Rare, Most Commonly Inherited Recessive Or Xlinked Dz

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 amount of residual enzyme activity

o  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

o  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

o  "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

·  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

·  Malnutrition

·  Hepatic cirrhosis

·  Intestinal obstruction

·  Male infertility

o  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

·  Increased binding of bacteria to plugged mucins

·  Pancreatic insufficiency always present when CFTR mut w/abnormal bicarb conductance

o  Class I - defective protein synthesis

·  Complete lack of CFTR protein

o  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

o  Class III - defective regulation

·  Prevent activation of CFTR by preventing ATP binding and hydrolysis

·  Normal amount of CFTR, but is nonfunctional

o  Class IV - decreased conductance

·  Transmembrane domain, forms ionic pore for Cl- transport

·  Normal amount of CFTR, but w/reduced function, milder phenotype

o  Class V - Reduced abundance

·  Intronic splice sites or CFTR promoter

·  Reduced amount of normal protein, milder phenotype

o  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

o  Severe (Class I, II, III), Mild (Class IV, V)

·  Pancreatic dz (mild), pancreatic insufficiency (severe)

·  GI Sx (severe)

o  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 end-stage lung dz

§  TGFB1 - direct inhibitor of CFTR function

o  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

o  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

§  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

o  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

§  Diffuse biliary cirrhosis in less than 10% pts

o  Dx:

·  Persistently elevated sweat electrolyte concentrations

·  Characteristic clinical findings

·  Abnormal newborn screening test

·  Family hx

·  Sequencing of CFTR gene is "gold standard"

o  Tx:

·  Potent antimicrobial therapies

·  Pancreatic enzyme replacement

·  Bilateral lung transplantation