B2.030 Mitochondrial Disease

Question 1

what can cause heterogeneity in genetics and disease manifestation?

Answer 1

variable tissue energy requirements
heteroplasmy
nature of disease causing mutation
accumulation of additional mtDNA mutations

Question 2

what is a threshold effect?

Answer 2

severity of functional defect in heteroplasmic cells determined by ratio of WT:mutant mtDNA
usually 70-90% mutation load for clinical manifestation
tissues that require high oxidative metabolism will have lower thresholds

Question 3

discuss mutations in mtDNA and how they affect mitochondrial disease

Answer 3

sporadic or maternal inheritance
small mutations or large deletions
cause defects in ETC or rRNA and tRNA within mitochondria

Question 4

discuss mutations in nDNA and how they affect mitochondrial disease

Answer 4

sporadic or Mendelian
small mutations or large deletions
cause defects in ETC, mtDNA maintenance, protein import, lipid dynamics, biosynthesis of coQ

Question 5

what are some exceptions to maternal inheritance of mitochondrial disease due to mtDNA mutations?

Answer 5

de novo point mutation in mtDNA of maternal germ line cell–may not be passed on to all kids if it occurs sporadically in one oocyte
not always clinically evident due to heteroplasmy and threshold effect

Question 6

what are the 3 mitochondrial diseases we need to know? what are their patterns of inheritance?

Answer 6

MELAS- maternal
Kearns-Sayre- maternal
PEO- autosomal dom or recessive

Question 7

what mutations are associated with MELAS?

Answer 7

point mutations in tRNA genes in mtDNA

Question 8

what mutations are associated with Kearns-Sayre?

Answer 8

large deletions of mtDNA

Question 9

what mutations are associated with PEO?

Answer 9

point mutations in nuclear genome encoding for POLG

Question 10

what are clinical features of MELAS?

Answer 10

CNS (seizures, ataxia)

muscle weakness

Question 11

what are clinical features of K-S?

Answer 11

ataxia
muscle weakness
pigmentary retinopathy
can have endocrine, blood, or cardiac involvement

Question 12

what are clinical features of PEO?

Answer 12

ptosis, myopathy, sensorineural hearing loss, ataxia, hypogonadism, cataracts

Question 13

what histopathology is associated with mitochondrial disease?

Answer 13

ragged red fibers due to compensatory proliferation of mitochondria
-not a universal feature

Question 14

what does SDH do in the ETC?

Answer 14

transfers electrons to complex 2 (evaluation of complex 2 function)

Question 15

what does COX do in the ETC?

Answer 15

is complex 4

Question 16

what does serum lactate:pyruvate ratio reflect?

Answer 16

NADH:NAD+ ratio

redox state

Question 17

what ratio would indicate a defective oxidative metabolism?

Answer 17

high

accumulation of NADH thus used to make lactate

Question 18

what ratio would indicate defects in pyruvate dehydrogenase (converts pyruvate to Acetyl-coA)?

Answer 18

normal, slightly low ratios
elevated levels of both lactate and pyruvate
increased NAD+ and low redox state