5. metabolic and genetic disorders; pediatric pathology

Pediatric PathologyPediatric Pathology

Dr. Krishna Tadepalli, MD, www.mletips.com

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5. Inborn Errors of Metabolism and Other Genetic Disorders

5. Inborn Errors of Metabolism and Other Genetic Disorders

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• 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 teratogenic effects)

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PKUPKU

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• Galactosemia


• 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 & Progression5


• 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)

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GalactosemiaGalactosemia

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GalactosemiaGalactosemia

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• Cystic Fibrosis (MUCOVISCIDOSIS)


• 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 precipitation and plugging of ducts, ↑ bacterial binding to mucin plugs

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• 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 )

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• 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 +bilateral lung transplantation

• Gene therapy =undergoing early-phase clinical trials

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Normal CFTRNormal CFTR

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Cystic FibrosisCystic Fibrosis

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Cystic Fibrosis – Disease SpectrumCystic Fibrosis – Disease Spectrum

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Cystic Fibrosis – PancreasCystic Fibrosis – Pancreas

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Cystic Fibrosis – LungsCystic Fibrosis – Lungs

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Health & Medicine

5. metabolic and genetic disorders; pediatric pathology