Exam 3 - Mitochondrial Genetics and Disease

Question 1

What is Heteroplasmy and how does it relate to mitochondrial diease?

Answer 1

• If \mutation occurs: a mixture of normal mitochondria and mutant mitochondria occurs in one cell
• Heteroplasmy and MERRF
  
  • Characteristics of mitochondrial disorders: clinical variability and age related progression of disease
  • Ex: 25 yr old has 95% mutation and sever clinical pesentation of mitochondrial myopathy but a 25 yr old with 85% is healthy

Question 2

What are the rules of materal inheirtance as it relates to mitochondrial genetics ?

Answer 2

MItochondiral DNA is inheirted from the mother.

Question 3

What is the threshold concept and its relationship to mitochondrial genetic dieases

Answer 3

• Need a certain level of aberrant mitochondria vs. normal mitochondria for disease to occur
• Threshold effect of mutant mitochondria are required for disease manifestation

Question 4

What is the mitochondria?

Answer 4

• Power house
• ELetrons flow down ETC
  
  • Pumping of H ions between Im and OM
• H+ gradient formed
  
  • When H+ goes down gradient, energy is captured in the form of ATP
• COntains machinary to make protiens (rRNA and mRNA)
  
  • has 13 proteins and 24 parts for machinary = 37 genes

Question 5

WHat are the four types of mitchondrial Myopathies

Answer 5

MERRF: Myoclonus epilespy with ragged red dibers

MERLAS: Mitochondrial Encephalopathy, Lacti Acidosis and Stroke like epispodes

KSS: Kearns Sayre Syndrome

CPEO: Chromic Progressive External Opthalmoplegia

Question 6

WHat is a mitchondrial genetic diease that is NOT a myopathy?

Answer 6

LHON: Leber Hereditary Optic Neuropathy - blindness in late adolescence (muscle is not affected)

Question 7

How Much of the Mature egg is the mitochondrial genome

Answer 7

1/3

Question 8

WHat are Genes endoded for mitochondria?

Answer 8

• 5 complex for mitchondrial Repsiration they are encoded by nuclear and mitchondrial DNA
• ETC -= I, II, III, IV which are used to oxidizee NADH to FADH2
• Complex V is uses as an ATP SYNTHASE.
  
  • uses H gradient to change adp to ATP
    *

Question 9

What are the two divsions of Mitochondrial Mutations?

Answer 9

• Two major divisions
  
  • point mutations in mt DNA tRNA genes lead to
    
    • MELAS and MERRF
  • mtDNA genome deletions and rearrangements lead to
    
    • KSS and CPEO

Question 10

What are the clinical features of MERRF?

Answer 10

• myoclonus epilepsy with ragged red fibers
• Myoclonus
  
  • often the first symotin ( involuntary muscle jerk)
• Myclonic Epilepsy
• Ataxia (lack of coordinated muscle movements)
• Ragged Red Fibers (muscle tissue )
• Seizures, Dementia
• 90% caused by 2 mutations of tRNA lys

Question 11

What are the clinical symptoms of MELAS

Answer 11

• mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
• Seizures
• stroke-like episodes of hemiparesis (weakness on one side of the body)
• Blindness Headaches
• Anorexia
• Recurrent Vomiting
• Lacti Acidosis
• Ragged Red fibers
• Age of onset is 2 - 10 years
• Typically caused by A3243G mutation in t-RNA-leu

Question 12

What is Kearns Sayre Syndrome?

Answer 12

• Retinitis Pigmentosa (degerative eye disease leading to blindness)
• At least one of the following
  
  • cardiac conduction abnormaility
  • cerbellar ataxia
  • cerbral spinal protein level above 100 mg/dl
• May have other presentations: optic atrophy, hearing loss, dementia, seizures, cardiomyopathy, lactic acidosis
  *

Question 13

What are the clinical symptoms of CPEO?

Answer 13

• Chronic Progressive External Opthalmoplegia
• Mild to moderate mitchondrial myopathy (ragged red fibers observed in skeletal muscle) mtDNA Rearrangements
• Ptosis (droopin gof the eyelid)

Question 14

What are the Clinical symptoms of LHON?

Answer 14

• MItochondiral mutation that only effects the optic nerve
• no muscle involvement
• Acute or subacute, bilateral, central vision loss,
• Degeneration of retinal ganglion cell layer and optic nerve
• age of onset = 20 s and 30 s
• mtDNA mutations in coding genes of comlpex 1 proteins
  
  • Typically onset and progression is rapid
  • initally affects one eye but eventually both eyes affected at the same time
• Maternal inheritance (mitochondria)
• no tRNA or mtDNA rearrangments
  
  • Mutations affect mtDNA genes encoding Complex I proteins – single base pair substitutions
  • Remember 5 complexes (I through V) for mitochondrial respiration