Single gene disorders & X- Linked Genetic Disorders

SINGLE GENE DISORDERS
The mechanisms involved in single-gene disorders can be classified into four categories:
Alterations in the structure, function, or quantity of non enzyme proteins.
Enzyme defects and their consequences.
Defects in membrane receptors and transport systems.
Mutations resulting in unusual reactions to drugs.
Diseases caused by mutation in structural proteins
Marfan syndrome
Autosomal dominant disorder.
Abnormality affect fibrillin 1(gp secreted by fibroblasts).
Encode by FBN 1gene which maps to ch 15q21.
Over grwth of bones & myxomatous MV due to dysregulation of TGF ? production.”Marf Syn II”
Clinical manifestation related to 3 sys. (skel, eyes & CVS)
Morphology:
Skeletal abnormality:
The most obvious feature of marfan syndrome. (abnormal long legs, arms and fingers). High arches palate and hyperextensibility of joints.
2. Ocular changes:
Bilateral dislocation or subluxation of the lens.
3. Cardiovascular involvement.
Aneurysmal dilation (Fragmentation of tunica media of the aorta).
Aortic dissection.
Aortic incompetence& floppy valve.
Congestive cardiac failure.
Ehler –Danos syndromes:
(EDS) are ch by defects in collagen synthesis or structure.
All are single gene disorders.
The mode of inheritence encompasses all three of mendelian patterns.
Six clinical and genetic variants of EDS are recognised.
Tissues rich in collagen e.g. skin , ligaments and joints are frequently affected. (hyperextensible skin &hypermobile jo)
Classification of Ehlers-Danlos Syndromes (EDS)
Classical (I/II)
CL/F : Skin and joint hypermobility, atrophic scars, easy bruising.
Inheritance: Autosomal dominant.
Gene defects: COL5A1, COL5A2.
Hypermobility (III):
CL/F : Joint hypermobility, pain, dislocations.
Inheritance: Autosomal dominant.
Gene defects: Unknown.
Vascular (IV):
CL/F : Thin skin, arterial or uterine rupture, bruising, small joint
hyperextensibility.
Inheritance: Autosomal dominant.
Gene defects: COL3A1.
Kyphoscoliosis (VI):
Cl/F: Hypotonia, joint laxity, congenital scoliosis, ocular fragility.
Inheritance: Autosomal dominant.
Gene defects: Lysyl-hydroxylase.
Arthrochalasia (VIIa,b):
Cl/F: Severe joint hypermobility, skin changes mild, scoliosis, bruising.
Inheritance: Autosomal dominant.
Gene defects: COL1A1, COL1A2.
Dermatosparaxsis (VIIc):
Cl/F: Severe skin fragility, cutis laxa, bruising.
Inheritance: Autosomal dominant.
Gene defects: Procollagen N-peptidase.
Familial Hypercholesterolemia
Familial hypercholesterolemia:
It is a "receptor disease" that is the consequence of a mutation in the gene encoding the receptor for low density lipoprotein (LDL), which is involved in the transport and metabolism of cholesterol.
As a consequence of receptor abnormalities, there is a loss of feedback control and elevated levels of cholesterol that induce premature
atherosclerosis, leading to a greatly increased risk of myocardial infarction.
Incidence: 1:500.
70% of plasma ch. Transported through this pw.
2/3 of the resultant LDL metabolised through LDL recepter PW.
Scavenger PW responsible for metabolism of 1/3.
Cholesterol Homeostasis (feed back control):
Suppresses ch synthesis by inhibiting the activity of enzyme 3-HMG co A reductase. (Rate limiting enz.)
Activate the enz. Acyl co A: ch ACTA. Favor esterification & storage of CH.
Down regulate the synthesis of cell surface LDL recep.
Other function of CH. Membrane synthesis.
Diseases caused by mutations in enzyme proteins
Phenyketonuria
Autosomal recessive disorder cased by a lack of the enzyme phenyl alanin hydroxylase and consequent in ability to metabolize phenyalanine.
Cl.F. include severe mental retardation, seizures, and decreased pig. of the skin that can be avoided by restriction the intake of phenylalanin in the diet.
Female PKU pt. who discontinue dietary treatment can give birth to mentally retarded children with malformations due to transplacental passage of phenyalanin metabolites.
Galactosemia
Autosomal recessive disorder.
Inherited lack of galactose-1-phosphate uridyltransferase causing accumulation of galactose 1-phosphate and its metabolites.
Accumulation of G-1- ph & galactitol in many tissue. liver,spleen lens kid. Cerebral cortex.
Cl.F. include jaundice, liver damage, vomiting, diarrhea & E.coli sepsis.
Dx by assay of trasferase in leukocytes anf RBC , antenatal dx by enz. assay or DNA based testing.

lysosomal storage diseases
Common features of lysosomal storage dis.:
Autosomal recessive.
Commonly affect infants and young children.
Storage of insoluble intermediates in the MPS. Lead to HSM.
Frequently CNS involvement.
Cellular dysfunction due to storage of undigested material and secondary events e.g. Macrophage activation &release of cytokines.
Common in Ashkenazi jews.

X-linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome.
Only a few disorders have this inheritance pattern, with a prime example being X-Linked hypophosphatemic retickes.
Males and females are both affected in these disorders, with males typically being more severely affected than females.
X-linked recessive
X-linked recessive conditions are also caused by mutations in genes on the X chromosome.
Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women.
The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene and are therefore carriers.

X-linked recessive conditions include the serious diseases Hemophilia A, Duchenne muscular dystrophy and Lesh-Nyhan syndrome as well as common and less serious conditions such as male type baldness and red-green color blindness.
X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
Y-linked
Y-linked disorders are caused by mutations on the Y chromosome. Because males inherit a Y chromosome from their fathers, every son of an affected father will be affected. Because females inherit an X chromosome from their fathers, female offspring of affected fathers are never affected.
Since the Y chromosome is relatively small and contains very few genes, there are relatively few Y-linked disorders. Often the symptoms include infertility, which may be circumvented with the help of some fertility treatments. Examples are male infertility and hypertrichosis pinnae.
Inborn errors of metabolism:

It comprise a large class of genetic diseases involving disorders of metabolism.
The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrate) into others (products).
In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds.
Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases.
Micro RNA (mi RNA)
Micro RNAs (miRNAs):
are post-transcriptional regulators that bind to complementary sequences in the three prime untranslated regions (3 UTRs) of target messenger RNA trnscripts (mRNAs), usually resulting in gene silencing.