Lecture 19-Mitochondrial genetics Flashcards
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
What’s the size of mDNA?
- 16.5kb
How many genes does mDNA have? What do they code for?
- 37: 22 tRNAs, 2 rRNAs, 13 subunits of the ETC
The vast majority of mitochondrial proteins are encoded in the ______
nucleus
Heteroplasmy
- having both normal and abnormal mit in a cell or tissue and can vary from tissue to tissue
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
mitochondrial diseases are clinically heterogeneous in that they ______
can show up in any person at any age, in any tissue in any place.
Note: mitochondrial diseases have extreme clinical variability!
.
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)
Mitochondrial diseases primarily affect what tissues?
- those that are metabolically active like: the heart, brian, liver, muscle
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
Mitochondrial cytopathies: CNS (7)
- myoclonus
- generalized seizures
- stroke
- migraine headache
- ataxia
- mental retardation
- psychiatric disease
Mitochondrial cytopathies: Skeletal muscle (4)
- myopathy (hypotonia)
- CPEO (progressive paralysis of the eye muscle)
- recurrent myogloburia
- weakness/fatigue
Mitochondrial cytopathies: bone marrow (2)
- anemia
- pancytopenia
Mitochondrial cytopathies: renal function (1)
- fanconi syndrome (spilling of aas into urine)
Mitochondrial cytopathies: systemic symptoms (4)
- lactic acidosis
- short stature
- fatigue
- failure to gain weight
Mitochondrial cytopathies: endocrine (4)
- DM (islet cells are very metabolically active)
- hypoparathyroidism
- exocrine pancreatic failure
- thyroid disease
Mitochondrial cytopathies: heart (2)
- cardiomyopathy
- conduction defects
Mitochondrial cytopathies: vision (2)
- optic neuropathy
- retinitis pigmentosa
Mitochondrial cytopathies: hearing (2)
- high frequency hearing loss
- aminoglycoside-induced deafness
Mitochondrial cytopathies: gi (3)
- pseudo-obstruction (failure of peristalsis)
- constipation
- vomiting
Mitochondrial cytopathies: liver (3)
- hypoglycemia
- gluconeogenic defects
- liver failure and cirrhosis
Alpers Sx (3)
- hypotonia
- seizures
- liver failure
What should provoke suspicion of a mitochondrial disease?
- any progressive, multisystemic disorder, particularly those with neurologic symptoms
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)
PDH inheritance.
XL but females can also have severe disease
PDH treatment
- ketogenic diet (like Atkins) to give alternative pathway for ACoA production
- doesn’t help with brain malformations but does give some energy
PDH prognosis?
- poor, ketogenic diet does little for patient
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.
Leigh syndrome signs (4)
- progressive neurodegenerative disorder
- psychomotor regression
- hypotonia, spasticity, chorea, ataxia, peripheral neuropathy
- cardiomyopathy
- potentially brainstem and/or basal ganglia disease
What happens when someone with Leighs is exposed to another catabolic stressor?
- further decompensation
Leigh Syndrome prognosis?
most die by 2-3 years
MELAS stands for what?
- mitochondrial encephalopathy, lactic acidosis, stroke-like episodes
MELAS onset?
- childhood
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
What is the mutation that results in MELAS?
- MT-TL1 (mitochondrial tRNA gene)
MELAS treatment
- mitochondrial cocktail: CoQ10, carnitine (both can become deficient), creatine (another source of energy), lipoic acid (antioxidant)
What is given to MELAS patients when they’re having a stroke-like event? Why?
- Argnine because it acts as a NO donor
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
High levels of what are indicative of Leigh syndrome? What is seen on neuroimaging?
- lactate in blood or CSF
- multiple focal lesions
Leigh syndrome is mostly a dysfunction of _____ due to genetic mutations.
- oxidative phosphorylation
(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)
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
(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
How are POLG disorders identified?
- identification of a direct mutation
- or depletion of mtDNA
Treatment for POLG disorders
- no specific effective therapy because people are progressively losing their DNA
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
What is usually the first symptom of Alpers? Later?
- seizures
- liver dysfunction
Alpers age of onset?
- 2-4 years
Alpers can be generalized as a _________ disease
- severe and progressive encephalopathic
Generally speaking, POLG disorders can cause one of what 2 types of diseases?
- hepatocerebral
- encephalomyopathic
MNGIE stands for …
mitochondrial NeuroGastroIntestinal encephalopathy
MNGIE Age of onset?
- adolescence
MNGIE Symptoms?
- GI mostly–severe dysmotility, nausea, vomiting, constipation, incontinence
- peripheral neuropathy
- opthalmoplegia/ptosis
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
MNGIE inheritance?
- AR
