Inborn errors of metabolism

1. Inborn errors of metabolism & SIDS

2. Inborn errors of Metabolism • Phenylketonuria • Galactosemia • Cystic Fibrosis

3. Phenylketonuria • Autosomal recessive disorder • Phenyl alanine hydroxylase deficiency • Hyperphenylalaninemia 2% Dietary restriction of phenyl alanine

4. Variants • Classical PKU • 5 fold increase in Phenyl alanine levels • Maternal PKU • Mother affected • Teratogenic effects of phenyl alanine to the normal foetus • Benign hyperphenylalaninemia • PAH mutation causing modest elevation of phenyl alanine

5. General Mousy odour of urine & sweat Dysmorphic features Deafness Self – mutilation Hydrops HSM Cardiomegaly Neuro Hypo/Hypertonia Coma Lethargy Seizures GIT Poor feeding Recurrent vomiting Jaundice Eyes Cataract cherry red macula Dislocated lens Glaucoma Muscle Joints Myopathy Abnormal mobility Diagnosed by Serum phenyl alanine levels Molecular diagnosis Not feasible

6. Galactosemia • Autosomal recessive disorder • 2 variants • Galactose 1 – phosphate uridyl transferase deficiency • Galactokinase deficiency • Accumulation of Galactose – 1 – phosphate Mammalian milk Glucose + Galactose Galactose when not converted to glucose Galactitol Galactonate Liver – Eyes – Brain – spleen – kidney – Heart – RBCs

7. Liver Hepatomegaly Fatty change Cirrhosis Eyes Cataract (6 – 12 months) Brain (dentate nuclei & olivary nuclei) Loss of neurons Gliosis Edema Kidneys Aminoaciduria Blood Hemolysis coagulopathy

8. Diagnosis & Treatment • Diagnosis • Screening: Flurometric assay of GALT enzyme • Antenal: GALT activity in cultured amniotic fluid cells • Treatment • Removal of galactose from diet till 2 years of age

9. Cystic fibrosis (Mucoviscoidosis) • Most common lethal genetic disease • Autosomal recessive • Abnormal transport of chloride & bicarbonate ions by anion channel • Encoded by CFTR gene • Chromosome 7q31.2 • Affects fluid secretions of respiratory, GIT and reproductive tracts

10. Channel encoded by CFTR gene • 2 transmembrane domains • 2 cytoplasmic nucleotide- binding domains • 1 Regulatory domain Agonists increase cAMP levels Protein kinase A activated R domain phosphorylated Ion channel opens

11. Important facts of CFTR function • Multiple ion channels & cellular processes • Outwardly rectifying Cl- channels • Inwardly rectifying K+ channels • ENaC • Gap junction channels • Tissue – specific • Sweat ducts • Respiratory epithelium ENaC Epithelial cells Increased activity Hypotonic Sweat ducts Decreased activity Hypertonic

12. CFTR in sweat duct

13. Decreased Cl- secretion Increased Na & H20 reabsorption Dehydration of mucous layer Defective mucociliary function Airway plugging

14. Important facts of CFTR • Regulates transport of bicarbonate ions • Sometimes Cl- transport is preserved & HCO3- transport is affected • Acidic fluids secreted by epithelia • Decreased luminal pH • Precipitation & plugging of ducts • Recurrent infections • Pancreatic insufficiency

15. Classes of Cystic fibrosis Class Defect Mutation type I Defective protein synthesis Null II Abnormal protein folding, processing & trafficking Processing III Defective regulation Gating IV Decreased conductance Conduction V Reduced abundance Production VI Decreased membrane CFTR stability Instability

18. Environmental modifiers Colonisation of LRT by bacteria Concurrent viral infection predispose to bacterial infections Hypoxic environment due to static mucous Production of alginate – a mucoid polysaccharide capsule Formation of protective biofilm by bacteria Chronic destructive lung disease

19. Morphology • Sweat glands are morphologically unaffected • Pancreatic abnormalities • Mild cases • Mucus accumulation in small ducts • Some dilation of exocrine glands • Severe cases • Completely plugged ducts • Exocrine gland atrophy • Progressive fibrosis • Squamous metaplasia of duct • Meconium ileus

20. Morphology • Liver involvement • Bile canaliculi are plugged • Ductular proliferation • Portal inflammation • Hepatic steatosis • Focal biliary cirrhosis • Salivary glands • Progressive duct dilatation • Squamous metaplasia • Glandular atrophy • Fibrosis

21. Morphology • Pulmonary changes • Distended bronchioles with thick mucus • Hyperplasia/ hypertrophy of mucus-secreting cells • Superimposed infections • Severe chronic bronchitis & bronchiectasis • Infertility • Azoospermia • Congenital bilateral absence of the vas deferens

22. Oppurtunistic pulmonary infections • Staphylococcus aureus • Hemophilus influenzae • Pseudomonas aeruginosa • Alginate producing Pseudomonas aeruginosa • Burkholderia cepacian complex • Burkholderia cenocepacia • Stenotrophomonas maltophilia • Nontuberculous mycobacteria • Allergic bronchopulmonary aspergillosis Most common

23. Clinical features Chronic sinopulmonary disease • Persistent colonisation/infection • Chronic cough & Sputum production • Chest X ray abnormalities • Wheezing & air trapping • Nasal polyps • Digital clubbing GIT • Intestinal • Meconium ileus • Intestinal obstruction (distal) • Rectal prolapse • Pancreatic • Insufficiency • Acute & chronic pancreatitis GIT • Hepatic • Focal / multilobular cirrhosis • Prolonged neonatal jaundice • Nutritional • Failure to thrive • Hypoproteinemia • Edema • Fat soluble vitamin deficiency

24. Clinical features Salt loss syndromes •Acute salt depletion •Chronic metabolic alkalosis Male urogenital abnormalities •Obstructive azoospermia •Congenital absence of vas deferens

25. Criteria for diagnosis of Cystic fibrosis • > 1 characteristic phenotypic features OR • H/o Cystic fibrosis in sibling/ parent/ child OR • Positive newborn screening test result

Inborn errors of metabolism

Inborn errors of metabolism

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