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Pathology
Lecture 11 Hereditary Disorders
1) Know the major types of mutations and be able to give an example of each.
Point Mutation (missense, nonsense) – replacement of one base pair with another
creating a codon for a different amino acid (missense) or a stop codon (nonsense). Ex:
Sickle cell anemia.
Frameshift (deletion or insertion) – addition or removal of a number of base pairs
causing the reading frame to shift and thus resulting in faulty transcoding downstream
from the mutation. Ex: Tay Sachs disease.
Trinucleotide repeats – excessive reproduction of the same three base pairs in
sequence causing increased susceptibility to genetic disease. Ex: Fragile X syndrome
(CGG) and Huntington’s Disease (CAG).
2) Know the mode of inheritance, pathological features and clinical presentation of
the disorders discussed in lecture.
Disorder
Mode of
Inheritance
Familial
Autosomal
Hypercholesterolemia Dominant
Adult Polycystic
Kidney Disease
Autosomal
Dominant
Gaucher’s disease
Autosomal
Recessive
Tay-Sachs
(GM2 gangliosidosis)
Autosomal
Recessive
Niemann-Pick
disease (Type A)
Autosomal
Recessive
Fragile X syndrome
X-linked
Down Syndrome
(Trisomy 21)
Cytogenic
Klinefelter’s
Syndrome
Cytogenic
Turner’s Syndrome
Cytogenic
Pathological Features
Clinical Presentation
Mutations in chromosome
19 (35 identified) for the
cell surface receptor for
LDL removal.
Hundreds of cysts form all
over the nephron. Three
different mutations exist.
Increased plasma LDL
accumulating to form arterial
plaques and lipid laden
macrophages (xanthomas).
Chronic pain, hypertension, and
bilateral enlargement of the
kidneys. Other organs may be
involved.
Splenomegaly (anemia,
leucopenia, thrombocytopenia),
Bone involvement (pain and
fractures)
Motor and mental deterioration.
“Cherry red spot” on macula,
vision impairment and blindness.
Death occurs at 2-3 years.
Mutation of gene encoding
β-glucosidase. Phagocytic
cells accumulate large sums
of glucocerebrosides.
Mutation of α-subunit of
hexosaminidase A gene.
GM2 ganglioside
accumulates in all organs
(mostly neurons and retina)
Mutation of gene for
Loss of motor and mental
sphingomyelinase. Foam
function. Progressive wasting
cell formation in spleen,
and death by age 3. (Type B is
lymph nodes, bone marrow, less severe with no CNS
GI tract and lungs.
involvement – live to adulthood)
Long repeating sequence of Leading cause of familial mental
trinucleotides (CGG) on the retardation. Constriction in the
X chromosome.
long arm of X chromosome.
Progressive MR, flat face and occiput, reduced interpupillary
distance, epicanthal folds, brushfield spots, small stature,
“Simian crease”, increased risk of Leukemia, heart defects,
heart disease, and Alzheimer’s disease.
47, XXY – Tall stature thin build, no masculinization at
puberty, feminine characteristics predominate (high voice,
gynecomastia), and Azoospermia (infertility).
45, X – Primary amenorrhea and sterility, short stature, neck
webbing, wide carrying angle of arms, broad chest,
cardiovascular abnormalities, oocyte degredation (none by 2yr),
and ovaries are converted to fibrous streaks (uterus+ normal)
3) Be able to identify the major chromosome abnormalities secondary to alterations
in chromosome structure and/or number.
Alterations in Chromosome structure include:
Deletions, Duplications, Inversions, and Translocations, which result from
chromosome breakage followed by loss or rearrangement of material.
Alterations in Chromosome number include:
Polyploidy – more than two complete chromosome sets, usually resulting in
spontaneous abortion.
Trisomy – three repeats of a chromosome. Most result in spontaneous abortions but
trisomies of chromosomes 13, 18, 21, X, and Y do occur with appreciable frequency.
Monosomies – most are nonviable, except Turner’s syndrome (45, X).