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
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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
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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