Chromosomal Disorders: Sex Chromosome Abnormalities
Turner Syndrome
-an example of monosomy, in which a girl is born with only one sex chromosome, an X chromosome.
-a rare disease with an incidence of 1 in 2500 female births, it is nevertheless the most common sex
chromosome abnormality of human females.
Klinefelter Syndrome
-is a result of an additional X chromosome.
● male with genotype 47, XXY are classified as having a sex chromosome trisomy (three sex
chromosome), because they carry two X chromosomes and Y chromosome.
● The most common feature of this syndrome is infertility.
● The XXY has an increased risk for developing malignancy, including breast cancer, germ cell
tumors, non-Hodgkin lymphomas, and lung cancer.
● The XXYY syndrome is a variant of KS with hypogenitalism disorders, mental retardation, and
psychiatric problems.
SINGLE-GENE DISORDERS
These disorders are caused from mutations in a single gene occurring in all cells of the body.
Achondroplasia (ACH)
● most frequently encountered type of generic dwarfism.
● It is a skeletal disorder. ACH is characterized by a disproportionately short stature and other
skeletal abnormalities resulting from a defective gene coding for fibroblast growth factor receptor
3 (FGFR3).
● Majority of ACH cases are caused by unique amino acid substitution of G380R as a result of G to
A transition (97%) and G to C transition (3%).
● FGFR3 gene makes a protein called fibroblast growth factor receptor 3 that is involved in
converting cartilage to bone. FGFR3 is the only gene known to be associated with
achondroplasia.
Alpha-1 Antitrypsin Deficiency
● causes low levels of, or no, alpha-1 antitrypsin (AAT) in the blood.
● Predominantly affects the lungs and liver.
● AAT is a protein that is made in the liver and is released into the bloodstream AAT protects the
lungs so they can work normally. Without enough AAT, the lungs can be damaged, and this
damage can make breathing difficult.
● Most individuals who have one normal gene can produce enough AAT to live healthy lives,
especially if they do not smoke.
Autosomal Dominant Polycystic Kidney Disease (PKD)
● the most common forms of polycystic kidney disease.
● PKD is a genetic disorder characterized by the growth of numerous fluid-filled cysts in both
kidneys.
● The progressive expansion of PKD cysts slowly replaces much of the normal mass of the
kidneys, can reduce kidney function, and lead to kidney failure.
● PKD also can cause cysts in the liver and problems in other organs, such as the heart, blood
vessels in the brain.
Cystic fibrosis
● the most common fatal autosomal recessive genetic disease in the US.
● CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)
gene, whose protein product is involved in the transport of chloride ions across the apical
membrane of epithelial and blood cells. Loss of CFTR protein function causes the thickened
extracellular mucus to accumulate, which impairs mucociliary clearance in the airways. CK
prominently leads to microbial pathogen colonization in the lungs, followed by recurrent
pulmonary infection and chronic inflammation.
Duane’s Retraction Syndrome
● congenital anomaly of the sixth cranial nerve nuclei with aberrant innervation supplied from the
third cranial nerve.
● It is the most common of the congenital cranial dysinnervation disorders.
Duchenne Muscular Dystrophy
● is an X-linked recessive disorder.
● It occurs in boys and it is caused by an alteration in dystrophin gene, called the DMD gene , that
can be inherited in families in an X-linked recessive fashion.
● Boys with Duchenne muscular dystrophy do not make the dystrophin protein in their muscles.
● Dystrophin is the largest gene in the human genome. The full length transcript expressed in
human skeletal muscle encodes of protein of 3685 amino acids.
● the well-known types of DMD-causing mutations include large mutations (deletion larger than 1
exon), large duplications (larger than 1 exon), small mutation (deletions less than 1 exon), small
insertions (less than 1 exons), splice site mutations (less than 10 base pair from exon), point
mutation (nonsense, missense) and mid intronic mutation.
Fragile X syndrome (FXS)
● the most common monogenic cause of intellectual disability and autism.
● partial or complete loss-of-function mutations in the fragile X mental retardation 1 (FMR1) gene
cause FXS. Most FXS affected individuals harbor a hypermethylated CGG-repeat stretch in the
5’-untranslated region of the FMR1 exon.
● absence of the FMR1-encoded fragile X mental retardation protein (FMRP), which is critical for
neuronal development and synaptic plasticity, results in the manifestation of FXS.
Hemophilia
● is a bleeding disorder that slows down the blood clotting process.
● individuals with hemophilia often have longer bleeding after an injury or surgery, while severe
bleeding into the joints and muscles.
● is caused by permanent gene changes. mutations in the FVIII gene cause hemophilia A, and
mutations in the FIX gene cause hemophilia B.
● being an X-linked recessive disorder, females are generally not affected although they can be
carriers of this disorder.
● Hemophilia A and B are diagnosed by measuring factor clotting activity. Hemophilia A have low
factor VIII clotting activity while hemophilia B has low factor IX.
Hungtington’s disease (HD)
● an autosomal dominant genetic neurodegenerative disorder that can affect motor, cognitive and
psychiatric functioning.
● mutant hungtington protein (mHTT) gains toxic function, primarily in medium spiny neurons.
● the mHTT is ubiquitously expressed and evidence is growing that it causes cytotoxicity not only in
the CNS but also in the peripheral tissue of patients with HD. HD is progressive
neurodegenerative disorder that presents with motor symptoms, cognitive impairment, and
psychiatric disturbances.
Marfan Syndrome
● the most common inherited disorders of connective tissue.
● The most notable clinical symptoms occur in the eyes, skeleton, connective tissue, and
cardiovascular systems.
● The most common symptom is myopia which is the nearsightedness from the increased curve of
the retina because of connective tissue changes in the globe of the eye.
● individuals with Marfan syndrome also have an increased risk of retinal detachment, glaucoma,
and early cataract formation.
Sickle Cell Disease
● an autosomal recessive disorder, the most common inherited blood disorder in the US.
● is caused by mutation in the hemoglobin-B (beta) gene found on Chromosome 11. Hemoglobin
transports oxygen from the lungs to other parts of the body. Red blood cells with normal
hemoglobin are smoother and round and glide through blood vessels. In people with sickle cell
disease, abnormal hemoglobin molecules (Hbs) stick to one another and form long,
rod-like-structures. These structures cause red blood cells to become stiff, assuming a
sickle-shape that causes them to pile up, causing blockages and damaging vital organs and
tissues.
● The sickle cell also blocks the flow of blood through vessels, resulting in lung tissue damage that
causes acute chest syndrome, pain episodes, stroke, and priapism. It also causes damage to the
spleen, kidneys, and liver. The damage to the spleen makes patients, especially young children,
easily overwhelmed by bacterial infections.
Thalassemia
● group of autosomal recessive inherited diseases of the blood that affect a person’s ability to
produce hemoglobin.
● The two main types of thalassemia are called “alpha” and “beta” depending on which part of an
oxygen-carrying protein in the red blood cells is lacking.
Tay-Sachs Disease
● is a fatal autosomal recessive genetic disorder, most commonly occurring in children.
● TSD is caused by mutations in the HEXA (hexosaminidase-A) gene localized on chromosome 15.
Without normal HEXA, a fatty substance, or lipid, called GM2 ganglioside, accumulates
abnormally in cells, especially in the nerve cells of the brain. The ongoing accumulation causes
progressive damage to the cells and leads to a neurodegenerative disease.
Alcohol dependence
● common, complex psychiatric disorder characterized by the excessive and compulsive use of
alcohol which often results in physical and social consequences.
● Overconsumption of alcohol is known to be a contributing factor to more than 60 diseases.
● The most robust association with AD has been with the alcohol metabolizing enzyme genes,
especially ALDH2 in East Asian populations, and SDH1B in European-American and
African-American populations.
Charcot-Marie-Tooth Disease
● the most common inherited neuromuscular disorders with an incident of 1 in every 2500
individuals worldwide. The classical symptoms include slowly progressive distal muscle
weakness, muscle atrophy, and sensory loss of the lower and then upper limbs.
● as the motor and sensory peripheral nerves are affected, it is also called hereditary sensory and
motor neuropathy.
● The three most common genetic forms of CMT are those caused by mutations in GJB1, MPZ,
and MFN2, accounting for the majority of the additional yield of current genetic testing.
Cri du chat Syndrome
● known as 5p-syndrome and cat cry syndrome. It is a rare genetic condition caused by the
deletion of genetic material on the small arm of chromosome 5, and is among the most common
deletion syndromes.
● The hallmark features of CdCS include a high-pitched monotonous cry, low birth weight,
microcephaly, hypotonia, poor growth, and development delay.
Cardiovascular Disease (CVD)
● leading cause of morbidity and mortality in developed countries.
● hypercholesterolemia and Tangier disease generally are well recognized and their genetic
backgrounds have been explained.
● With increasing age, arterial walls typically undergo gradual stiffening, thickening, accumulation of
atherosclerotic plaques, and deposition of calcium. Structural changes, such as a vascular
thickness, calcification, plaque composition, and pulse wave velocity.
Dominant Optic Atrophy (DOA)
● most common hereditary optic neuropathy that severely impairs vision. DOA is caused by a loss
of retinal ganglion cells located only in the inner retina, and projecting their axons via the optic
nerve to the brain. Retinal ganglion cell loss and atrophy of the optic nerve are accompanied by
weakening of the optic nerve and the characteristics of the fundus with pallor of the optic disc.
● Mutations in two genes- OPA1 and OPA3- and three loci- OPA4, OPA5, OPA8- are known for
DOA. OPA1 is a multifunctional protein located within the mitochondrial inner membrane, which
regulates a number of critical cells.
● The OPA1 mutations can affect mitochondrial fusion, energy metabolism, apoptosis, calcium
levels, and maintenance of mitochondrial genome integrity.
● the lack of OPA1 function results in a misbalance toward mitochondrial fission that leads to
mitochondrial network fragmentation, impaired mitochondrial oxidative phosphorylation, increase
in reactive oxygen species, and altered calcium homeostasis.
Parkinson’s Disease (PD)
-Neuronal development requires both mitochondrial dynamic proteins Drp1 and mitofusin-2. PD shows
abnormal mitochondria dynamics
-autosomal recessive mutations in mitophagy related proteins, such as PINK1 and Parkin. Mutations in
one or both proteins impair mitophagy and cause neurons to accumulate Drp1, resulting in an excessive
mitochondrial fission, oxidative stress and reduced ATP production.
-PD is a common, age-related progressive neurodegenerative disease. In PD degeneration of
dopaminergic neurons between the substantianigra and striatum occurs. As a result, a great majority of
dopamine-producing cells in the substantianigra is lost in patients.
-Genes responsible for EARLY ONSET disease: Parkin (PARK2), ubiquitin carboxy-terminal hydrolase L1
(UCH-L1), PTEN Induced Putative Kinase (PINK1), oncogene DJ1 (DJI1)
-Genes responsible for LATE-ONSET disease: a(alpha)-synuclei (SNCA) and leucine-rich repeat kinase2
(LRRK2)
