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5. metabolic and genetic disorders; pediatric pathology


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5. metabolic and genetic disorders; pediatric pathology

  1. 1. Pediatric Pathology Pediatric Pathology 1 Dr. Krishna Tadepalli, MD,
  2. 2. 5. Inborn Errors of Metabolism and Other Genetic 5. Inborn Errors of Metabolism and Other Genetic Disorders Disorders 2 Dr. Krishna Tadepalli, MD,
  3. 3. • • • • • Early diagnosis  appropriate dietary regimens  prevent clinical illness (PKU and Galactosemia) Phenylketonuria (PKU) Autosomal recessive Mutations of the gene encoding phenylalanine hydroxylase (convert phenylalanine into tyrosine in liver) hyperphenylalaninemia  PKU PKU variants = benign hyperphenylalaninemia pts, have positive screening tests but not develop PKU (serum phenylalanine levels differentiate) – defects in BH4 (cofactor )recycling – neurologic disturbances cannot be treated by dietary control of phenylalanine • Clinical – – – – – • • Musty or mousy odor (due to phenylacetic acid in sweat) Brain damage (due to excess phenylalanine or its metabolites Normal at birth but in within a few weeks impaired brain growth By 6 months  severe mental retardation Other features decreased pigmentation of hair and skin, and eczema can’t, walk & talk ,Seizures Maternal PKU = normal female PKU patients with hyperphenylalaninemia Children born to this mothers =mentally retarded and microcephalic (due to 3 teratogenic effects) Dr. Krishna Tadepalli, MD,
  4. 4. PKU PKU 4 Dr. Krishna Tadepalli, MD,
  5. 5. • • • • • • Galactosemia Autosomal recessive disorder of galactose metabolism Lactose of milk split into glucose and galactose in the intestinal microvilli by lactase Galactose is converted to glucose Two variants – Common variant = total lack of galactose-1-phosphate uridyl transferase (also known as GALT) • galactose-1-phosphate accumulates in liver, spleen, lens of the eye, kidneys, heart muscle, cerebral cortex, and erythrocytes – converts into galactitol &galactonate (toxic) – Rare variant =deficiency of galactokinase (Milder with mental retardation) • Clinical – Liver= Hepatomegaly ( due to fatty change) and Cirrhosis (Fibrosis) – Eye lens= Cataract (Galactitol absorbs more water) – CNS= non-specific changes (Neuronal loss +gliosis+edema mainly at Dentate and oilvary nuclei) • Clinical course & Progression 5 Dr. Krishna Tadepalli, MD,
  6. 6. • • • • • • • • • • • Galactosemia Clinical course & Progression Immediately after birth = failure to thrive First few days = vomitings &diarrhea, Hemolysis & Coagulopathy First few weeks = Jaundice, Hepatomegaly & Cataracts Months (6-12) = MR, Aminoaciduria and fulminant E. Coli sepsis, Diagnosis Urine positive for reducing sugars – gives doubt Deficiency of enzyme inWBC or RBC = confirmation Antenatal = GALT in Aminotic fluid or cultured cells Genetic polymorphisms – In Non- Hispanics = glutamine to arginine at 188 – In Africans = serine to leucine at 135 • • Prevention Avoid galactose in diet for at least for first two years of life • Can’t avoid speech disorders, Gonadal (ovarian) failure and ataxia (despite dietary restriction) 6 Dr. Krishna Tadepalli, MD,
  7. 7. Galactosemia Galactosemia 7 Dr. Krishna Tadepalli, MD,
  8. 8. Galactosemia Galactosemia 8 Dr. Krishna Tadepalli, MD,
  9. 9. • • • • • • • • • • • • • • Cystic Fibrosis (MUCOVISCIDOSIS) Autosomal recessive MC lethal genetic disease that affects Caucasian populations (1 in 2500 live births with carrier frequency 1 in 20 among Caucasians ) Disorder of ion transport in epithelial cells Secretion in exocrine glands and epithelial lining of the respiratory, gastrointestinal, and reproductive tracts Abnormally viscous secretions obstruct organ passages Even heterozygote carriers have respiratory and pancreatic diseases The Cystic Fibrosis-Associated Gene: Normal Structure and Function CFTR gene on chromosome 7q31.2 Normal CFTR  decreases ENaC activity (in cystic fibrosis, ENaC activity increases with exception of sweat ducts to this rule ) CFTR can regulate multiple ion channels and cellular processes interaction of CFTR with the ENaC most pathophysiologic relevance CFTR functions are tissue-specific & impact of CFTR mutation also tissue-specific (sweat  hypertonic, respiratory and intestinal secretions  low volume but isotonic) CFTR mediates transport of bicarbonate ions (some CFTR mutant variants  Cl ¯ transport is normal but HCo3 ¯ transport is abnormal  epithelia secrete acidic fluids ↑ mucin 9 precipitation and plugging of ducts, ↑ bacterial binding to mucin plugs Dr. Krishna Tadepalli, MD,
  10. 10. • • • • • • Cystic Fibrosis (MUCOVISCIDOSIS) contd… Classic cystic fibrosis phenotype  Severe mutations (pancreatic insufficiency, sinopulmonary infections, and gastrointestinal symptoms) less severe phenotype  "mild“ mutations Genotype -phenotype correlation is most consistent for pancreatic disease but less consistent in pulmonary disease Non-classic or atypical cystic fibrosis  have CFTR mutations but do not other features of cystic fibrosis (examples =idiopathic chronic pancreatitis, late-onset chronic pulmonary disease, idiopathic bronchiectasis, and obstructive azoospermia ) Genetic and Environmental Modifiers = decide the phenotypic features ( mainly pulmonary ) 10 Dr. Krishna Tadepalli, MD,
  11. 11. • Cystic Fibrosis (MUCOVISCIDOSIS) contd… • • • Morphology Pancreatic abnormalities (seen in 85% to 90% of patients ) Varies from only accumulations of mucus and duct dilation to severe duct obstruction (by mucus plugs)atrophy and progressive fibrosis of exocrine pancreas Liver = Bile canaliculi obstruction ductular proliferation and portal inflammation and later steatosis & biliary cirrhosis salivary glands = similar to pancreas Pulmonary changes =most serious complications – chronic bronchitis and bronchiectasis – Staphylococcus aureus, Hemophilus influenzae, and Pseudomonas aeruginosa are most common organisms – Burkholderia cenocepacia (group of pseudomonads) =most common of all Azoospermia and infertility =in 95% of the males associated with congenital bilateral absence of the vas deferens • • • • • • • • • Diagnosis Most cases =persistently elevated sweat electrolyte "gold standard" =Sequencing the CFTR gene Management = potent antimicrobial therapies +pancreatic enzyme replacement 11 +bilateral lung transplantation Dr. Krishna Tadepalli, MD, Gene therapy =undergoing early-phase clinical trials
  12. 12. Normal CFTR Normal CFTR 12 Dr. Krishna Tadepalli, MD,
  13. 13. Cystic Fibrosis Cystic Fibrosis 13 Dr. Krishna Tadepalli, MD,
  14. 14. Cystic Fibrosis – Disease Spectrum Cystic Fibrosis – Disease Spectrum 14 Dr. Krishna Tadepalli, MD,
  15. 15. Cystic Fibrosis – Pancreas Cystic Fibrosis – Pancreas 15 Dr. Krishna Tadepalli, MD,
  16. 16. Cystic Fibrosis – Lungs Cystic Fibrosis – Lungs 16 Dr. Krishna Tadepalli, MD,
  17. 17. 17