Download Path Chapter 10 inborn errors [5-11

Chapter 10 PKU
Thursday, November 29, 2012
5:20 PM
 Inborn errors of metabolism
 Rare, most commonly inherited recessive or Xlinked dz
 Phenylketonuria (PKU), Galactosemia, Cystic Fibrosis
 PKU
o Abnormalities of phenylalanine metabolism -> hyperphenylalaninemia
o Autosomal recessive condition
o Majority caused by bi-allelic mutations of gene for phenylalanine hydroxylase PAH
o Degree of hyperphenylalaninemia and clinical phenotype is inversely related to the
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amount of residual enzyme activity
Mutations
 Those resulting is lack of PAH activity present w/classic PKU features
 Those w/up to 6% residual activity present w/milder dz
 Benign hyperphenylalaninemia only modest elevations of blood phenylalanine
levels are w/o assoc neurologic damage
 May have positive screening tests but don't develop stigmata of classic PKU
Inability to convert phenylalanine into tyrosine
 Normal kids
 Less than 50% dietary phenylalanine is necessary
 Rest is irreversibly converted to tyrosine by PAH in liver "Hepatic PAH
System"
 Cofactor tetrahydrobiopterin BH4 -> required for tyrosine and
tryptophan hydroxylation
 Enzyme dihydropteridine reductase -> regenerates BH4
 98% cases attributable to abnormalities in PAH
 2% abnormalities in synthesis or recycling of BH4
"Classic" PKU - severe deficiency of PAH -> hyperphenylalaninemia
 Minor shunt pathways
 Phenylpyruvic acid, phenyllactic acid, phenylacetic acid (musty/mousy
odor), o-hydroxyphenylacetic acid -> excreted thru urine in large amounts,
some in sweat
 Excess phenylalanine or metabolites contribute to brain damage in PKU
 Normal at birth, w/in few weeks develop a rising plasma phenylalanine -> impairs
brain development
 6 months -> severe mental retardation (only 4% w/IQ's higher than 50-60)
 1/3 can't walk, 2/3 thirds can't talk
 Seizures, decreased pigmentation of hair/skin, eczema in untreated kids
 Hyperphenylalaninemia and retardation can be avoided by restriction of
phenylalanine intake early -> screening procedures in immediate postnatal period
 Normal female PKU patients w/tx can live to childbearing years
 75-90% of these pts kids are mentally retarded and microcephalic
 15% have congenital heart dz
 Although the infants are heterozygous
 Maternal PKU
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Results from teratogenic effects of phenylalanine that cross the
placenta, affect specific fetal organs during development
 Maternal dietary restriction of phenylalanine must occur before
conception and continue thruout preg
Galactosemia - autosomal recessive disorder of galactose metabolism
o Normally, lactose -> glucose and galactose by lactase
o Galactase -> (3 steps) glucose
o Two variants
 Total lack of galactose-1-phosphate uridyl transferase (GALT) - rxn 2 (common)
 Accumulations in liver, lens, spleen, kidneys, heart muscle, cerebral cortex,
erythrocytes
 Liver: hepatomegaly due to fatty change, w/time resembles cirrhosis
 Lens: opacification develops - lens absorbs water/swells as galactitol
accumulates & increases its tonicity
 Brain: loss of nerve cells, gliosis, and edema
 Kidneys: accumulation causes aminoaciduria
 IS: depressed neutrophil bactericidal activity -> E. coli septicemia
 Erythrocytes: hemolysis and coagulopathy
 Infants usually "fail to thrive"
 Vomiting/diarrhea w/in a few days of milk ingestion
 Jaundice/hepatomegaly during 1st week
 Cataracts w/in a few wks
 Mental retardation w/in 1st 6-12 months
 *even untx infants mental retardation isn't as severe as in PKU
 Alternate pathways activated -> production of galactitol and galactonate
which both accumulate in tissues
 Heterozygotes may have mild deficiency, but no real consequences like
homozygotes
 Deficiency of galactokinase - rxn 1 (rare) milder form (no mental retardation)
o Dx: demonstration in urine of reducing sugar other than glucose, but directly identifying
def of transferase in leukocytes/erythrocytes is more reliable
 Antenatal Dx - assay of GALT activity in amniotic culture
 Determination of glactitol lvl in amniotic fluid supernatant
 GALT - 140 mutations
 Glutamine to arginine sub at codon 188 most prevalent mut in whites
 Serine to leucine sub at codon 135 most common mut in blacks
o Tx: changes can be prevented/ameliorated by early removal of galactose from diet for
at least 2yrs of life (may still develop speech disorder and gonadal failure or possibly
ataxic condition)
Cystic Fibrosis - disorder of ion transport in epithelial cells that affects fluid secretion in
exocrine glands and epithelial lining of respiratory, GI, and reproductive tracts
o Incidence:1/2500 live births, most common lethal genetic dz that affects caucasians
(freq1/20 US)
o Autosomal recessive - hetero carriers have higher incidence of resp/pancreatic dzs
o Usually leads to abnormally viscous secretions which obstruct passages
 Chronic lung dz 2ndary to recurrent infections
 Pancreatic insufficiency
 Steatorrhea
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Malnutrition
Hepatic cirrhosis
Intestinal obstruction
Male infertility
Primary defect - abnormal function of an epithelial Cl- channel protein encoded by CFTR
gene (cystic fibrosis transmembrane conductance regulator)
 Regulates multiple additional ion channels and cellular processes
 Interaction of CFTR w/ENaC most pathophys relevance is CF
 ENaC - apical surface of exocrine epithelial cells, responsible for Na+ uptake
from luminal fluid (hypotonic)
 Inhibited by normal func of CFTR
 In CF, ENaC activity increase augmenting Na+ uptake across apical
membrane
 Exception - human sweat ducts, ENaC activity decreases b/c mut,
hypertonic luminal fluid containing both high sweat Cl- &Na+ - "salty
sweat"
 CFTR functions are tissue-specific
 Sweat glands - CFTR reabsorb luminal Cl- and augment Na+ reabsorption,
CF leads to decreased reabsorption of NaCl -> hypertonic sweat
 Resp/Intestinal Epithelium - CFTR active luminal secretion of CL-, CF loss or
reduction of Cl- secretion into lumen -> lowering H2O content of surface
layer coating mucosal cells, no diff in [salt] of surface fluid layer coating
resp/intestinal mucosal cells
 In lungs this dehydration leads to defective mucociliary action and
the accumulation of hyperconcentratede viscid secretions that
obstruct air passages and predispose to pulmonary infections
 CFTR mediates transport of bicarb ions
 Mediated by SLC26 (anion exchangers) - coexpressed on apical surface
w/CFTR
 Some mutant variants Cl- transport okay, while bicarb is abnormal
 Alkaline fluids secreted by normal tissues, acidic secreted by epithelia
w/mutant CFTR alleles
 Decreased luminal pH ->
increased mucin precipitation and plugging of ducts
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 Increased binding of bacteria to plugged mucins
 Pancreatic insufficiency always present when CFTR mut
w/abnormal bicarb conductance
Class I - defective protein synthesis
 Complete lack of CFTR protein
Class II - abnormal protein folding, processing, and trafficking
 Defective processing, protein doesn't become fully folded/glycosylated, is
degraded
 Most common is deletion of 3 nucleotides coding for phenylalanine
 70% of CF pts
 Complete lack of CFTR protein
Class III - defective regulation
 Prevent activation of CFTR by preventing ATP binding and hydrolysis
 Normal amount of CFTR, but is nonfunctional
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Class IV - decreased conductance
 Transmembrane domain, forms ionic pore for Cl- transport
 Normal amount of CFTR, but w/reduced function, milder phenotype
Class V - Reduced abundance
 Intronic splice sites or CFTR promoter
 Reduced amount of normal protein, milder phenotype
Class VI - altered regulation of separate ion channels
 Affect regulatory role of CFTR
 Given mut affects conductance by CFTR AND regulation of other ion channels
Severe (Class I, II, III), Mild (Class IV, V)
 Pancreatic dz (mild), pancreatic insufficiency (severe)
 GI Sx (severe)
Genetics
 Pts w/varied apparently unrelated clinical phenotypes may harbor CFTR
mutations, but may not demonstrate other features of CF (even w/bi-allelic CFTR
mut) - nonclassic/atypical CF
 Idiopathic chronic pancreatitis
 Late-onset chronic pulmonary dz
 Idiopathic bronchiectasis
 Obstructive azoospermia - bilateral absence of vas deferens
 Pulmonary manifestations - caused by variants at several genes
 MBL2 - assoc w/lower circulating levels of the protein, 3X higher risk of endstage lung dz
 TGFB1 - direct inhibitor of CFTR function
Environmental Modifiers - esp for pulmonary
 Pseudomonas aeruginosa - colonize lower resp tract (intermittent then chronic)
 Concurrent viral infections predispose colonization
 Static mucus creates hypoxic microenvironment - favors alginate
production (mucoid polysaccharide capsule)
 Permits formation of biofilm that protects the bacteria from Abs and
antibiotics
 Chronic destructive lung dz
Morphology
 Sweat glands - unaffected
 Pancreatic abnormalities - 85 to 90% of CF pts
 Mild - accumulations in small ducts w/some dilation
 Severe - (older kids/teens) ducts completely plugged -> atrophy of exocrine
glands and progressive fibrosis causing loss of pancreatic secretion
 Thick viscid mucus plugs found in SB of infants -> can cause
obstruction (meconium ileus)
 Liver
 Bile canaliculi plugged, ductular proliferation and portal inflammation
 Hepatic steatosis
 Focal biliary cirrhosis in 1/3 pts
 Diffuse hepatic nodularity less than 10% pts
 Salivary glands - same a pancrease, progressive dilation of ducts, squamos
metaplasia and atrophy
 Pulmonary changes - most serious
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Viscous mucus secretions of submucosal glands of resp tree leading to
secondary obstruction and infection of air passages
 Bronchioles distended w/thick mucus assoc w/marked hyperplasia
and hypertrophy of mucus-secreting cells
 Infections
 Severe chronic bronchitis and bronchiectasis and lung absesses
 Staphylococcus aureaus, Hemophilus influenzae, and
Pseudomonas aeruginosa - 3 most common responsible
 P aeruginosa - alginate forming, freq and causes chronic
inflammation
 Burkholderia cepacia (pseudomonad)
 B cenocepacia most common in CF pts
 "cepacia syndrome" - long hospitals
stays/increased mortality
 Stenotrophomonas maltophila, nontubercuous mycobacteria,
allergic bronchopulmonary aspergillosis
 Azoospermia and infertility
 95% of males - congenital bilateral absence of vas deferens
Clinical Features
 Meconium ileus - 5 to 10% of cases at or soon after birth
 Distal intestinal obstruction (older pts) - recurrent episodes of RLQ pain
(sometimes w/palpable mass in R iliac fossa)
 Exocrine pancreatic insufficiency
 85-90% assoc w/severe CFTR mut on BOTH alleles
 10-15% w/one severe and one mild or two mild (don't require enzyme
supplements)
 Assoc w/protein and fat malabsorption and increase fecal loss during 1st yr
of life
 May cause def of fat-soluble vit (A, D or K)
 Hypoproteinemia -> generalized edema
 Persistent diarrhea -> rectal prolaps is up to 10% kids
 Pancreatic-sufficient
 Usually no other GI Sx
 Idiopathic chronic pancreatitis is subset and is assoc w/ recurrent abd pain
 Cardiorespiratory complications
 Persistent lung infections, Obstructive pulmonary dz, Cor pulmonale 80%
deaths in US
 By age 18, 80% harbor P aeruginosa (many resistant strains from
antibiotic abuse)
 One severe and one mild mut -> late-onset mild pulmonary dz
 Mild pulmonary dz -> usually little/no pancreatic dz
 Adult-onset idiopathic bronchietasis linked to CFTR mut
 Recurrent sinonasal polyps ~25% pts
 Liver dz
 Late in natural hx
 Onset at/around puberty in 13-17%
 Asymptomatic hepatomegaly in up to 1/3 pts
 Obstruction presents w/abd pain and acute onset of jaundice
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Diffuse biliary cirrhosis in less than 10% pts
Dx:
Persistently elevated sweat electrolyte concentrations
Characteristic clinical findings
Abnormal newborn screening test
Family hx
Sequencing of CFTR gene is "gold standard"
Tx:
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Potent antimicrobial therapies
Pancreatic enzyme replacement
Bilateral lung transplantation