Peds Flashcards
What is the mode of inheritance of phenylketonuria?
Autosomal recessive
What is the pathogenesis of PKU?
deficiency in the enzyme phenylalanine hydroxylase (PAH)–> result is hyper-phenylalanine-emia.
[nb: 2% mutation in cofactor BH4, cannot be treated with dietary restriction]
cannot convert phenylalanine to tyrosine
off-pathway metabolites and phenylalanine build up (5x normal) and contribute to brain damage
Concomitant lack of tyrosine = precursor to melanin –> reduced skin and hair pigmentation.
List clinical manifestations of PKU
Normal at birth
within 6 months –> intellectual disability
failure to thrive; untreated, cannot walk, 2/3 cannot talk
Seizures
decreased pigmentation of hair and skin
characteristic musty odor
eczema
What are the consequences of PKU particular to females?
Discontinued treatment as adults –> hyperphenylalaninemia –> teratogenic effect –> intellectual disability, microcephaly, congenital heart disease in offspring.
Solution: must be on dietary restriction pre-conception and during pregnancy to prevent teratogenic effects of serum phenylalanine build-up.
What is the pathogenesis of galactosemia?
Lack of enzyme GALT to convert galactose-1-phosphate to glucose
Result is buildup of G1P in many organs: liver spleen lens of eye kidneys myocardium cerebral cortex erythrocytes
Clinical features of galactosemia?
Failure to thrive almost from birth; vomiting and diarrhea with ingestion of milk
Jaundice & hepatomegaly first week of life; eventual cirrhosis
Cataracts within weeks
Intellectual disability
kidney impairment –> aminoaciduria
fulminant e.coli infection/septicemia
How can galactosemia be diagnosed? (tests to use)
Fluorometric assay of GALT enzyme activity on a dried blood spot test
Positive screen: verified by GALT levels in erythrocytes (are affected in galactosemia)
Antenatal diagosis: assay of GALT activity in amniotic fluid; galactitol levels in amniotic fluid
Gene mutation in cystic fibrosis & Inheritance pattern?
CFTR (cystic fibrosis transmembrane conductance receptor)
ch. 7q31.2
AUTOSOMAL RECESSIVE
What is the function of CFTR protein?
Protein encoded by CFTR encodes a transmembrane chloride channel.
It ALSO regulates multiple ion channels and cellular processes, including ENAC (epithelial sodium channel), which is responsible for sodium uptake from luminal fluid, rendering it hypotonic –> normally, CFTR inhibits ENAC so when it’s mutated, sodium uptake gets unregulated/augmented across the luminal membrane (important in pulmonary and GI manifestations of CF).
How does the function of CFTR on sweat ducts differ from that in the lungs?
Sweat ducts: in NORMAL situation, CFTR augments chloride reabsorption and sodium via ENAC. When it’s MUTATED –> no chloride reabsorption from the sweat, and no augmentation of sodium reabsorption = sweat is full of Cl and Na ions, hypertonic = “sweaty baby”
Airways: in NORMAL situation, CFTR secretes chloride into the airway mucus and controls the flow of sodium in (and the water that follows it). When MUTATED, there is a loss of chloride secretion into the mucus, and the sodium resorption is uncontrolled = increased passive water resorption from the mucus layer, leading to DEHYDRATED mucus.
executive summary:
Sweat ducts: CFTR resorbs Cl while ENAC resorbs Na; mutation in CFTR leads to decreased ENAC activity
Airway: CFTR excretes CL while ENAC resorbs Na (& water passively); mutation means loss of inhibition on ENAC and sodium and water resorption is uncontrolled, resulting in dehydrated lumenal mucus.
What is the function of CFTR in the pancreas?
CFTR regulates bicarbonate ions.
The channel is not specific to chloride and is permeable to bicarb as well. Normal tissue secretes alkaline fluids; in contrast, tissues that are acidic due to absence of bicarbonate ions are secreted by epithelia harboring CFTR mutations.
Acidic secretions lead to decreased luminal pH, with increased mucin precipitation, plugging of ducts and increased binding of bacteria to plugged mucins.
Pancreatic insufficiency results. Virtually always present in patients with abnormal bicarbonate conductance.
List the 6 classes of CFTR mutations.
Class 1: total loss of CFTR (null mutation)
Class 2: abnormal protein folding, processing and trafficking (processing mutation); results in degradation before it reaches the cell surface
Class 3: Defective regulation (gating mutations); ATP cannot bind, cannot activate CFTR; it’s present but nonfunctional.
Class 4: Decreased conductance (conductance mutations); normal amount of CFTR but it doesn’t conduct chloride properly.
Class 5: Reduced abundance (production mutations); reduced amount of normal protein
Class 6: Decreased membrane CFTR (instability mutations)
What is the mode of inheritance of Cystic Fibrosis?
Autosomal recessive
