Autosomal Recessive Flashcards
PKU (Phenylketouria)
Epilepsy, mental retardation, hyperactivity
Newborn screen used to be Guthrie test (high phenylalanine overrides bacterial inhibitio, leading to bacterial growth), now by Tandem Mass Spectrometry
Screening timing is important because PAH is normal at birth because mom’s PAH is still in fetus, so test a few days later but still early enough to avoid CNS damage
Defect in PAH-phenylalanine hydroxylase enzyme (common) or BH4 cofactor (rare, also have high neurotransmitter imbalance because BH4 involved is involved in neurotransmitter synthesis)
High phenylalanine in blood, toxic to CNS
Side note: pregnant mothers advised to keep a low phenylalanine diet, irrespective of child genotype, because reduces risk of miscarriage and congenital malformations)
ATD (alpha1-Antitrypsin Deficiency)
Late onset: increased risk of developing emphysema, liver cirrhosis/cancer (risks increase with smokers)
Screen with sequence specific oligonucleotide probes for Z and S alleles
Defective alpha1-AT protein (normally protease inhibitor of elastase; elastase recruited by neutrophil) → increased elastase activity→ decreased elastin in lungs→ emphysema and lung damage
Smoking accelerates disease b/c causes lung damage, increasing neutrophil expression and thus elastase
Z allele (Glu342Lys) expresses misfolded protein that aggregates in the endoplasmic reticulum of liver cells, causing damage to the liver in addition to the lung. Is more common
S allele (Glu264Val) expresses an unstable protein that is less effective.
(M allele is wild-type)
Tay-Sachs Disease
Progressive neurodegeneration of CNS. Onset at 3-6 months, with muscle weakness, decreased attentiveness, and increased startle response appear.
Later on: seizures, vision and hearing loss, diminishing mental function, and paralysis. An eye abnormality called “cherry-red spot” is a characteristic of T-S. Children of T-S usually live only till 3-4 years of age
Screen enzyme activity (at low temp, both enzymes active, at high temp HexA degrades and B still functions) test and DNA test (three mutant alleles account for 95% of cases)
Can screen carriers (have less HexA in blood)
Lysosomal storage disease; from defect in alpha subunit of HEXA (has alpha and beta subunits), which degrades GM2 ganglioside
Inability to degrade GM2 ganglioside, which aggregates in lysosomes in CNS neurons;
Over 100 HEXA mutations are known; most common mutant allele (~80%) in the Ashkenazi Jewish population is a 4 bp insertion in exon 11 of HEXA, causing a frameshift and a premature stop codon (null allele)
Sandhoff Disease
Symptoms similar to Tay-Sachs
Screening enzyme activity shows that both HexA and HexB are inactive (just Hex A in Tay-Sachs)
Defects in both HexA (αβ) and HexB (homodimer of ββ) caused by a defective β subunit
AB-Variant of Tay-Sachs
Resemble Tay-Sachs disease
Rare form where HexA and HexB are normal but GM2 accumulates due to defect in the GM2 activator protein (GM2AP), which facilitates interaction between the lipid substrate and the HexA enzyme within the cell
Cystic Fibrosis
Salty skin, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath
Mutation of CFTR gene; CFTR protein needed to regulate components of sweat, digestive juices, and mucus by regulating movement of chloride and sodium ion across epithelial membranes
Hereditary Hemochromatosis
Hepatic cirrhosis in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation.
Mutation in HFE gene on Chr. 6, important in iron regulation; defect causes iron overload
Congenital adrenal hyperplasia
Ambiguous genitalia, masculization of females
ACTH secretion increased (b/c lack of negative feedback via cortisol to pituitary), such that adrenals are hyperplastic, overproducing androgens
5α reductase deficiency
Incomplete phallic development, severe hypospadias (pseudovaginal perineal hypospadius); ambigous external genitalia in 46 XY males
Failure of end organs to activate testosterone to dihydrotestosterone (DHT) in 46, XY individuals; 5-alpha reductase needed to covert tetosterone to active DHT
Leydig cell hypoplasia
Male psuedohermaphriditism
Homozygous mutations in the LHR the gene for luteinizing hormone receptor (LHR) receptor, leading to lack of testosterone production
Smith-Lemli-Opitz Syndrome
Feminization of males
Cholesterol synthesis disorder, decreasing testosterone production
Pompe Disease
Progressive muscle failure, cardiomegaly, hypotonia, cardiomyopathy, respiratory distress, muscle weakness, feeding difficulties, and failure to thrive (used to die by 1 yr)
Accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme
Sickle Cell (HbS)
Anemia
Diagnosis: when the sequence changes at codon 6, lose a restriction site for MstII
βA: -Pro-Glu-Glu- -CCTGAGGAG
MstII site present (1.15 kb+.20 kb fragments)
βS: -Pro-Val-Glu- -CCTGTGGAG
MstII site gone (one 1.35 kb fragment)
βC: -Pro-Lys-Glu- -CCTAAGGAG
MstII site present (1.15 kb+.20 kb fragments)
Note: Restriction digest doesn’t work to diagnose HbC because MstII site is intact
Used to do protein electrophoresis, but liquid chromatography more common now
Can also have Sβ0-thalassemia, Sβ+-thalassemia, and HbSC (sickle syndromes)
Novel Property Mutation: Single base mutation at codon#6 in the β-globin gene changes glutamate to valine. HbS is 80% less soluble than HbA when not bound to O2, and polymerizes into long fibers that distort the RBC into a characteristic sickle shape. These sickled cells become lodged in the micro-capillaries and further exacerbate the sickling crisis.
Treat with Butyrate given to sickle cell patients increases the expression fetal hemoglobin which could reduce the polymerization of Hemoglobin S which leads to complications in Sickle Cell anemia.
