Understanding metabolic disease Let s build a restaurant Chris Hendriksz Birmingham Children s Hospital 2006
The Task
Let s build a restaurant! 2 Partners join to draw the plan. How can we change the plan?
Changes Different partners-population screening Change partner-gene manipulation Example repair the defective gene Gene therapy is a long way off Prenatal testing and diagnosis
The Real Future of Biotechnology
Lysosomes Nucleus Mitochondria Enzymes Cytoplasm Golgi & ER
Disease processes Easily get tired-inappropriately!- Energy deficiency Inability to make the enzyme systems work- Multi organ failure Inability to make the transport system work- Poisoning Inability to let the cleaners get on with their work-storage material
What does a restaurant need to function? Power/electricity Food suppliers Staff Suppliers of utensils
Who s hungry Lets go out for a meal The main aim of food is to supply calories Many conditions can be treated by increased energy supply.
Example: MCADD Inability to use certain fats efficiently Especially at risk when unwell Detected by screening or hypoglycaemia.
Medical energy Supplied by 10% Dextrose in drip or other high energy drinks (Maxijule or Polycal or Lucozade or Ribeena original) This is not to prevent only hypoglycaemia but also provide extra energy Oral solutions actually contain more calories than IV Don t forget to check U&E s (Urea and Electrolytes)
Conditions managed with emergency regimes of high energy content Fatty acid oxidation defects like MCADD, LCHADD, CPT2 Glycogen storage disorders Urea cycle defects- OTC, Arginosuccinic aciduria Organic acidemias like Propionic acidaemia
Hypoglycaemia Fasting Glycogen storage disorders Fatty acid oxidation defects GSD1a GSD 1non a GSD 3 SCHAD MCADD LCHADD LCAD CPT1 GSD6 GSD9 Decompensation Fatty acid oxidation defects Organic acideamias Urea cycle defects LCAD LCHAD CPT1 Carnitine defects Propionic acidaemia OTC CPS ASS MMA IVA MCADD GA1
What would you like to eat? Restaurant (Body) finely prepared with lots of finesse or Take away (Emergency plan) high in sugar with lots of unwanted effects. Can t live on this for long!
Enzyme function Chemical scissors Cutting a ribbon Too many long pieces too few short pieces or combination.
Long term dietary manipulation Restrict total protein or fat or carbohydrate content Restrict specific components and replace the deficiencies. Example PKU (Phenylketonuria)
Phenylalanine Phenyl ketones BH 4 PAH Tyrosine Neuro transmitters-dopamine 4-oh-Phenylpyruvate FA Fumarate Aceto acetate
Food suppliers Food provider Specialist dieticians
Conditions with specific restrictions Should be treated in expert centres by specially trained dieticians Needs monitoring and supportive services Conditions like PKU, MSUD, Homocystinuria, LCHAD
Alternative pathway therapy Aim to detoxify or alter pathway Direct detoxification use of carnitine in organic Acidaemias Alternative pathway to detoxify ammonia
Hippurate Phenylacetylglutamate Sodium Benzoate Sodium Phenylbutyrate Dietary protein Amino acids Body protein Transamination Amino nitrogen Carbon skeletons Organic acids Ammonia Urea Non-essential amino acids Energy carniti ne Acyl carnitines
Energy Mitochondria are batteries of cells Natural aging process If damaged all systems may be affected Supercharge batteries with co factors Common co factors are vitamins like Biotin, riboflavin, thiamine, Ubiquinone
Staff Supportive workers Waiters, cleaners, chef etc Peroxysomes, Golgi etc Correct associated abnormalities like hypocalcaemia, acid base
Utensil suppliers Need cutlery Enzymes can be seen as cutlery of body Used to break parts up and their failure cause disease Suppliers of enzymes are liver, bone marrow or external
Change suppliers Liver transplantation for Hyperlipidaemia, urea cycle disorders, liver disease due to illness like Tyrosinaemia Bone marrow transplantation for X-ALD, MPS1H, MLD External enzyme for MPS1, 6,Gaucher, Fabry
Birmingham Children s Hospital Royal Manchester Children s Hospital Great Ormond Street and Evelina Hospitals London
Therapies and outcome Previously very few treatable At present 50% by diet alone Diet plus medication 20% Novel therapies 2% Transplantation 1% Enzyme replacement therapies 5% But 22 % no therapy with early death or significant disability
Long term outcome Early diagnosis- knowledge or screening Available therapies Expertise in field Support in the community
Key Developments in Biotechnology leading to significant Commercial Applications
The Birth of the Biotechnology Industry Academic Scientists Business People Financial Groups
New therapies Controversial Expensive Research is not cheap Ethical dilemmas is one person s health worth more than another?
What does society want?
Questions????