Inborn Errors of Metabolism
Online
Mendelian Inheritance in Man (OMIM)
Alkaptonuria (Garrod 1902) (OMIM
citation 203500)
Homogentisic Acid (formerly alkapton) accumulates in urine black
diapers
dark (ochronic) pigment
deposited in cartilage of nose & ears
Alkaptonuria
is a defect of Homogentisic Acid
Oxidase
Homogentisic Acid
accumulates in urine, blood, & cartilage
phenotype results from build-up of
substrates: not life-threatening
[Alkaptonuria provides an excellent
example of Ascertainment Bias in human
genetics]
Defective of tyrosinase in melanocytes
tyrosinase in
other organs unaffected (separate locus)
Sickle
Cell Anemia (Neel & Beet 1949) (OMIM citation 603903)
Defect of beta-globin subunit of
hemoglobin tetramer
recall: two alpha + two
beta chains
One beta-chain
allele inherited from each parent
protein
tetramers occur in ratio 1 MM : 2 FM : 1
FF [M = Mother, F = Father]
Both
alleles are expressed in molecular
phenotype:
call this "co-dominant"
expression
Standard hemoglobin has standard allele (A)
for beta chain
Alternative
allele (S) when homozygous (SS) produces sickle-cell anemia
crystallization of hemoglobin molecule as parallel fibers
& consequent
"sickling" of
red blood cells at low [O2]
causes
an infarctive crisis
pleiotropic effects include anemia &
skeletal anomalies
Heterozygotes
(AS) show "sickle-cell trait": mild anemia
25% of hemoglobins are SS: AA & AS tetramers don't crystallize readily
Both alleles are expressed in sickling phenotype
A mutation of the
primary beta-globin gene DNA
sequence
Huntington
Disease
(formerly Huntington's Chorea) (OMIM citation 143100)
Progressive, degenerative neural disorder; uncontrolled ("choreic") movements
Late onset: first symptoms may not appear until after
child-bearing years
Biochemical
indications ambiguous in early stages
A
genetic counseling
ethical dilemma:
Tiresias'
Dilemma: 'It is but sorrow to be wise when
wisdom profits not.'
Very common
in some pedigrees
huntingtin protein [sic]
has extra Gln residues at N-terminus
due to poly-CAG at 5' end of gene
poly-glutamine
tract forms plaques on Central Nervous System
Phenotypic effect is a consequence of the presence of huntingtin [sic]
protein
in homozygotes and heterozygotes,
irrespective of standard protein
Huntington Disease therefore
shows dominant expression:
Alleles
with poly-CAG tract
dominate expression of non-poly-CAG alleles
(Woody
Guthrie had it: some of his tunes;
Last thoughts
on Woody Guthrie by Bob Dylan)
All text material ©2024 by Steven M. Carr