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62 Cards in this Set
- Front
- Back
- 3rd side (hint)
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When people say mitochondrial diseases, what are they referring to?
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When people say mitochondrial diseases, sometimes they mean diseases with mitochondrial inheritance and sometimes they mean diseases with mitochondrial dysfunction that aren’t necessarily inherited on the mitochondrial genome
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What are mitochondria?
How many per cell? |
-Intracellular organelles
-Lots of variability from tissue to tissue in how mitochondria work and what they do -100’s to 1000’s per cell -->The more metabolically active a cell is, the more mitochondria you’ll see -->1000s: Heart muscle, skeletal muscle, liver -->Mature RBC’s don’t have mitochondria -Maternally inherited -->Egg has lots of mitochondria --?Sperm has a few but doesn’t give any to the developing embryo. They’re chewed up as the sperm enters the egg -Have their own genome -->Only a small number of genes, but all are important for mitochondrial function -Major function is metabolism – What does metabolism mean? |
-Generation of ATP through oxidative phosphorlyation
-Involved in most major metabolic pathways -->Proximal part of the UREA CYCLE -->Organic acid metabolism -->Fat metabolism |
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What is the Endosymbiotic theory?
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-Lynn Margulis 1970s
-Mitochondria are similar to primitive prokaryotes, so the thought was that billion of years ago: -->Eukaryotes arose from symbiotic relationship between several prokaryotes where one became subsumed within the other -->Nature of the selection is debated -->Many mitochondrial features resemble prokaryotic systems -->Mito have their own DNA |
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What does mitochondrial DNA look like?
How many genes? What do they code for? How many copies are present? |
-Unique structure
~16.5 kb length! -Compared to our nuclear DNA, -->it’s a lot smaller -->It’s more dense in terms of important information. There is a lot less space in between the genes, in fact there’s actually some overlap between the genes in some places. -->Tend not to have introns -->A bit simpler – not a lot of regions of big, non-coding, unexpressed DNA sections like you see in the nuclear genome -DS, circular DNA (may be linear in some tissues) -->37 genes -->22 tRNAs **Distinct triplet code from nuclear DNA, so the tRNAs are different, each codon is a little bit different -->2 rRNAs -->13 subunits of electron transport chain -Each mitochondrion has 2-10 copies -->They’re not always the same in each mitochondria. There are levels of complexity here we don’t see in the nuclear genome where you have multiple mitochondria in each cell and multiple genomes within each mitochondria |
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Where are the vast majority of mitochondrial proteins encoded?
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-Vast majority of mitochondrial proteins are encoded in nucleus (including enzymes and proteins for mtDNA replication and transcription system)
-->Way more than just 13 proteins (the number of ETC subunits encoded for in the mitochrondrial DNA) important in mitochondrial metabolism |
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Is mtDNA replication cell-cycle specific?
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NO!
mtDNA replication not cell-cycle specific like the nuclear genome |
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How does the mutation rate in the mitochondrial DNA compare to that of nuclear DNA? Why?
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-Far higher spontaneous mutation rate than nDNA
Why? -Fewer DNA repair mechanisms -More exon-dense -Entirely maternally inherited |
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What is super notable about this pedigree?!
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-This is what maternal inheritance might look like
-This is a pedigree -What we’re looking for that tells us that it’s mitochondria is that you get mom’s (circle) passing on the traits/condition and NO male transmission. It STOPS with males ! -If you see a pedigree like this it has to be mitochondrial inheritance |
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What is heteroplasmy?
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Heteroplasmy
-Presence of both normal and abnormal mitochondria within a cell or tissue -One person may have 20% mitochondria with abnormal genome, another 80%, another 100% -->Those percentages can affect how severe or early a disease might progress -May be highly variable from tissue to tissue within the same person -->Two people can have the same mitochondrial mutation, but one person can have primarily muscular involvement another primarily brain involvement -Explains some of the clinical heterogeneity |
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How can heteroplasmy come about?
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-This is a picture of how mitochondrial inheritance happens and how heteroplasmy can come about
-When eggs are being formed, the mitochondria are not necessarily divided equally -If you have a mom that only have mutations in a few of her mitochondria, she can make eggs that have a disproportionally high percentage of mutations or a disproportionally low percentage of mutations -Mom could have children with severe disease if they have mostly mutant mitochondria or a child with no disease if it’s mostly normal -This happens at the level of oocyte production |
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Describe the difference between homoplasmic and heteroplasmic cells!
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Homoplasmic cells:
-->Cells where every mitochondria is the same Heteroplasmic cells: -->Cells with variable levels of mutant/mutation load |
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What do mitochondria do?
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-Create energy in the form of ATP
-->Oxphos – if we don’t do this we don’t live -Regulate apoptosis (programmed cell death) -Central location for many cellular metabolic processes, such as ____. |
1. Urea cycle
2. Fatty acid oxidation 3. Organic acid metabolism *Phenomenon of variable levels of DNA variation is part of what informs the complexity of mitochondrial disease, but another part is that mitochondria just do an incredibly complicated number of things |
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What are some of the intermediates in the breakdown of glucose, fats, and proteins that show up in the mitochondria?
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-How we go from glucose, fats, and proteins into ATP
-There are intermediates that show up primarily in the mitochondria, things like the TCA cycle, like lactate production, a lot of those happen either in the mitochondria or at the mitochondrial membranes |
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What is the most important thing the oxidative phosphorylation chain does? Where is it located again?
MNE THROWBACK!! |
-Remember the most important thing they do is convert the ion gradient – let the ions come back into the mitochondria and produce ATP
-That happens at the inner mitochondrial membrane |
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What produces most of the substrate for producing the ion gradient in the mitochondria?
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The citric acid cycle is what produces most of the substrate for producing the ion gradient, but it can also come from fat metabolism and from protein or carbohydrate metabolism
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What do mitochondrial diseases look like?
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- Can show up with any symptom, in any tissue, in any age, in any person
-Clinically heterogenous 1. Heteroplasmy 2. A single change in the mitochondria can affect so many metabolic pathways -Respiratory chain dysfunction -->Once the respiratory chain is not working properly it can affect all the other pathways as well -May be single affected tissue/organ or systemic -May present at any age -Some well defined, discrete syndromes -Extreme clinical variability |
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Mitochondrial dysfunction?? Wait what?
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-May be primary or secondary mitochondrial dysfunction
-Primary genetic abnormality of critical mitochondrial protein -->Nuclear or mitochondrial genome -Secondary to other cellular/biological processes 1. Infections -->Eg. herpes can affect the mitochondria in particular 2. Medications -->Some poison the mitochondria 3.Other physiologic stressors -Final common pathway for lots of other diseases, so it can be hard to sort out, for example, if someone’s lactate is high because they have a metabolic disease or are their mitochondria not working because they’ve been hypoxic, or in shock, or is it a medication effect, or an infection effect |
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Mitochondrial diseases:
-What organs can they affect? -What are they exacerbated by? |
-May affect any organ/tissue
-Tends to affect those levels of our body that are most energetically demanding a. Brain b. Muscle c. Heart d. Liver *NOT things like skin, bones -Exacerbated by external sources of physiologic stress. Under these conditions our metabolic needs go up and the mitochondria might not meet those needs and thus you can get sicker than other people. List categories of these "external sources of physiologic stress" ! |
1. Infections
-->fever 2. Fasting 3. Medications |
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What happened if your mitochondria didn't work at all? Does this describe the mitochondria of the kids with mitochondrial diseases?
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-Even people with mitochondrial dysfunction have the ability to generate SOME energy
-If your mitochondria didn’t work at all, you probably wouldn’t make it out of blastocyst or something -Most of the kids who have mitochondrial disease are okay if they aren’t sick -It’s like an engine that can get to 1st or 2nd gear but not 3rd or 4th. As soon as they need more energy, they fail to meet those needs and they have a crisis |
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Mitochondrial Cytopathies: Clinical Features
associated with the CNS |
CNS
-Myoclonus -Generalized Seizures -Stroke -Migraine Headache -Ataxia -Mental Retardation -Psychiatric Disease (see back for more details on myoclonus and ataxia) |
Myoclonus is a brief, involuntary twitching of a muscle or a group of muscles.
Ataxia (from Greek α- [a negative prefix] + -τάξις [order] = "lack of order"), is a neurological sign consisting of lack of voluntary coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum. |
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Mitochondrial Cytopathies: Clinical Features
associated with the Skeletal Muscle |
Skeletal Muscle
-Myopathy (hypotonia) -Chronic progressive external opthalmoplegia (CPEO) -Recurrent Myogloburia -Rhabdomyolysis -Weakness/Fatigue -->Can exercise for a short period but not a long period (see back for more information on CPEO and rhabdomyolysis!) |
Chronic progressive external ophthalmoplegia (CPEO), also known as progressive external ophthalmoplegia (PEO), is a type of eye movement disorder. It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the diagnosis.
Rhabdomyolysis is the breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream. Myoglobin is harmful to the kidney and often causes kidney damage. |
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Mitochondrial Cytopathies: Clinical Features
associated with the Bone marrow |
Bone Marrow
-Anemia -Pancytopenia (see back for more details on pancytopenia!) |
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.
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Mitochondrial Cytopathies: Clinical Features
associated with Renal function |
Renal Function – Tubules are particularly active
-Fanconi Syndrome –> amino acids spill over into urine |
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Mitochondrial Cytopathies: Clinical Features
associated with Systemic Symptoms |
Systemic Symptoms
-Lactic Acidosis elevation -->Inefficiency of Krebs cycle -Short Stature -Fatigue -Failure to Gain Weight |
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Mitochondrial Cytopathies: Clinical Features
associated with the Endocrine system |
Endocrine
-Diabetes Mellitus -->Islet cells are metabolically active -Hypoparathyroidism -Exocrine Pancreatic Failure -Thyroid Disease |
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Mitochondrial Cytopathies: Clinical Features
associated with the heart |
Heart
-Cardiomyopathy -Conduction Defects (see back for deets on cardiomyopathy!) |
Cardiomyopathy (literally "heart muscle disease") is the measurable deterioration of the function of the myocardium (the heart muscle) for any reason, usually leading to heart failure; common symptoms are dyspnea (breathlessness) and peripheral edema (swelling of the legs). People with cardiomyopathy are often at risk of dangerous forms of irregular heart beat and sudden cardiac death.[1]
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Mitochondrial Cytopathies: Clinical Features
associated with vision |
Vision – Retina is another energetically busy organ
-Optic Neuropathy -Retinitis Pigmentosa (see back for deets on both of these!) |
The optic nerve contains axons of nerve cells that emerge from the retina, leave the eye at the optic disc, and go to the visual cortex where input from the eye is processed into vision. There are 1.2 million optic nerve fibers that derive from the retinal ganglion cells of the inner retina.[1] Optic neuropathy refers to damage to the optic nerve due to any cause.
Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment and blindness.[1] Sufferers will experience one or more of the following symptoms: - Night blindness or nyctalopia; - Tunnel vision (no peripheral vision); - Peripheral vision (no central vision); - Latticework vision; - Aversion to glare; - Slow adjustment from dark to light environments and vice versa; - Blurring of vision; - Poor color separation; and - Extreme tiredness. |
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Mitochondrial Cytopathies: Clinical Features
associated with hearing |
Hearing
-High-frequency Hearing Loss -Some genetic forms of hearing loss are mitochondrially encoded -->Aminoglycoside-induced Deafness (see back for deets on Aminoglycoside-induced deafness) |
Hearing loss triggered by aminoglycoside drugs (e.g. gentamicin) in patients with the m.1555A>G mutation. Besides causing AID, this maternally inherited mitochondrial DNA mutation also causes spontaneous deafness called non-syndromic hearing loss (NSHL)
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Mitochondrial Cytopathies: Clinical Features
associated with the gastrointestinal tract |
Gastrointestinal
-Pseudo-obstruction -Failure of peristalsis -Constipation -Vomiting |
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Mitochondrial Cytopathies: Clinical Features
associated with the liver |
Liver – think of liver as analogous to mitochondria in terms of varied function in energy production
-Hypoglycemia -Gluconeogenic Defects -Liver Failure and Cirrhosis |
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What are the classic originally described mitochondrial disorders?
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-These are the classic originally described mitochondrial disorders
-described originally based on symptoms -Many of these will be discussed more in detail later!! 1. Alpers 2. Chronic progressive external ophthalmoplegia (CPEO) 3. Kearns-Sayre 4. Pearson 5. Leigh Syndrome 6. Neurologic weakness with Ataxia and Retinitis Pigmentosa -- NARP (like carp with an N) 7. Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes -- MELAS (me-lass) 8. Myoclonic Epilepsy with Ragged Red Fibers -- MERRF (like nerf with an M) 9. Leber’s Hereditary Optic Neuropathy -- LHON |
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CPEO
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-Chronic progressive external ophthalmoplegia
-Progressive weakness or paralysis of the eye muscles -Eye muscles are very energetically dependent |
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Kearns-Sayre
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Progressive external ophthalmoplegia (PEO), retinopathy, ataxia, heart block – conduction problems
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Pearson
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Bone marrow failure, exocrine pancreatic failure
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MERRF
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MERRF (like nerf with an m)
-Myoclonic Epilepsy with Ragged Red Fibers -Seizures and muscle disease |
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LHON
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-Leber’s Hereditary Optic Neuropathy
-Patients have a particular look to the retina |
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How do you make the diagnosis for mitochondrial syndromes?
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1. First step = Suspicion
-->None of these are particularly common -->Any child with progressive, multisystemic disorder -->Particularly with neurologic symptoms 2. Straightforward if it fits into a well-defined syndrome, but lots of patients don’t neatly fit into one of those disorders -->MELAS, MERRF, LHON, others with known genetic cause |
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What do you do when a mitochondrial syndrome is suspected?
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1. Do some screening metabolic labs first
-->These can give us a sense of how well metabolism is working a. Plasma Lactate (may measure in CSF also) b. Ketones, acylcarnitines (intermediates in fat metabolism), urine organic acids (intermediates in protein breakdown) c. Plasma amino acids -->Which plasma amino acid do you look at in particular? Why? (next side) 2. Neuroimaging -->Brain MRI can be informative for some of these diseases 3. If suggestive, muscle biopsy to look at mitochondrial function is most accurate -->Take some muscle, let it go in various substrates of energy production, and measure how efficiently it produces ATP -->Can look at how well Complex I works, how well complex II works, etc. -->Direct measurement of ox-phos activity --> Why are we moving away from doing muscle biopsies? (next slide) |
Which plasma amino acid do you look at in particular? Why?
-Look at alanine in particular because lactate and alanine get converted back and forth. -Lactate measurement is a tricky thing to do if you have a thrashing child or a crying kid or a difficult lab draw the lactate can be falsely elevated, but alanine won’t be affected like that **Alanine elevations may reflect long-term lactic acidosis** ___ Why are we moving away from doing muscle biopsies? -Moving away from doing as many muscle biopsies because the molecular genetic testing has gotten so much better. -Before could only do one gene at a time and it was slow and expensive. -Now can do whole exome analysis very quickly. -This is less invasive and can test for the known genes involved in mitochondrial disorders |
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What is MELAS?
When is the onset? How does it typically first present? Symptoms? |
MELAS (me-lass) = Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes
-Kids with MELAS tend to spend a lot of time in the hospital -Childhood onset -->Typically toddlerhood but can be any age Symptoms: -Neurologic -->Typically first presents with non-specific neurologic symptoms -->Seizures, headaches, altered consciousness, transient clumsiness for a day or hemiparesis or blindness, almost like a MS picture where you get nonspecific neurologic symptoms that come and go -->Progressive impairment of motor, visual, and cognitive abilities -->As time goes on, more and more of these neurologic effects become permanent -Lactic acidosis -Myopathy -->Weakness, progressive hypotonia |
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What are the genetics behind MELAS?
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-mt-DNA mutations
80% in MT-TL1 (mitochondrial tRNA gene) -->1 common mutation (m.3243A>G) -->Will often check just for that mutation first because they can get the results really quickly Maternal inheritance – most cases -->Mom may have mild symptoms like migraines, headaches, short stature and her affected child will be much worse with full fledge MELAS Heteroplasmy and tissue distribution affects phenotype/degree of severity |
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How do we treat MELAS?
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1. For a lot of these diseases, we use something called a “mitochondrial cocktail”.
2. Arginine during acute stroke-like events omg, tell me more about these mitochondrial cocktails! (next side) |
Combination of cofactors and vitamins they use to try to maximize mitochondria metabolic efficiency
Coenzyme Q10 and carnitine Both may become deficient in mito diseases Creatine Alternative energy source that can be helpful Lipoic acid and other antioxidants Used to help reduce oxidative stress from any inefficient Ox-phos activity Minimal benefit Cheap, relatively harmless |
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Why might you use arginine during acute stroke-like events?
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-Part of the problem with strokes in MELAS may be NO deficiency
-Arginine is the substrate for NO synthesis, so it does have some benefit likely as an NO donor -NO can help dialate cerebral vasculature, reduce the effects of the stroke-like episodes -It is important to get that started quickly so as soon as these patients start to show any symptoms they get rushed to the ER and have arginine started |
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What is pyruvate dehydrogenase deficiency?
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-PDH is the link between glycolysis and TCA (Krebs) cycle
-Multi-enzyme complex -->Multiple pieces of the complex are encoded for by different genes -->Multiple essential cofactors What are the cofactors??? |
-Thiamine
-α-lipoic acid -FAD, NAD, CoA |
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Where is pyruvate dehydrogenase in the cell? Why is it important?
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-This is where pyruvate dehydrogenase happens
-Glycolysis produces pyruvate, pyruvate is converted by PDH to acetyl coA -Acetyl co a is the entry point into the krebs cycle |
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How do kids with pyruvate dehydrogenase deficiency present?
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1. Psychomotor retardation
-->Intellectual disability 2. Hypotonia -->weakness 3. Progressive encephalopathy -->This can include Leigh syndrome 4. Brain malformations -->This depends on severity -->Brain development in utero is a very energetic process, so if you can’t do this well then you can have brain malformations at birth -->The brain malformations can be really bad -->There is NOT enough brain here -->The white is spinal fluid -->This little rim of brain here is what is left in these patients -->They do very poorly :( :( :( 5. Occasional extra-CNS manifestations -->Mostly neurologic disease, but can see some non-neurologic effects like: a. Cardiomyopathy b. Liver disease (These are pretty minor in PDH deficiency generally) |
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What abnormality do the vast majority of patients with pyruvate dehydrogenase deficiency have ?
What type of inheritance pattern does PDH deficiency have? |
-Vast majority of patients with PDH deficiency have abnormalities of one particular subunit -- E1α subunit
-X-linked Why is the fact that it's X-linked interesting? |
-This is interesting because most genetically encoded metabolic diseases are recessive
-Males generally worse, though females may certainly be similarly severe depending on Lyonization X-inactivation patterns |
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How do we treat pyruvate dehydrogenase deficiency?
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-Remember that in PDH deficiency, patients can’t get a lot energy from glycolysis, so we try to overload them with energy from the other side of the equation
-Thus, they try to give patients a ketogenic diet – basically the atkins diet to try to generate as much energy from ketones as possible -->Alternative pathway for acetyl-CoA production -This can help, although it doesn’t help with the brain malformations or the damage that is already done, but it can help prevent future episodes or reduce their severity -->Somewhat effective at reducing decompensations, but course still generally dismal -In general, these kids still do really poorly. |
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What is Leigh syndrome?
What else is it commonly called? When do patients present? |
Leigh Syndrome
-Neurologic degeneration, especially brainstem and cerebellum -->Progressive neurodegenerative disorder -Other aliases: Subacute necrotizing encephalomyelopathy -These kids are usually normal at birth and for the first few months of life -->Generally presents at 3-12 months of age -->Typically with mild infection (cold, flu, overnight fast) as trigger -Psychomotor regression – lose whatever skills they had -After the first hit, there is progressive neurologic degeneration – snowball effect -->Decompensation with each catabolic stress (Infection, fasting, etc). Stepwise loss of skills --> Hypotonia, spasticity, chorea (abnormal movements), ataxia, peripheral neuropathy -Cardiomyopathy *Most die by age 2-3 years |
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How do we diagnose Leigh disease?
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-Progressive neurologic disease with motor and intellectual delay
-Primarily affects the brainstem and/or basal ganglia disease -->A bit unusual in that there are a lot of neurologic degenerative diseases that affect the cortex, but not many that primarily affect the basal ganglia and brain stem -->If we see on neuroimaging a healthy looking cortex and a rotten looking brain stem and basal ganglia, we’re worried about Leigh syndrome -Elevated lactate in blood or CSF -One of: -->Typical LD features on neuroimaging a. Can have changes that are specific for Leigh disease -->Typical neuropathologic changes a. Multiple focal symmetric necrotic lesions b. Looking at brain under histopathology can give it away c. Typically need to have an autopsy for this --> Typical neuropathologic changes in affected sibling a. Family history __ -This is what Leigh syndrome looks like -This cortex looks pretty good, but what you see is kind of moth eaten basal ganglia -Note little punctate changes that aren’t supposed to be there -Can do spectroscopy on MRI and note high levels of __ acids (??? Min 30:45, can’t understand him) here, lactates here, you shouldn’t see a peak of lactate there |
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What causes Leigh syndrome?
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-It’s complicated
-There are many different genes that can be affected – most can be either mitochondrial or nuclear genes that lead to the same phenotype -Mostly oxidative phosphorylative function. -In figuring out which one it is is really important for the families for recurrence risk counseling Here's the list: Complex I genes -->mitochondrial-encoded MTND3 , MTND5, and MTND6 -->nuclear-encoded NDUFV1, NDUFS1, NDUFS3, NDUFS4, NDUFS7, and NDUFS8 Complex II gene: -->the flavoprotein subunit A (SDHA) Complex III gene: -->BCS1L which is involved in the assembly of complex III Complex IV genes -->mitochondrial-encoded MTCO3 nuclear-encoded COX10, COX15, SCO2, and SURF1 -->SURF1 is involved in the assembly of complex IV. Complex V gene: -->the mitochondrial-encoded MTATP6 This is a list from ~1 year ago, but they keep adding new ones |
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How is Leigh syndrome an example of a genotype to phenotype correlation?
Name two genetic changes that occur, and we'll go from there! |
1. T8993G
2. T8993C What do patients present with for each mutation if their mutant load is: <60%? ~70-90%? >90%? |
1. T8993G
-->Mutant load <60% assymptomatic -you’re fine – no symptoms, no way of knowing you have it -->Mutant load ~70-90% have NARP -NARP (like carp with an n) -Neurologic weakness with Ataxia and Retinitis Pigmentosa -Late-onset peripheral neuropathy, ataxia and RP -Also retinal degeneration -Patients with NARP typically live into adulthood, they may not live well but it’s very different than Leigh -Peripheral neuropathy, ataxia, retinal degeneration -->Mutant load >90% have Leigh syndrome *** This is a typical classic example of heteroplasmy effects*** 2. T8993C -->Less severe -->Mutant load <90% assymptomatic -->For patients to have symptoms, patients need >90% mitochondria with the T8893C mutation Can display as full fledged Leigh syndrome if you have the right/wrong heteroplasmy **Can also have GENOTYPE effects A different mutation at the same locus – in this case, instead of mutating T8893 to G, it’s T8893C -This has a less severe phenotype |
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What is NARP?
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-If ~70-90% of your mitochondria have the T8893G mutation, you have NARP
-NARP (like carp with an n) -Neurologic weakness with Ataxia and Retinitis Pigmentosa -Late-onset peripheral neuropathy, ataxia and RP -Also retinal degeneration -Patients with NARP typically live into adulthood, they may not live well but it’s very different than Leigh |
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What does the mutant load / outcomes of individuals with T8893G compare? When do you see threshold effects?
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-Mutant load of individuals v. probability of severe outcomes
-Threshold effects at about 70% for the T8893G mutation |
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How do you manage Leigh syndrome?
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-Not much we can do
-No specific treatment -Sodium bicarbonate to correct acidosis when these patients are acutely sick -->Helps patients breathe easier but does not prevent neurologic degeneration -Antiepileptics – to control seizures ***Avoid valproic acid and barbituates because they inhibit respiratory chain and can worsen the disease !!!!! -Mitochondrial cocktail -->No evidence for success -Patients are referred to hospice care as soon as the diagnosis is made to keep them as comfortable as possible and to give as much support for the family as possible |
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What are POLG1 related disorders?
Also, what even is POLG1? What does it do? How does it affect the mitochondria? |
POLG1 (DNA polymerase subunit gamma) – related disorders
-Nuclear gene -->Present on chromosome 15 -Plays a role in mitochondrial DNA maintenance and replication -3 main functional domains (some genotype/phenotype correlation) 1. Polymerase 2. Exonuclease 3. Linker -How this affects mitochondria is by causing depletion of DNA within mitochondria -->Reduction in copy number of mtDNA -->Depletion is also caused by other genes and result in similar phenotypes with either brain, liver, or both diseases, although polymerase gamma is by far the most common cause of DNA depletion -->DGOUK, MPV17, TK2, others -Have normal numbers of mitochondria, but they progressively lose their genome and as they lose their genome they wont make substrates for the respiratory chain or the tRNAs they need and you’ll have progressive mitochondrial dysfunction -Continuum of overlapping phenotypes -->Generally cause either hepatocerebral disease (like POLG1) or encephalomyopathic disease -->Because symptoms are so vague and can be at any different age, they check of this a lot -->He’s found it in a couple different families, but they check for it more than they find it -Range in severity, organ specificity, and age of onset -All originally described separately and nobody realized they had a common cause until the molecular genetic techniques caught up to the clinical descriptions of the diseases -May be identified based on direct mutation detection or by mtDNA depletion -No specific effective therapy -Not much to offer in terms of cures or therapy |
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What is Alpers?
What causes it? Symptoms? What's the first symptom typically? Age of onset? |
SEIZURES – NEUROLOGIC DEGENRATION – LIVER DYSFUNCTION
-Also caused by POLG (DNA polymerase subunit gamma) mutations Alpers -->Hypotonia (poor tone), seizures, liver failure Severe and progressive encephalopathy -Brain dysfunction – have seizures, severe intellectual disability -Neuroimaging with gliosis (scar-like appearance), atrophy -Cortex is much more involved than the brainstem and basal ganglia (opposite of Leigh) -->Sometimes will have a free floating brain stem and basal ganglia and the cortex is mostly gone with this disease -Seizures often first symptom -->That can happen at any age -->He’s had patients that seemed fine, and then at 10 months they had a seizure and by 2 years they were dead :( meep. -Can progress very quickly -Age of onset variable (2-4y typical) -->Most common descriptions are in toddlerhood but he’s seen babies and older kids -Liver dysfunction What precipitates the liver dysfunction? |
->May be precipitated by anticonvulsants
some anti-seizure medications are clearly responsible for the liver dysfunction associated with this, but other kids will have liver dysfunction without having been exposed to these anti-seizure medications -Variable progression to liver failure -Can be minor to sever liver disease -Can progress to full on liver failure and cirrhosis -Liver disease itself usually does not kill these patients, its mostly the neurologic problems |
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What are diseases caused by POLG1 (DNA polymerase subunit gamma)?
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1. Alpers
2. Childhood Myocerebrohepatopathy 3. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) -- "Meem-sah” 4. Ataxia neuropathy spectrum 5. AR and AD PEO (Autosomal recessive/dominant progressive external ophthalmoplegia) -- eye movement problems |
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What is Childhood Myocerebrohepatopathy?
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-Similar to Alpers in a lot of ways but it’s milder and has later onset
-Seizures, neurologic regression -Liver dysfunction -->Less of a cirrhotic liver dysfunction and more of a synthetic liver disease – not making coagulation factors and things like that |
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What is Ataxia neuropathy spectrum (ANS)?
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Children with more movement disorders and peripheral neuropathy can be caused by POLG1
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What happens if you have just one POLG1 mutation?
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-If you have just one POLG1 mutation (carrier) then you can have doubled vision, eye movement issues
-All of these are more severe phenotypes that are caused by recessive disease (having mutations on both copies of your polymerase gamma gene) |
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What is MNGIE?
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-Mitochondrial NeuroGastroIntestinal Encephalopathy
-Symptoms start in adolescence (variable) 1. Usually a gastrointestinal disease first. Gastrointestinal symptoms: a. Severe GI dysmotility -->Intestines simply won’t move. It’s like they have a post surgical illeus their whole life b. Cachexia (flip for more on cachexia) c. Nausea, vomiting, constipation, incontinence (sphincter dysfunction) -->Pretty socially debilitating early on -Can be diagnosed with anorexia early on because they’ll be so skinny and so uncomfortable when they eat they just won’t, but it’s really a different phenomenon than anorexia 2. Peripheral neuropathy 3. Opthalmoplegia/Ptosis (flip for more on this!) |
Cachexia ( from Greek kakos "bad" and hexis "condition“ – this was too funny not to include)[1] or wasting syndrome is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in someone who is not actively trying to lose weight. The formal definition of cachexia is the loss of body mass that cannot be reversed nutritionally: Even if the affected patient eats more calories, lean body mass will be lost, indicating a primary pathology is in place.
Opthalmoplegia: paralysis of one or more extraocular muscles which are responsible for eye movements Ptosis = drooping of the eyelids |
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What are the genetics behind MNGIE?
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-Caused by Thymidine phosphorylase deficiency
-->Nuclear encoded, cytoplasmic protein that causes a mitochondrial disease -->he’s literally having a braingasm over this, you can hear it in his voice **Autosomal recessive -People with thymidine phosphorylase deficiency have massive elevations of thymidine in their cytoplasm and mitochondria and in their blood stream == looking for high levels of thymidine is the main way to diagnose this disease -->Thymidine phosphorylase is present in the cytoplasm and helps to break down thymidine -Having high levels of thymidine levels around disrupts mitochondrial DNA replication system -->A lot of the error prevention part of the mitochondrial DNA duplication comes from tight control of nucleotide availability -->When you have this crazy amount of high thymidine around it introduces new mutations into the mitochondria as time goes on -->Leads to progressive accumulation of various mt-DNA mutations |
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