Genetic disorders of metabolism. Screening methods.

1. Genetic disorders ofmetabolism.Screening methods. Bruno Sopko

2. Biochemical genetics:Genetic disorders of metabolism Biochemistry Genetics Clinical medicine

3. Geneticdisordersofmetabolism. Rare diseases Prevalence < 1:2000 • GDM=cca 1/10 of rare diseases • Cca 700-800 nosologic units (>1000 genes) • Total incidence 1:500 • Each GP has, at least, 1-2 patients with GDM • Cca 30% of these diseases are curable (100 diseases well) Rare diseases GDM

4. Geneticdisordersofmetabolism - overview

5. Genetic disorders of metabolism– small and large molecule (organelle) disease

6. Genetic disorders of metabolism – small and large molecule (organelle) disease < 1500 Da • gases, inorganic ions • Aminoacids • organic acids • Saccharides • Polyols • simple lipids • purins, pyrimidins • Vitamins • oligomers: peptids up to cca 5-10 AA, oligosaccharides • cytosol, mitochondrial stroma, blood, urine > 1500 Da • Glycolipids • Sphingolipids • Plasmalogenes • neutral polysaccharides (glycogen) • Mucopolysaccharides (other oligomers: proteins, nucleic acids...) • Usually associated with membranes • Usually not observed in larger amounts in body fluids ( x MS/MS technology)

7. Genetic disorders of metabolism – small and large molecule (organelle) disease < 1500 Da • Dependent of exogenous intake • manifested (repeated) by acute toxicity, frequently accompanied by encephalopathy/coma • common hepatopathy • Frequent deviations in common biochemical tests-ammonia, ABB, ketone bodies , glycemia, uric acid... • Symptom occurence dependent on specific nutrition part, fasting catabolism • Possibly chronic (low toxicity) • Usually well cured by diet and vitamin supply > 1500 Da • Usually independent on exogenous nutrition supply • Frequently progressive • Possible fetal dysmorphia • Commonly impairment of nervous system and muscles • Organomegalia as theresulting from lysosomal storage diseases • Diet and vitamins do not have any long term effect

8. Newbornscreeningin the Czech Republic • Newborn (or neonatal) screening is a process of testing newborn babies for increased risk of certain rare diseases, which in case of early detection and early treatment can prevent serious injury to a child. • At the age of 48-72 hours after birth several drops of blood from the heel of the child are sampled on a special paper and sent for analysis to the screening laboratory. In the event that there was no suspicion of the screened disease (negative result), the respective laboratory does not issue a formal statement on normal findings.

9. Newbornscreeningin the Czech Republic Lysosmal storage disorders Aminoacidopathy, organic acidurias Fatty acid -oxidation disorders Peroxisomal disorders Mitochondrial diseases Glycosylation disorders Others

10. Newbornscreeningin the Czech republicScanned disorders • EndocrineDisorders • Congenitalhypothyroidism • Congenitaladrenalhyperplasia • Disturbancesofaminoacidmetabolism • Phenylketonuria • Glutaricaciduria, Type I (glutaryl-CoAdehydrogenasedeficiency) • Isovaleryl-CoAdehydrogenasedeficiency (Isovalericacidemia) • Maplesyrup urine disease • Disordersoffattyacidoxidation • Carnitineuptake/transporterdefects • Carnitine-acylcarnitinetranslocasedeficiency • Carnitinepalmitoyltransferase I deficiency (CPT I) • Carnitinepalmitoyltransferase II deficiency (CPT II) • Verylongchain acyl-CoAdehydrogenasedeficiency (VLCADD) • Longchain L-3 hydroxyacyl-CoAdehydrogenasedeficiency (LCHADD) • Medium chain acyl-CoAdehydrogenasedeficiency (MCADD) • Cysticfibrosis • Cysticfibrosis

11. Newbornscreeningin the Czechrepublic: Probability according to ethnic group

12. Congenitaladrenalhyperplasia(CAH) • Autosomal recessive • Laboratory diagnosis: 17-hydroxyprogesterone - increased • Treatment – supplementing steroids • Girls – surgical correction

13. Phenylketonuria (PKU) and Hyperphenylalaninemia (HPA)

14. Phenylketonuria (PKU) andHyperphenylalaninemia (HPA) PKU HPA

15. Phenylketonuria (PKU) andHyperphenylalaninemia (HPA) • Autosomal recessive • Laboratory diagnosis: increased phenylalanine, and ratio Phe/Tyr • Treatment – alimentary – decreased intake Phe and supplemented Tyr

16. Cystic fibrosis (CF) • Autosomalrecessive • Laboratory diagnosis: Three level model IRT/DNA/IRT: • immunoreactivetrypsinogen (IRT) • following DNA analysis • sweat test • Treatment: • Lungs: inhalation mucolytics + breathing physiotherapy in several (idealy 3) short blocks daily. • Well balanced nutrition, high caloric : 130 -150 % RDA, supplementing vitamins soluble in fats, supplementation of NaCl. • Infection control: antibiotics at all acute exacerbation respiratory infection, broad-spectrum antibiotics, with antistaphylococcus effect; when deteced Pseudomonas aeruginosaspecificATB therapy, even withou clinical manifestation. High limit dosages, at least 14 days.

17. Citations: • http://www.novorozeneckyscreening.cz • Kožich, V. : Úvod do biochemické Genetiky • Jean-Marie Saudubray, Georges van den Berghe, John H. Walter:Inborn Metabolic • Diseases; Diagnosis and Treatment;Fifth Edition, Springer, 2012 • William L. Nyhan, Bruce A. Barshop, Pinar T. Ozand, MD: Atlas of Metabolic Diseases; Second edition, HodderEducation,2005 • Joe T. R. Clarke: A Clinical Guide toInherited MetabolicDiseases;Second Edition, Cambridge University Press, 2004