Simple and Complex Genetic Diseases

Simple: One gene -> one disease Example: sickle-cell anemia Complex: Many genes interacting

with other and the environment -> one

disease Examples: MS, Types I, II diabetes

Single Gene Disorders

Autosomal recessive Albinism Cystic fibrosis Phenylketonurea

Galactosemia

Metabolic disorder defect in galactose meatbolism, The problem in the enzyme galactose 1- phoshate

uridyl transferese, Which breakdown glucose. This leads to accumulation of galactose in blood,

leads to blood poisoning which cause: 1- Hepatomegaly 2- Cirrrhosis 3- Renal failure 4- Cataracts 5- Brain damage

Mucopolysaccharidosis

Absence of lysosomal enzymes (α-L-iduronidase) which digest Mucopolysaccharide (also named

Glycosaminoglycans) This sugar is found in the liquid

between joints and act as lubricant.

Autosomal dominant

Achondroplasia Askeletal disorder causeing

dwarfism, shortening in limbs and digits, enlargement in skull.

Caused as a defect in Fibroblast Growth factor Receptor Gene3 (FGFR3)

This leads to a defect in cartilage and bone growth.

Marfan syndrome

15q 15-21 Affect c.t Defect in FBN1 gene

Neurofibromatosis

17q11 Swallow sacs under skin affect

skin, bone and nerves Caused as a defect in the

Neurofibromin gene.

Brachydactyly

5p13 and 2q33 Problem in fingers Noonan syndrome Defect in PTPN11 gene which encode Protain Tyrosine Phosphatase, which

play a role in embryonic development, Differentiation and migration

Huntington's disease

4p16 Trinucleotide repeat expansion in

the gene which encode Huntington protein.

This leads to defect in the produced protein, degeneration in neurons, and chorea.

1 Glucose-6-ph. Dehydrogenase deficiency

X-Linked r Deficiency in Glucose-6-ph. dehydrogenase enzyme ( G6PDH) This enzyme is related to Pentose

phosphorylation Pathway This enzyme converts Glucose-6-ph to

6- Phosphogluconate delta-lactone

Duchenne muscular dystrophy

Defect in the gene which encode Dystrophin

Haemophilia A Defect in the gene which encode

Factor VIII

Hypophosphatemia

X-linked dominant disorders a form of vitamin D- resistant

rickets

Y-linked genes Sex determining gene (SRY) encodes

SDF which important in sex determination by playing a role in early stages of testis differentiation.

Any defect cause XY female (Swyer syndrome)

Translocation of part Y chromosome which contain SRY gene to X chromosome give XX male syndrome

ANT3 (adenine nucleotide translocase)

Produce enzyme change and transfer ADP from internal mitochondria to ouside as ATP

CSF2RA

Colony stimulating factor 2 receptor α

Produce cell surface receptor for growth factor

Control production, differentiation of granulocytes and macrophages.

H-Y gene

Plasma membrane protein Play a role in testis differentiation

ZFY

Zinc finger protein DNA binding protein that regulate

gene expression

Mitochondrial disorders

Mitochondrial myopathy neurodegenerative disorder seizures, diabetes mellitus, hearing

loss, short stature, and exercise intolerance are clearly part of the disorder.

MERRF syndrome

muscular disorders cause a dysfunction of the brain

and muscles (encephalomyopathies).

The most characteristic symptom of MERRF syndrome is seizures that are usually sudden, brief, jerking, spasms that can affect the limbs or the entire body.

Impairment of the ability to coordinate movements (ataxia), as well as an abnormal accumulation of lactic acid in the blood (lactic acidosis) may also be present in affected individuals.

Difficulty speaking (dysarthria), optic atrophy, short stature, hearing loss, and involuntary jerking of the eyes (nystagmus)

Leigh syndrome progressive neurodegenerative disorder in

one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord.

The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved.

The most common underlying cause is a defect in oxidative phosphorylation

Sideroblastic anemia abnormal production of RBCs which can evolve

into leukemia. Thus, the body has iron available, but cannot

incorporate it into hemoglobin The common feature of these causes is a

failure to completely form heme- whose biosynthesis takes place partly in the mitochondria. This leads to deposits of iron in the mitochondria that form a ring around the nucleus of the developing RBCs. This leads to a stage in bone marrow disorder that leads to acute leukemia.

Myoclonus involuntary twitching of muscles. The myoclonic twitches or jerks are

usually caused by sudden muscle contractions; Contractions are called positive myoclonus; relaxations are called negative myoclonus.

myoclonic jerks are also a sign of a number of neurological disorders.

Hiccups are also a kind of myoclonic jerk specifically affecting the diaphragum.

myoclonus is one of several signs in a wide variety of nervous system disorders such as Parkinson’s disease, Alzheimer’s disease, and some forms of epilepsy

Myopathies

affect muscles connected to bones (called skeletal muscles), such as the biceps in the upper arm and the quadriceps in the thigh.

Myopathies can be caused by inherited genetic defects (e.g., muscular dystrophies), and endocrine, inflammatory , and metabolic disorders.

Cardiomyopathy

the heart muscle becomes inflamed and doesn't work as well as it should.

There may be multiple causes including viral infections.

Cardiomyopathy can be classified as primary or secondary.

Primary cardiomyopathy can't be attributed to a specific cause, such as high blood pressure, heart valve disease, artery diseases or congenital heart defects.

Secondary cardiomyopathy is due to specific causes. It's often associated with diseases involving other organs as well as the heart.

Renal tubular acidosis (RTA)

is a disease that occurs when the kidneys fail to excrete acids into the urine, which causes a person's blood to remain too acidic.

Without proper treatment, chronic acidity of the blood leads to growth retardation, kidney stones, bone disease, and progressive renal failure.

The word acidosis refers to the tendency for RTA to lower the blood's pH. When the blood pH is below normal (7.35), this is called acidemia.

Its causes are diverse, and its consequences can be serious, including coma and death.

Variation in chromosome number

Trisomy 18 (47,XY,+18) – Edward Syndrome

Trisomy 18• Incidence 1:3333 live births• Most common abnormality in stillbirths with multiple congenital abnormalities• Prenatal growth deficiency resulting in a small for gestational age infant (SGA)• 90% congenital heart defect VSD• 10% alive at one year• Marked developmental disability

Trisomy 18 -Physical Features

• Prominent occiput • Micrognathia • Microcephaly • Low set malformed ears • Characteristic clenched fists • Rocker-bottom feet • Short big toe that is dorsiflexed

Trisomy 18 –Edward Syndrome Trisomy 18 • Prominent Occiput • Low-set malformed ears • Small chin • Clenched fists

Trisomy 18 • Ocular manifestations in 10% • Low-arch dermal ridge pattern • Underdeveloped nails • Congenital anomalies of

lungs,diaphragm, and kidneys • Hernias, cryptorchidism, rectus muscle

separation

Trisomy 13 (47,XY,+13) – Patau Syndrome

Trisomy 13 • Incidence 1:5,000 births • Distinctive malformation pattern (Craniofacial and Central Nervous

System) • 95% spontaneously aborted • Survival rate and development

similar to Trisomy 18

Trisomy 13 PatauSyndrome • Microcephalywith sloping forehead • Holoprosencephaly • Ophthalmologic abnormalities

microphthalmiaor anophthalmia Colobomataof iris and ciliarybody

• Cleft lip +/-palate • Low set ears with abnormal helices

Trisomy 13 PatauSyndrome • Cardiac defects: ASD, PDA, VSD • Males: cryptorchidism ; Females:

Bicornuateuterus • Polycystic kidneys • Aplasiacutis congenita • Polydactylyof hands +/-feet • Rockerbottomfeet

Turner syndrome

SHORT STATURE OVARIAN DYSGENESIS INFERTILITY LEARNING DISABILITIES SPATIAL PERCEPTION

XXX females About one woman in 1000 has an extra

X chromosome. It seems to do little harm, individuals are

fertile and do not transmit the extra chromosome.

XYY males XYY males Incidence 1 in 1000

male births. May be without any symptoms.

Males are tall but normally proportioned.

Glu Ab 5i GTG CAC CTG ACT CCT GAG

GAG AAG TCT O O O 3i Sb 5i GTG CAC CTG ACT CCT GTG

GAG AAG TCT O O O 3i Val