Week 12 Cyto

• 1. X linked dominant disorders


  • Seen more commonly in females than in males, or in the case of some diseases, affect only females (XX)
  • A mutation would have to occur in both copies of the gene to cause the disorder
  • If 1 chromosome is affected, female is considered as CARRIER
  • Hemizygous males are so severely affected, they do not survive
• 1. X linked dominant disorders are uncommon relative to other types of mendelian diseases and show an excess of affected females in a family, since women have two X chromosomes
• 1. X linked dominant disorders do not show father to son transmission, and affected males (hemizygous for the mutant allele) are usually more severely affected than female heterozygotes
• Danon disease


  • X-linked dominant disorder
  • Characterized by intracytoplasmic vacuoles containing autophagic material and glycogen in cardiac and skeletal muscle cells
  • Patients have cardiomyopathy and skeletal myopathy, with or without conduction defect
  • Elevated level of CREATINE KINASE
  • Caused by mutations in the LAMP 2 gene
• Incontinentia pigmenti


  • X-linked dominant disorder
  • Associated with seizures and mental retardation
  • Presumed to be lethal to boys in utero because nearly 100% of cases are female
  • Affects the skin
  • Caused by mutations in the IKBKG gene
• Incontinentia pigmenti: Stage 1


  Vesicular stage: Lines of blisters are present on the trunk and extremities of the newborn that disappear in weeks or months
• Incontinentia pigmenti: Stage 2


  Verrucous stage: Lesions develop in the patient at about 3 to 7 months of age that are brown and hyperkeratotic, resembling warts; these disappear over 1 to 2 years
• Incontinentia pigmenti: Stage 3


  Pigmented stage: Whorled, swirling (marble cake–like), macular, hyperpigmented lines develop. These may fade over time, leaving only remnant hypopigmentation in late adolescence or adulthood
• Incontinentia pigmenti: Stage 4


  1. Skin pallor, atrophy, and scarring

  2. Reduction of hair in the involved scarred areas, both on the limbs and scalp
• Rett Syndrome


  • Most common genetic cause of severe intellectual disability in females
  • Disorder of the nervous system
  • Affects language skills and hand use
  • Caused by mutations in the X-linked MECP2 gene
• The available molecular data suggest that MeCP2 is a key protein in brain and that its level and functions cannot be altered without severe consequences in both genders
• RTT in principle is a reversible condition and that MeCP2-related disorders can be treated even at late stages of disease progression
• 1. X linked recessive disorders


  • Inherited through a genetic defect on an X chromosome
  • Causes the phenotype to be always expressed in males
  • Females with one copy of the mutated gene are carriers
• Red-green color blindness


  • Affected individuals have trouble distinguishing between some shades of red, yellow, and green (usually blue-green)
  • Blue-yellow color vision defects (tritan defects) cause problems with differentiating shades of blue and green and cause difficulty distinguishing dark blue from black
  • Also known as DALTONISM
  • Caused by mutations in the OPN1LW, OPN1MW, and OPN1SW genes (found in RETINA)
• Hemophilia A


  • Disorder where the blood cannot clot properly due to a deficiency of a clotting factor called Factor VIII
  • Results in abnormally heavy bleeding that will not stop, even from a small cut
  • Occurs in around 1 in 4500 live male births
  • Female carriers may show some mild signs of Factor VIII deficiency
• 1. Y linked disorders


  • Mutated gene that causes the disorder is located on the Y chromosome
  • A mutation can only be passed from father to son
  • Difficult to detect
• Deafness, Y-linked 1 (DFNY1)


  • Also known as HEARING IMPAIRMENT
  • Duplicated region was found in the DFNY1 Y chromosome
• Examples of X-linked dominant disorders include Rett syndrome, the X-

  linked lissencephaly and double-cortex syndrome, and incontinentia pigmenti type 1,

  characterized by dermatological, ocular, dental, and neurological abnormalities.
• Mother is affected

  • Two children (one girl and one boy) will have the disease
  • Two children (one girl and one boy) will not have the disease
• Father is affected

  • Two girls will have the disease
  • Two boys will not have the disease
• Cardiomyopathy: weakens and enlarges the heart
• Skeletal myopathy: occurs in most men

  weakness typically occurs in the muscles of the upper arms, shoulders, neck, and upper thighs
• WPW syndrome, visual acuity abnormalities due to choriocapillary ocular atrophy, or mental retardation
• Wolff-Parkinson-White (WPW) syndrome : extra electrical pathway in the heart that leads to periods of rapid heart rate (tachycardia)
• LAMP 2 GENE provides instructions for making a protein called lysosomal

  associated membrane protein-2 (LAMP-2)

  LAMP2 PROTEIN: found in LYSOSOMES
• IKBKG gene: involved in the regulation of the cell’s division and programmed cell

  death.

  • provides instructions for producing one piece (subunit) of the IKK protein complex
  • IKK Protein complex: regulates the activity of nuclear factor-kappa-B.
  • Nuclear factor-kappa-B: appears to play a role in the signaling pathway that is critical for the formation of ectodermal tissues including the skin, hair, teeth, and sweat glands
• X-linked MECP2 gene.

  • provides instructions for making MecP2 protein (abundant in brain)
• The occurrence of hemophilia B (Factor IX deficiency) is one in 20,000 live male births.
• Hemophilia A accounts for most cases. Treatment is available by infusion of Factor VIII

  (blood transfusion).

  Female carriers of the gene may show some mild signs of Factor VIII deficiency, such as bruising easily or taking longer than usual to stop bleeding when cut. However, not all female carriers present these symptoms.

  One-third of all cases are thought to be new mutations in the family (not inherited from the mother).