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, www.mletips.com
  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, www.mletips.com
  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, www.mletips.com
  4. 4. PKU PKU 4 Dr. Krishna Tadepalli, MD, www.mletips.com
  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, www.mletips.com
  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, www.mletips.com
  7. 7. Galactosemia Galactosemia 7 Dr. Krishna Tadepalli, MD, www.mletips.com
  8. 8. Galactosemia Galactosemia 8 Dr. Krishna Tadepalli, MD, www.mletips.com
  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, www.mletips.com
  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, www.mletips.com
  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, www.mletips.com Gene therapy =undergoing early-phase clinical trials
  12. 12. Normal CFTR Normal CFTR 12 Dr. Krishna Tadepalli, MD, www.mletips.com
  13. 13. Cystic Fibrosis Cystic Fibrosis 13 Dr. Krishna Tadepalli, MD, www.mletips.com
  14. 14. Cystic Fibrosis – Disease Spectrum Cystic Fibrosis – Disease Spectrum 14 Dr. Krishna Tadepalli, MD, www.mletips.com
  15. 15. Cystic Fibrosis – Pancreas Cystic Fibrosis – Pancreas 15 Dr. Krishna Tadepalli, MD, www.mletips.com
  16. 16. Cystic Fibrosis – Lungs Cystic Fibrosis – Lungs 16 Dr. Krishna Tadepalli, MD, www.mletips.com
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