DISEASE BY INHERITANCE PATTERN PART 2
exception of terms like holandric
OUTLINE
I PATTERNS OF INHERITANCE
II X-LINKED PATTERN OF INHERITANCE
III X-LINKED RECESSIVE GENETIC DISORDERS
A Duchenne Muscular Dystrophy
B Hemophilia A
C Fragile-X Syndrome
IV X-LINKED DOMINANT GENETIC DISORDERS
A X-Linked Hypophosphatemia / Vit. D Resistant
Rickets
B Alport Syndrome
DISEASE BY INHERITANCE PATTERN
PATTERNS OF INHERITANCE
● AUTOSOMAL DOMINANT
● AUTOSOMAL RECESSIVE
● X-LINKED
○ DOMINANT
○ RECESSIVE
X-LINKED PATTERN OF INHERITANCE
● X-link pattern of inheritance are genes or traits that
are linked to the X chromosome; if the gene is on
the X chromosome it is X-linked, if it is on the Y
chromosome it is Y-linked.
● Genes on X chromosome: X-linked
● Genes on Y chromosome: Y-linked
● For X-linked traits:
o Females XX, XX*, or X*X*
▪ females having the two XX
chromosomes, the female will
either inherit 2 normal X
chromosomes, 1 normal and 1
with the affected, or both of the X*
chromosomes housing
affected gene
▪ Female can be homozygous if the
female has either 2 affected or 2
normal X chromosomes.
▪ Females can also
heterozygous if only 1 of the X
chromosomes is affected
o Males XY or X*Y
▪ For males either they will inherit
the normal X and Y chromosome
from the father, or the affected X
and normal Y chromosome
o Males cannot be homozygous or
heterozygous, they are hemizygous for
genes on X
▪ Because they only have 1 X
chromosome
o Distinctive pattern of inheritance
▪ In rare instances there is a Y-
linked pattern of inheritance,
because the Y chromosome
contains the instruction or the
genetic information necessary to
produce proteins necessary for
spermatogenesis and
testosterone formation; With the
traits.
▪ A male with a Y-linked gene
mutation is essentially infertile - he
could not pass Y-linked trait to his
male offspring
▪ Holandric traits in males can be
seen in some parts of India, where
they have long hair in their
external auditory canal.
X-LINKED RECESSIVE GENETIC DISORDERS
Table 1. Examples of X-Linked Recessive Genetic Disorders
TRAIT PHENOTYPE
Red-green Inability to see green and red
colorblindness colors
Hemophilia A Inability to form blood clots
Lesch-Nyhan Lack of HGPRT protein, mental
syndrome retardation, self-mutilation
Duchenne-type, progressive
Muscular dystrophy
condition with muscle wasting
DUCHENNE MUSCULAR DYSTROPHY
● Most common x-linked recessive muscular
dystrophy
● Inherited disorder of skeletal muscle
● DMD gene deletion/frameshift mutation -> (-)
Dystrophin
o Mutation in the DMD gene, which encodes
information to produce dystrophin. So, if
there is a deletion or frame shift mutation in
your DMG genes you will not be able to
dystrophin
● Dystrophin:
o Key component of Dystrophin Glycoprotein
Complex (DGC)
o Links the cytoskeleton and the BM outside
the cell the muscle fibers - provides
the myofiber stability
▪ Acts as an anchor between the
cytoskeleton of the muscle cells
and the surrounding basement
membrane of the sarcolemma,
be which enables proper contraction
of the muscle fibers
● (+) Myofiber defects -> (+) membrane tears which
causes (+) Ca2+ influx -> (+) myofiber
degeneration
o The lack of dystrophin causes membrane
tears in the muscle fibers because of the
defect of DGC
o The membrane tears leave an opening in
the muscle fibers, which causes an influx of
calcium ions. This influx would result into
the degeneration of your myofibers
▪ During muscle cell death, when a
person dies, there is a
dysregulation of the calcium ions
in and out of the cell because
there is already inactivity (the
person is already dead) - all
cellular process will come to a halt
and included in that is the
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 regulation of calcium ions in and
out of the muscle cells
▪ Calcium is an intracellular ion, so,
the dysregulation of the balance of
calcium ions in and out of the
muscle cell, which causes an
accumulation of calcium ions
inside the cell will stiffen the
muscle fiber. The actin and
myosin filaments will come to a
stop, and the surge of calcium ions
will hold them in place that is why
you have rigor mortis (hardening
of the extremities) in a deceased
patient after a few hours. The
muscles will assume a paralyzed
state where the actin and myosin
filaments will not intertwine
● “Fatty Infiltration” of muscle fibers

o There will be damage to the muscle fibers

in the muscle cells such that the muscle
cells will be replaced by fat or adipose
tissue, and fibrotic tissue.
o As seen in the muscle tissue, there are
scanty muscle tissue fibers, because they
are replaced by adipose tissues (white
patches).
o Pseudohypertrophy can be observed,
where there is an abnormally large size of
the extremity, but upon viewing in cross-
section in a histologic slide, the majority of
the muscle cells are replaced by fat. This
makes the muscles ineffective, where they
cannot support or move the body weight.
● Muscle weakness, pseudohypertrophy, joint
contractures, cardiomyopathy
o Pseudohypertrophy: The muscle fibers
will appear large, but it contains more fat
rather than muscle cells
o Joint contractures: joint deformities in
which the patient can no longer move
his/her joint due to the impairment of the
muscles. When movement of the joints are
halted in a long period of time, it will
eventually develop contractors where the
synovial joints will harden.
o Cardiomyopathy: cardiac muscles are
also affected
● Muscular dystrophy is a spectrum of disease. In the
image, where the patient is suspected to have
Duchenne muscular dystrophy, even in their younger
years, their advancement in motor development is
expected to be hindered, because of the impaired
muscles. Even if the child is already 3 or 4 years old,
they are still having difficulties in standing, sitting,
walking, and, etc…. Even as the child progresses
into 10 yrs old, patients with muscular dystrophy
would have early dependence on prosthetics or
wheelchairs.
HEMOPHILIA A
● Most common hereditary disease associated with
LIFE-THREATENING BLEEDING
● Deletions, nonsense mutations in Factor VIII = (-)
Factor VIII synthesis
o Factor VIII is part of the intrinsic pathway of
the coagulation cascade
o If there is a factor lacking in the coagulation
pathway, this will cause problems in
bleeding control
● X-Linked Recessive
o Males and Homozygous Females affected
● Clinical Manifestation
o Easy bruising
o Massive hemorrhage
o Hemarthrosis
▪ Bleeding in the joints

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FRAGILE-X SYNDROME
● Trinucleotide repeat disorder
● X-linked Recessive
● Second most common cause of Mental Retardation*
o Down syndrome is the most common cause
of Mental Retardation
● FMR1 (Familial Mental Retardation 1) Gene
(Xq27.3) trinucleotide mutation
o “Fragile” site in the X chromosome
▪ The X chromosome has an extra
appendage that can be easily
broken down/removed
▪ There are some stains actually
that there is a discontinuity of the
staining of the chromosome
o The gene is located in the long arm of the X
chromosome
o Loss of FMRP (Familial X Mental
Retardation Protein) function
● Signs and symptoms/Clinical Manifestation
o Neurodegenerative effects - MR
o Abnormal Facial Features
▪ Long face w/ large mandible
▪ Large everted ears
o Macro-orchidism (90%)
▪ Large testicles
In the right most chromosome, there is a discontinuity of the
staining of the chromosome where there is a faint staining in
the connection between the large part and the fragile part of
the chromosome
● FMR1 gene
o Located on Xq27.3 (long arm of the X
chromosome)
o Multiple trinucleotide tandem Repeats of
CGG
▪ Trinucleotide: 1 cytosine and 2
guanine(CGG)
▪ There is a repeating trinucleotide
(CGG) along the DNA strand of
the FMR1
o Normal: 6-55 (ave. 29) repeats of the CGG
o Premutation: 55-200
▪ The appearance of a particular
number of CGG repeats in the
FMR1 gene does not guarantee
the clinical manifestation of the
Fragile-X syndrome
▪ These are very subtle changes,
and sometimes phenotypically
normal offspring with premutation
defect
o Full Mutation: 200-4000 or greater
▪ This will constitute the
manifestation of the phenotype of
the fragile-X syndrome
● Amplified CGG repeats
o During the translation of this specific gene,
the CGG repeats will be recopied. The next
time that the DNA strand is transcribed, it
might produce another set of trinucleotide
(CGG) repeats between the normal range
(6-55)
▪ Sometimes the trinucleotide
repeats would be excessively
copied
▪ Amplification: copied more times
than normal
o Carrier female > Carrier male
▪ A carrier female has a greater
amplification of the CGG repeats
than a carrier male
▪ Once the DNA is transcribed in a
female oocyte, the number of
times that this CGG repeats will be
recopied would be greater. There
are more generated copies, and
there are multiple times of copying
(greater times of copying) in an
oocyte containing the premutation
variant of FMR1 gene.
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In the diagram, there is a carrier male and normal female.
● The carrier male, having the premutation variant of
the FMR1 gene, may exhibit phenotypically normal
or may exhibit subtleties in the clinical manifestations
– but for the most part, the carrier male would have
normal phenotype
● The resulting offspring of a carrier male and normal
female, would result in a 50% carrier female and 50%
normal male. This indicates that all males are normal
and all females would be carriers.
o During the formation of oocytes by
oogenesis, in the carrier female, the
premutation gene will expand into a full
mutation because there is frequent
copying/replication of the CGG repeats.
There is greater amplification of gene
copying in a female carrier, ones it she
will produce oocyte through oogenesis
which is greater compared to the
spermatogenesis in males
o Once there is an existence of a carrier
female or inheriting the premutation gene
from the carrier male, that permutation can
or is most likely going to progress to a
full mutation gene
o In carrier males, it will only be
premutation
● Once the carrier female mates with a normal male
and passes the premutation gene to her offspring, to
the 2nd generation, there would be a full mutation of
the gene.
o Once a carrier female and a normal
(unrelated) male would have a male
offspring, 50% of the time the child will
inherit the full mutation of the gene which
manifests into the sign and symptoms of
fragile-x syndrome, or 50% normal.
o For female offspring, there is 50% chance
that a female child would obtain the normal
chromosomes, or 50% chance of getting
the fully mutated X chromosome. However,
since only one X chromosome is affected,
only 50% of the female offspring that
inherited the affected x chromosome would
exhibit the clinical manifestation. The
clinical manifestation for female offspring
would sometimes only manifest into mild
form mental retardation
● RECAP: The 1st generation offspring, all the sons are
normal while all the daughters are carriers
(premutation). During oogenesis of a carrier female,
the premutation gene that is inherited from a carrier
male would expand into a full mutation because once
the female carrier would produce oocytes, the
affected chromosome would have a greater
amplitude of replication of the CGG repeats. Hence,
in the next generation, all males who would inherit
the X chromosome with the full mutation are affected.
However, only 50% of the female offspring that
inherited the X chromosome with full mutation would
be affected (phenotypically), and of those affected
only mild symptoms are observed.
● Too many CGG repeats -> hypermethylation of
the 5’region -> (-) No FMRP
o A normal FMR1 gene must only contain
around 6 to 55 trinucleotide CGG base
repeats. If it exceeds beyond the
premutation, it will become a full mutation.
This will cause hypermethylation of the
5’region.
▪ Hypermethylation is one of the
correcting stages in DNA
transcription – one of the ways
that the DNA transcribed is
proofread and corrected in such a
way that there are no defects or
mistakes on the transcribed DNA.
o Too many CGG repeats would cause
Hypermethylation of the entire 5’region of
the gene, up until such time that this would
silence the gene.
▪ To silence the gene means to
devoid the gene’s capability to
produce the necessary
information to transcribe a mRNA
transcript
o A silenced FMR1 gene will result into no
FMRP production
● Familial Mental Retardation Protein (FMRP)
o Regulates intracellular transport of
polysomes to dendrites
▪ form a complex with the mRNA
transcript necessary within the
dendrites in the nerve cells, in a
form of Polysomes (FMRP +
mRNA transcript = Polysomes)
▪ This complex will be transported
within the dendrites to facilitate
synaptic function.
▪ In histology, the purpose of
dendrites is to serve as bridges to
other dendrites, axons, or nerve
cells, to give the necessary
electrical potential needed to
propagate the signal needed for
the next cell. This would form a
continuous neural signaling.
o Regulates translation
● Without the FMRP, there would be abnormal
dendritic development
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 o There would no longer be a vessel that
would carry the information necessary to
make the protein responsible for ensuring
the other processes of the dendrites
o The dendrites will become defected without
the FMRP
o Only abnormal ineffective dendrites are
produced by a person with fragile-x
syndrome, because of the lack of FMRP
caused by the hypermethylated FMR1 gene
(too many CGG repeats)
o There is a cascading of events, from a
particular mutation of the gene, to the
resultant purpose, in making whatever
protein necessary to perform a particular
physiologic function – In this case the
development of dendrites and to ensure
some degree of translational regulation of
the mRNA transcripts between the
dendrites
▪ The dendrites need the proteins
for it to propagate neural signals,
maintain the cell of the dendrite
itself, proteins necessary to make
other cell dendrites, and etc.
o Poor dendritic development = poor
synaptic development. There is difficulty
in forming synaptic connections between
the brain cells. Thus, causing some degree
of mental retardation. The more synaptic
connections are developed within the brain,
the higher the cognitive development could
be.
CLINICAL FEATURES:
● Neurodegenerative effects - MR
o IQ 20-60/80
o Ave: 50
o Low cognitive development or low IQ is
caused by the abnormal dendritic
development and the inability of the
dendrites to function due to the lack of
necessary proteins it needs to make the
physiological function characteristic of a
dendrites.
● Abnormal Facial Features
o Long face w/ large mandible
o Large everted ears – more common and
present even in young children
● Macro-orchidism (90%)
o Abnormally large testicles
X-LINKED DOMINANT GENETIC DISORDERS
X-LINKED HYPOPHOSPHATEMIA / VIT. D RESISTANT
RICKETS
● X-Linked Dominant
o Low levels of phosphate in the blood.
o Previously named Vit. D Resistant Rickets
because the signs and symptoms are
similar to rickets
▪ Rickets is a nutritional disorder
due to the deficiency of Vit. D. This
disease would characterize
patients having problems with
bone development.
o But in this case, it is a form of resistance,
which means the intake of Vit D. to
normalize the amount of it in the body would
be ineffective, the signs and symptoms
would still be apparent.
o It is not a nutritional defect, rather a defect
on the gene necessary to regulate and
balance calcium phosphate in the blood
which is necessary for proper
mineralization of bone
● PHEX (Xp22) gene mutation
o Located in the short arm of the X
chromosome
o (-) Deficiency of PHEX protein
▪ PHEX protein regulates the
fibroblast growth factor 23
(FGF23)
▪ The FGF23 plays a role in
regulation of phosphate
absorption by the kidneys.
Normally, once there is an
accumulation of phosphate in the
bloodstream, the FGF23 would
exert its effort promoting excretion
of excess phosphate levels from
the blood to the urine.
o (+) abnormal Vit. D receptor
● FGF23 excess due to absent PHEX protein
o Dysregulated PO4 reabsorption by the
kidneys
▪ This would cause excessive
excretion of phosphate by the
kidneys to the blood causing
hypophosphatemia
o Impaired bone mineralization
▪ Even with sufficient intake of Vit. D
to subsidize the mineralization of
the bones through the
reabsorption of calcium and
phosphate (necessary for bones),
since most of the phosphate is
secreted outside the body this
would also cause deficiency in
calcium. Both deficiencies
(Phosphate and calcium) means
that a person would have no
essential element to form effective
and strong bones.
● Mineral portion of the
bones are composed of
calcium phosphate
● Abnormal bone development
o Compared to the normal or traditional
nutritional deficiency rickets, where you
could counteract the deficiency by intake of
supplements, in the X-Linked
Hypophosphatemia, this measure is
ineffective because the problem is in the
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 mutation of the gene that supposed to
regulate the levels of phosphate in the
blood
One of the most common clinical manifestations in both
vitamin D deficient crickets or vitamin D resistant crickets,
where there is an ineffective bone mineralization of the
femoral and the tibiofibular bones which results in a bow
legging/legged deformity.
● There is a curvature of the long bones, since there is
minimal to absent mineralization of the bones, only
the collagen.
● There little amount of calcium phosphate in the
bones, causing a malleable characteristic of the
bones
● Since the long bones of the lower extremities are
designed to bear the vertical weight of the body,
these bones will give up causing the upward
curvature of the lower extremities (Bow legged
deformity)
ALPORT SYNDROME
● Familial Glomerular Disorder
o Glomerular disorders = affects the kidneys
● Mutation in the gene encoding GBM Type 4
Collagen:
o Multitude of genes (500 – 600 genes)
necessary to produce Type 4 collagen and
place them in the glomerular basement
membrane
o Defective assembly of Type 4 collagen
▪ There is still production of Type 4
collagen but these are defective in
quality
o α3, α4, and α5 chains
▪ In Alport syndrome, it is more
characterized by the defect in the
α5 chain of the Type 4 collagen
● Primarily X-Linked Dominant; w/ Autosomal
Dominant/Recessive Variants
o The mutation of the genes that encodes the
type 4 collagen can be found on
Chromosome 2, 13, and X
▪ Usually the mutation is in the X
chromosome but there are
some autosomal variant, either
in the chromosome 2 or 13
(autosomes)
● Kidney problems and Audiovisual defects
o The collagen in the glomerular basement
membrane is made up of Type 4 collagen
which is defective.
o Hematuria & ESRD or End-Stage Renal
Disease (most common Clinical
Manifestation)
▪ There is an ineffective filtering of
the kidneys because the
glomerular basement membrane
is defective (bad quality collagen
4), in such a way that the blood is
also excreted in the urine
▪ If this hematuria is prolonged until
adulthood, the patient is prone to
having chronic kidney disease and
ESRD
o Lenticonus / Hearing Loss
▪ Type 4 collagen is also found in
the cochlea, in the ancillary bodies
of the inner ear.
▪ Lenticonus: abnormal protrusion
(anterior or posterior) in the
surface of the lens of the eyes,
distorting the refraction of the light.
There might be some degree of
blindness for patients with Alport
syndrome. However, the lenses
are not detached, rather there is a
defect in the collagen fiber lining of
the lens.
▪ Not to be confused with Ectopia
Lentis in Marfan syndrome where
there is subluxation of the lens
because of the impairment of
ciliary zonules which hold the lens
together.
● In Marfan syndrome,
there is a breakage of the
ciliary zonules which
holds the lens together
that suspends them in
such a way that they are
positioned at the right
angle and degree
ensuring the passing
through of the light
through the lens
● In Marfan syndrome, the
collagen fibers is also
bad quality because of
fibrillin 1 Gene defect,
which displaces the
lenses of the eyes
● There is protrusion in the posterior portion of the
lens, due to the defective quality of the collagen
fibers at the back of the lens. This is a tightly
pressurized environment (inside the eyes).
● In Marfan syndrome, the ciliary zonules (not seen in
the image) are defective causing the displacement of
the lens or the subluxation of the lens
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