder of modern neurology. The Pitié-Salpêtrière is now one of the biggest university hospitals in Europe, with departments focusing on most major medical specialties and research. Neurology and psychiatry are well represented through the «Brain and Spinal Cord institute”, constructed in 2010, is a major neurological and psychiatric research centre. The department of neurology has developed a unit dedicated to neurological aspects of inherited metabolic diseases. This neurometabolic unit has four main goals: 1) to care for patients previously managed in paediatric metabolic centres 2) to diagnose late onset forms of IEM, 3) to develop teaching and 4) to develop research in metabolic aspects of nervous system diseases. The hospital has an academic partnership with Pierre and Marie Curie School of Medicine (University Paris VI).

UNIVERSITY CHILDREN’S HOSPITAL, ZURICH

The University Children’s Hospital in Zurich is not only the largest paediatric clinic in Switzerland but also one of the leading centres for paediatric and youth medicine in Europe. Which is why patients come from all corners of Switzerland and abroad. Besides undertaking the normal tasks of a university hospital, we also train doctors to become specialists in their field. Therefore our children’s hospital houses the first and as yet only research centre in Switzerland that is solely dedicated to paediatric research.

Areas of specialisation: the University Children’s Hospital Zurich is the largest pediatric centre for many services including heart problems, bone marrow transplant and burns. With our comprehensive service range of 32 medical sub-specialisations, we are on par with the largest children’s clinics in the world. In fact, our medical and surgical clinic’s service range is typical of larger university hospitals.

ACADEMIC MEDICAL CENTER, UNIVERSITY OF AMSTERDAM

The Academic Medical Center (AMC) was founded in 1983, when two hospitals from the Amsterdam city centre, the Wilhelmina Gasthuis and the Binnengasthuis, merged with the medical faculty of the University of Amsterdam. Five years later, the Emma Children’s Hospital also became a part of the new university hospital. The AMC is one of the eight university medical centres in the Netherlands and has metabolic disorders as one of its core areas of research and patient care. In the area of metabolic diseases, research concentrates on unravelling illness attributed to fundamental defects in metabolism, growth and differentiation. In 2008, the Amsterdam Lysosome Center, Sphinx, was launched within the AMC. Already designated as a national centre for evaluation and treatment of LSDs, the innovative translational research in SPHINX involves participation in international clinical trials with new therapeutic agents (small compounds, plant-produced recombinant enzymes) and application of new treatment modalities (bone marrow transplantation, chaperone therapy). The laboratory for Genetic Metabolic Diseases at the AMC is well known for its combined diagnostic and research facilities with different sections for Metabolite, Enzyme and DNA analysis.