Patterns of Inheritance V

Question 1

describe mitochondrial inheritance

Answer 1

• Mitochondria are inherited from the mother
• All offspring of an affected female are affected
• Only females transmit the disease

Question 2

variable expression in mitchondrial disorders

Answer 2

• The severity of mitochondrial disorders can vary in individuals with the disorder
  
  • due to Heteroplasmy
• The severity of the disorders depends on the number of MT that have the mutant gene

Question 3

heteroplasmy in mt disorders

Answer 3

• mt DNA segregates passively when a cell divides
• Unequal distribution of mutant and non-mutant mt DNA, results in the phenomenon of heteroplasmy in mt disoders
• Explains the variable expression of the disease in the offspring

Question 4

describe MELAS

Answer 4

• mitochondrial inheritance and heteroplasmy
• mt encephalopathy, lactic acidosis and stroke like episodes

Question 5

describe the 3 mt diseases

Answer 5

• LHON
  
  • manifests as progressive blindness around 20-30 years
• MELAS: mt encephalopathy, lactic acidosis, and stroke like episodes
• MERRF

Question 6

name the disorders with non-Mendelian inheritance pattersn

Answer 6

• Digenic disorder
  
  • Retinitis pigmentosa
• Imprinting
  
  • Prader Willi syndrome
  • Angelman syndrome
• Triple repeat disorders with anticipation
  
  • Huntington disease
  • Myotonic dystrophy
  • Fragile X syndrome (X-linked)

Question 7

describe digenic disorders

Answer 7

• Mutations in 2 genes (A,B) are additive and necessary to produce the disorder
• One form of RP
  
  • a disease of progressive visual impairment
  • result of a mutation in 2 independent genetic loci (ROM1 and peripherin)

Question 8

describe imprinting

Answer 8

• Some genes are active only when transmitted by mother or father
• Imprinting involves methylation of specific loci (epigenetic change) and silencing of the gene
• Normal imprinting pattern on chromosome 15:
  
  • SNRPN gene is silenced by methylation on maternal ch15 but UBE3A is active. On paternal ch15, SNRPN is active and UBE3A is inactive (silenced by methylation)
    
    • UBE3A is active on the maternal ch15
    • SNRPN is active on the paternal ch15

Question 9

describe Prader Willi syndrome

Answer 9

• PWS can be caused by:
  
  • microdeletion of paternal ch15 (70% of patients)
  • maternal uniparental disomy of ch15
• Prader Willi syndrome due to microdeletion of Paternal 15q11-13 (absence of SNRPN)

Question 10

explain uniparental disomy

Answer 10

• Condition when the child has 2 copies of the maternal ch15 (absence of paternal ch15)
• The region on ch15 is normall inactive in the maternal chromosome due to imprinting (methylation)
• such children have 2 active copies of UBE3A and NO active copies of SNRPN gene
• Can be detected by methylation analysis–there are 2 methylated copies of ch15

Question 11

describe methylation analysis

Answer 11

*

Question 12

describe inheritance of Angelman syndrome

Answer 12

• Angelman syndome caused by:
  
  • deletion of maternal 15q11-13 (absence of active UBE3A)
  • uniparental disomy of paternal ch15 (2 copies of active SNRPN and absence of UBE3A geneb)
• Happy Puppet syndrome
• Severe intellectual disability

Question 13

name the 4 classes of triplet repeat disorders

Answer 13

• Triple repeat may be present at:
  
  • Promoter region
    
    • Fragile X syndrome
  • Intron
    
    • Friedrich ataxia
  • Coding region of gene
    
    • Huntington disease
  • 3’ end (UTR) of the gene
    
    • myotonic dystrophy
• Repeats are unstable and repeat size of influences disease severity and age of onset. Explains anticipation

Question 14

describe anticipation

Answer 14

• Individuals in the recent generations of a pedigree develop disease at an earlier age and generally w/ greater severity
• Huntington disease
  
  • Triple repeat expansion: CAG repeat in the exon
  • There is a polyglutamine tract in the huntingtin protein
• Greater the number of repeats, earlier is the age of onset of symptoms and more severe is the disorder

Question 15

name the 3 diseases where anticipation is observed

Answer 15

• Huntington disease (AD disorder) is more severe if transmitted from the father
• Myotonic dystrophy (AD disorder): expansion takes place in the mother
• Fragile X syndome (X-linked disorder) repeat expansion in the mother

Question 16

describe Fragile X syndrome

Answer 16

• triple repeat expansion (CGG repeat) on the X chromosome
• The triple repeat is present at the 5’ end (promoter region) of the FMR1 gene
  
  • results in increased methylation of this region and silencing of the FMR1 gene
• Intellectual disability, prominent ears, elongated face
• Shows anticipations in successive generations
• Diagnostic test:
  
  • Southern blot analysis of the triplet repeats gives an indication of the number of triplet repeat sequences