1. Pediatric Pathology
Pediatric Pathology
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Dr. Krishna Tadepalli, MD, www.mletips.com

2. 5. Inborn Errors of Metabolism and Other Genetic
5. Inborn Errors of Metabolism and Other Genetic
Disorders
Disorders
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Dr. Krishna Tadepalli, MD, www.mletips.com

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

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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)
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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)
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Clinical course & Progression
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Dr. Krishna Tadepalli, MD, www.mletips.com

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

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

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

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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
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precipitation and plugging of ducts, ↑ bacterial binding to mucin plugs
Dr. Krishna Tadepalli, MD, www.mletips.com

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

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Cystic Fibrosis (MUCOVISCIDOSIS) contd…
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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
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Diagnosis
Most cases =persistently elevated sweat electrolyte
"gold standard" =Sequencing the CFTR gene
Management = potent antimicrobial therapies +pancreatic enzyme replacement
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+bilateral lung transplantation
Dr. Krishna Tadepalli, MD, www.mletips.com
Gene therapy =undergoing early-phase clinical trials

12. Normal CFTR
Normal CFTR
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Dr. Krishna Tadepalli, MD, www.mletips.com

13. Cystic Fibrosis
Cystic Fibrosis
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Dr. Krishna Tadepalli, MD, www.mletips.com

14. Cystic Fibrosis – Disease Spectrum
Cystic Fibrosis – Disease Spectrum
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Dr. Krishna Tadepalli, MD, www.mletips.com

15. Cystic Fibrosis – Pancreas
Cystic Fibrosis – Pancreas
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Dr. Krishna Tadepalli, MD, www.mletips.com

16. Cystic Fibrosis – Lungs
Cystic Fibrosis – Lungs
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Dr. Krishna Tadepalli, MD, www.mletips.com

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