CYTOGEN MIDTERM: DISEASES OF THE PATTERN

OF INHERITANCE

4 Possible Patterns of Inheritance

 Autosomal recessive
 Autosomal dominant
 X-linked recessive
 X-linked dominant

Autosomal Recessive Pedigree

Xeroderma pigmentation
o An autosomal recessive genetic disorder of
DNA repair in which the ability to repair
damage caused by ultraviolet (UV) light is
deficient
o Multiple basal cell carcinomas (basaliomas)
and other skin malignancies frequently occur
AUTOSOMAL RECESSIVE GENETIC DISORDERS at a young age
o Metastatic malignant melanoma and
Autosomal Recessive Genetic squamous cell carcinoma
Disorders

Phenylketonuria
o Is caused by
absence of phenylalanine
hydroxylase (PAH)
enzymes activity resulting to
problem with phenylalanine
metabolism
o Build up of the
metabolic product of
phenylalanine causes mental retardation
o Albinism
o Musty odor of urine

Sickel Cell Anemia (SCA)

o High frequency in areas of West Africa,
Mediterranean Sea, Inda
o Abnormal hemoglobin molecules aggregate to
form rods
o RBC, cresent-or sickle-shaped, fragile and
break open

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o Hemoglobin consists of four protein subunits,
typically, two subunits called alpha globin and
two subunits called beta-globin
o Problem lies on the abnormality of the HBB
gene. The HBB gene provides instructions for
making beta-globin. HBB gene mutation o The sickle-shaped red blood cells die
products produces an abnormal version of
beta-globin known as hemoglobin S (HbS)

prematurely, which can lead to anemia.

Sometimes the inflexible, sickle-shaped cells get
stuck in small blood vessels and can cause
serious medical complications

Cystic Fibrosis (CF)

o CTFR gene: Cystic Fibrosis Transmembrane
Conductance Regulator Gene
— important in the balance of salt and
water in organs such as lungs and
pancreas
o CF causes production of thick mucus in lungs
and blocks airways
o CF affects glands that produce mucus and
enzymes (primarily affects the lungs and
digestive system)
o CF causes production of thick mucus in lungs
which blocks airways
o Develop obstructive lung diseases and
infections
o Mutations on the CFTR gene
o Defective chloride ion exchange system->
alterations in chloride, water, and salt
transport
o Results in heavy, thick, sticky mucus
production, clogging airway passages and
ducts
o Symptoms:
— Very-salty-tasting skin
— Persistent coughing, at times with
phlegm
— Frequent lung infection including
pneumonias or bronchitis
— Wheezing or shortness of breath
— Poor growth or weight gain in spite of a
good appetite

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 — Frequent greasy, bulky stools or  Affected individuals has at least one affected
difficulty with bowel movements parent
— Male infertility  Aa x aa: each child has 50% cahnce of being
affected

Achondroplasia
o People with achondroplasia have short
stature, with an average adult height of 131
centimeters (52 inches) for males and 123
cemtimeters (48 inches) for females
o Achrondroplasia is caused by a mutation in
fibroblast growth factor receptor 3 (FGFR3)
o In normal development
FGFR3 has a negative
regulatory effect on bone
growth
o In achrondroplasia, the
mutated form of the receptor
is constitutively active and
this leads to severely
shortened bones

Albinism
o Is a genetic condition which is the loss of
pigment in hair, skin and eye Familial Hypercholesterolemia

o A genetic disorder characterized by high

cholesterol levels, specifically vry high levels
of low-density lipoprotein (LDL, “bad
cholesterol”), the blood
o Many peopls have mutations in the LDLR
gene that encodes the LDL receptor protein,
which normally removes LDL from the
circulation

AUTOSOMAL DOMINANT GENETIC DISORDERS

 Requires one copy of the allele (Aa) rarely

present in a homozygous condition (AA)
 aa: Unaffected individuals

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 of one or more of these
substances

Marfan Syndrome

o The syndrome is caused by the misfolding of

fibrin-1, which forms elastic fibers in
connective tissue and contributes to cell
signaling activity by binding to and
Progeria
sequestring transforming growth factor beta
(TGF-Beta) o Caused by a mutation
o The mutated fibrillin binds poorly to TGF-Beta, o The person ages very rapidly
which results in an accumulation of excess o They die before they can reproduce
TGF-Beta in the lungs, heart valves, and aorta
o This is in turn causes abnormal structure and
function of vascular smooth muscle and
reduced integrity of the extracellular matrix,
which weaken the tissues and cause the
features of Marfan syndrome
o As a result, excess growth factors are
released and elasticity in many tissues is
Huntington’s disease
decreased, leading to overgrowth and
instability of tissues o In which the central nervous system starts to
break down around the age of 30

Porphyria
X-LINKED RECESSIVE TRAITS
o The porphyrias are a group of rare diseases in
 Genes on X chromosome: X-linked
which chemical substances called porphyrins
 Genes on Y chromosome: Y-linked
accumulate with high metabolism
 For X-linked traits:
o The body requires porphyrins to produce
o Females XX, XX*, or X*X*
heme, which carries oxygen in the blood
o Males XY or X*Y
 But in the porphyrias, there is a
deficiency (inherited or acquired) of o Males cannot be homozygous or
the enzymes that transform the heterozygous, they are hemizygous for
various porphyrins into others, genes on X
leading to abnormallly high levels o Ditinctive pattern of inheritance

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Fragile X syndrome
Duchenne Muscular Dystrophy (DMD)
o Most common form, affects 1/3,500 males
o Infants appear healthy, symptoms age 1-6
years
o Rapid, progressive muscle weakness
o Usually must use a wheelchair by age 12
o Death, age -20 from respiratory infection or
cardiac failure
o DMD gene on the end of X chromosome
o Encodes protein dystrophin that supports
plasma membrane during contraction
o If dystrophin absent or defective, cells are torn
apart
Hemophilia
o Lack of clotting: factor VIII in blood
o Affected individuals hemorrhage, often require
hospitalization to treat bleeding
o Hemophilia A most common form of X-linked
hemophilia
o Females are affected if XhXh, both parents
must carry the trait
o Factor VIII
 In 1980s, half of all people infected
with hemophilia became infected
with HIV
 Recombinant DNA technology now
used to make clotting factors free
from contamination
o The prevalence of severe learning difficulties
in males due to fragile X syndrome is about 1
in 4000
o This condition is initially diagnosed on the
basis of appearance of a gap (fragile site) in
the distal part of the long arm of the X
chromosome
o Diagnosis is now acheived by molecular
analysis of CGG (cytosine-guanine-guanine)
trinucleotide repeat expansion in the relevant
gene (FMR1)
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o These unusual findings are explained by the
nature of the mutation, which occurs in ‘pre-
mutation’ and ‘full-mutation’ forms
o Norma copy of gene <50 copies of CGG
trinucleotide
o Genes with premutation contain 55-199
copies
o Genes with full mutation contain >200 copies
of CGG
o This big number affects gene function, leading
to learning disabilities
o The main physical feature is often the
prominent ears
o Clinical findings in males
 Moderate-severe learning difficulty
(IQ 20-80, mean 50)
 Macrocephaly
 Macro-orchidism – postpubertal
 Characteristic facies – long face,
large everted ears, prominent
mandible and broad forehead,
most evident in affected adults
 Other features – mitral valve
prolapse, joint laxity, scoliosis,
autism, hyperactivity
o Fragile X syndorme is the second most
common genetic cause of severe learning
difficulties after down’s syndrome
X-LINKED DOMINANT TRAITS
 Males and females are equally likely to be
affected
 Xlinked hypophosphatemia or Vitamin D-
resistant rickets
o Is an X-linked dominant forms of
rickets that differs from most cases of
rickets in that ingestion of vitamin D is
relatively ineffective
o XLH is associtated with the mutation in
the PHEX gene sequence, located on
the human X chromosome
o The PHEX protein regualtes other
protein called fibroblast growth factor
23. Fibroblast growth factor 23
normally inhibits the kidney’s ability to
reabsorb phosphate into the
bloodstream
Alport syndrome
o Is caused by mutations in the genes involved in
collagen type IV biosyntesis
o Mutations in any of the above genes prevent
the proper production or assembly of the type
IV collagen network, which is an important
structural component of basement membrane in
the kidney, inner earr and eye


Traits
is

common in pedigree
 Affected fathers pass to ALL of their
daughters

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