Lecture 19-Mitochondrial genetics Flashcards Preview

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Flashcards in Lecture 19-Mitochondrial genetics Deck (56):
1

What is the difference between mDNA and nDNA? (4)

- mDNA is much more gene dense than nDNA
- mDNA doesn't have introns
- mDNA has a higher spontaneous mutation rate
- mDNA doesn't replicate with the cell cycle

2

What's the size of mDNA?

- 16.5kb

3

How many genes does mDNA have? What do they code for?

- 37: 22 tRNAs, 2 rRNAs, 13 subunits of the ETC

4

The vast majority of mitochondrial proteins are encoded in the ______

nucleus

5

Heteroplasmy

- having both normal and abnormal mit in a cell or tissue and can vary from tissue to tissue

6

What is the bottleneck effect?

- the random distribution of affected and unaffected mitochondria from a heteroplasmic mothers egg into new eggs. The proportion of affected mitochondria into a given egg determines severity of disease in the child

7

mitochondrial diseases are clinically heterogeneous in that they ______

can show up in any person at any age, in any tissue in any place.

8

Note: mitochondrial diseases have extreme clinical variability!

.

9

Mitochondrial dysfunction can be primary in that it affects a critical mitochondrial protein (or the mDNA or nDNA) or secondary to _______.

- infections (herpes)
- medications
- physiologic stressors (starvation)

10

Mitochondrial diseases primarily affect what tissues?

- those that are metabolically active like: the heart, brian, liver, muscle

11

Why may mitochondrial diseases be provoked by illness or starvation?

When we're sick our defective mitochondria may not be able to meet our bodies' needs if they're diseased. Often, people with these diseases are asymptomatic until they get some sort of infection/sick

12

Mitochondrial cytopathies: CNS (7)

- myoclonus
- generalized seizures
- stroke
- migraine headache
- ataxia
- mental retardation
- psychiatric disease

13

Mitochondrial cytopathies: Skeletal muscle (4)

- myopathy (hypotonia)
- CPEO (progressive paralysis of the eye muscle)
- recurrent myogloburia
- weakness/fatigue

14

Mitochondrial cytopathies: bone marrow (2)

- anemia
- pancytopenia

15

Mitochondrial cytopathies: renal function (1)

- fanconi syndrome (spilling of aas into urine)

16

Mitochondrial cytopathies: systemic symptoms (4)

- lactic acidosis
- short stature
- fatigue
- failure to gain weight

17

Mitochondrial cytopathies: endocrine (4)

- DM (islet cells are very metabolically active)
- hypoparathyroidism
- exocrine pancreatic failure
- thyroid disease

18

Mitochondrial cytopathies: heart (2)

- cardiomyopathy
- conduction defects

19

Mitochondrial cytopathies: vision (2)

- optic neuropathy
- retinitis pigmentosa

20

Mitochondrial cytopathies: hearing (2)

- high frequency hearing loss
- aminoglycoside-induced deafness

21

Mitochondrial cytopathies: gi (3)

- pseudo-obstruction (failure of peristalsis)
- constipation
- vomiting

22

Mitochondrial cytopathies: liver (3)

- hypoglycemia
- gluconeogenic defects
- liver failure and cirrhosis

23

Alpers Sx (3)

- hypotonia
- seizures
- liver failure

24

What should provoke suspicion of a mitochondrial disease?

- any progressive, multisystemic disorder, particularly those with neurologic symptoms

25

What should be tested when a mitochondrial disease is suspected? (7)

- plasma lactate
- ketones
- ACP
- UOAs
- PAAs (alanine may reflect long term lactic acidosis)
- neuroimaging
- maybe muscle biopsy to test oxidative phosphorylation activity (but less used now with advanced genetic testing)

26

PDH inheritance.

XL but females can also have severe disease

27

PDH treatment

- ketogenic diet (like Atkins) to give alternative pathway for ACoA production
- doesn't help with brain malformations but does give some energy

28

PDH prognosis?

- poor, ketogenic diet does little for patient

29

Leigh syndrome onset is when?

- when people's metabolic needs go up (sickness, fasting) and they completely stop growing. This is usually at 3-12 mos of age when there's a mild infection.

30

Leigh syndrome signs (4)

- progressive neurodegenerative disorder
- psychomotor regression
- hypotonia, spasticity, chorea, ataxia, peripheral neuropathy
- cardiomyopathy
- potentially brainstem and/or basal ganglia disease

31

What happens when someone with Leighs is exposed to another catabolic stressor?

- further decompensation

32

Leigh Syndrome prognosis?

most die by 2-3 years

33

MELAS stands for what?

- mitochondrial encephalopathy, lactic acidosis, stroke-like episodes

34

MELAS onset?

- childhood

35

MELAS symptoms? (3-kind of)

- neurologic: first nonspecific. Seizures, headaches, altered consciousness, transient hemiparesis or blindness. Progressive impairment of motor, visual and cognitive abilities
- lactic acidosis
- myopathy

36

What is the mutation that results in MELAS?

- MT-TL1 (mitochondrial tRNA gene)

37

MELAS treatment

- mitochondrial cocktail: CoQ10, carnitine (both can become deficient), creatine (another source of energy), lipoic acid (antioxidant)

38

What is given to MELAS patients when they're having a stroke-like event? Why?

- Argnine because it acts as a NO donor

39

PDH symptoms?

Largely a neurological disease!!
- psychomotor retardation
- hypotonia
- progressive encephalopathy (including Leighs): CSF accumulation in brain
- brain malformation
- sometimes extra-CNS manifestations like cardiomyopathy and liver disease

40

High levels of what are indicative of Leigh syndrome? What is seen on neuroimaging?

- lactate in blood or CSF

- multiple focal lesions

41

Leigh syndrome is mostly a dysfunction of _____ due to genetic mutations.

- oxidative phosphorylation

42

(T/F) Leigh syndrome has 2 different mutations in one gene. One mutation is more severe and one less and they are both dependent on the mutant load.

- True: T8993G is more harmful, T8993C is less severe (need more mutants to see disease)

43

What are the treatments for Leigh syndrome? (5)

- no specific treatment, just treating Sx
- Na bicarb to correct acidosis (doesn't prevent neural degeneration)
- antiepileptics but NOT valproic acid or barbiturates because they inhibit the respiratory chain
- Cocktail (although no evidence for success)
- hospice

44

(T/F) Pol G disorders tend to present with similar symptoms and are highly related.

False: they are a continuum of overlapping phenotypes but range in severity, organ specificity, and age of onset. They were originally described separately

45

How are POLG disorders identified?

- identification of a direct mutation
- or depletion of mtDNA

46

Treatment for POLG disorders

- no specific effective therapy because people are progressively losing their DNA

47

What are the types of POLG disorders? (5)

- Alpers
- Childhood myocerebrohepatopathy
- MEMSA: myoclonic epilepsy myopathy sensory ataxia
- ANS: Ataxia neuropathy spectrum
- AR and AD PEO: NOTE: the only AD POLG disorder

48

What is usually the first symptom of Alpers? Later?

- seizures

- liver dysfunction

49

Alpers age of onset?

- 2-4 years

50

Alpers can be generalized as a _________ disease

- severe and progressive encephalopathic

51

Generally speaking, POLG disorders can cause one of what 2 types of diseases?

- hepatocerebral
- encephalomyopathic

52

MNGIE stands for ...

mitochondrial NeuroGastroIntestinal encephalopathy

53

MNGIE Age of onset?

- adolescence

54

MNGIE Symptoms?

- GI mostly--severe dysmotility, nausea, vomiting, constipation, incontinence
- peripheral neuropathy
- opthalmoplegia/ptosis

55

MNGIE is caused by what?

- thymidine phosphorylase deficiency and therefore massive elevations in thymidine and disruption of the mitochondrial DNA replication system and mutations because of the high T

56

MNGIE inheritance?

- AR