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ABGC > mitochondrial genetics > Flashcards

mitochondrial genetics Flashcards

1
Q

heteroplasmy

A
  • results in variable penetrance and variable expressivity in mitochondrial disorders
  • only some mitochondria that are passed on carry disease-causing mutation (WT and mutant)
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2
Q

complex V deficiency

A

not clinically testable in US

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3
Q

failure in mitochondrial formation

A

only caused by nuclear DNA mutation

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4
Q

complex II

A

only comprised of nuclear subunits

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5
Q

mitDNA

A

-comprised of 37 genes
+13 proteins
+22 tRNAs
+2 RNAs-6S and 12S
-no introns, no recombination
-continuous replication with high mutation rate relative to nuclear DNA and no histone regulation
-disease causing mutations occur in a tissue-specific fashion

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6
Q

LHON c.11778G>A

A

protective vision mutation in certain ethnic groups

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7
Q

homoplasmy

A

can be 100% WT or mutant mitochondrial line presence

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8
Q

threshold effect

A

specific heteroplasmy load that can be tolerated in a tissue for a specific mtDNA mutation before showing signs of pathology

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9
Q

mit dz recurrence risk

A
  • 1-4% if mother shows no signs or symptoms
  • up to 50% if mom is symptomatic
  • testing recommended in parents and siblings of a proband to reveal level of heteroplasmy and manage them
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10
Q

high lactic acid

A
  • common reason for mitochondrial referral
  • not sensitive or specific though
  • complications: using a tournicate or having a child fight the blood stick can spike the levels, handling also tricky
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11
Q

plasma and CSF AAs

A
  • high alanine

- high glycine, tyrosine, proline or sarcosine

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12
Q

urine OAs

A
  • TCA intermediates
  • ethyl malonate
  • 3-methyl-glutaconate
  • dicarboxylic acids
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13
Q

plasma acylcarnitines

A
  • low free levels
  • elevated bound:free ratio
  • elevations suggestive of FAODs
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14
Q

Leigh syndrome genetics

A

-can be caused by mitochondrial and nuclear gene mutations; HIGH mtDNA mutation load
-involvement of brainstem, basal ganglia and cerebellum
+subacute necrotization

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15
Q

Brain MRI

A
  • symmetric sign abnormality in deep gray matter
  • transient v progressive
  • cerebellar atrophy
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16
Q

brain MRS

A

-provides chemical picture of brain
+not always specific
-shows decreased L-NAA, which is synthesized in mitochondria
-see lactate doublet in affected individuals related to increased lactic acid and a switch to anaerobic respiration
-can study different parts of brain individually

17
Q

tissue based skeletal muscle analysis

A
  • not as common anymore, though sometimes still useful
  • morphology can show increased proliferation, subsarcolemmal accumulation, abnormal RRFs and Cox-deficient fibers
  • electron microscopy identified increased count and structural anomalies
18
Q

ETC activity via biochemical tissue analysis

A
  • reported relative to citrate synthase
  • important to obtain the standard muscle type in biopsy
  • can show isolated or multiple enzyme defects
  • effects may be secondary to other conditions
19
Q

CoQ10 determination via biochemical tissue analysis

A
  • primary deficiency is rare, whereas secondary deficiency common in mit dz
  • may help adjust need for changes to therapy and dosage for patient or insurance-coverage
20
Q

mtDNA CNV and genetic analysis via biochemical tissue analysis

A

assesses for potential depletion

- <20% is considered clinical cutoff for depletion

21
Q

liver biopsy analysis

A
  • ETC deficiency

- mtDNA CNV and genetic sequencing

22
Q

skin biopsy analysis

A
  • ETC deficiency
  • mtDNA and gene sequencing
  • fibroblast cell line establishment (indefinitely storable)
23
Q

skeletal muscle analysis

A
  • morphology and staining
  • electron microscopy
  • ETC deficiency
  • CoQ10 determination
  • mtDNA CNV analysis and gene sequencing
24
Q

molecular testing

A

-mostly done by NGS
+often labs can report heteroplasmy as low as 1.2%
+older testing methods not as accurate
-tissue specific testing can also be important for identifying targeted heteroplasmy and mutation burden
-WES may be helpful because it includes del/dup analysis and avoids multiple panels being run, but still can’t diagnose all cases

25
Q

LHON presentation

A

-caused by mutations in MT-ND1, MT-ND4 and 4-L, and MT-ND6
+causes degeneration of the retinal ganglia and optic nerve, disc and vascular changes
+3 common mutations, mostly homoplasmy in blood
-development of painless, bilateral, subacute vision failure
+begins with central vision loss that usually starts unilaterally and progresses
-can also see arrhythmia and neurologic involvement (tremors, peripheral neuropathy, myopathy, MS-like features)
*males more likely to have vision loss than females

26
Q

LHON management

A
  • cardiac eval
  • neuro eval
  • optho eval
  • avoidance of mitochondrial toxins
27
Q

MELAS presentation

A

-80% caused by MT-TL1 mutation m.3243A>G (leucine tRNA)
-normal early development with seizures, headaches, exercise intolerance with vomiting and proximal limb weakness starting between 2-10y or delayed between 10-40y
+sz and stroke-episodes usually only present before 40y and can lead to hemiparesis, cortical blindness, progressive cognitive and motor impairment
-can also see dementia, HL, myopathy, short stature
-can see elevated LA+or-RRF

28
Q

Leigh syndrome phenotype

A
  • psychomotor retardation and regression
  • develop feeding problems with FTT, hypotonia, ataxia, seizures, respiratory failure, hearing and vision loss with or without nystagmus
29
Q

MERRF

A
  • tRNA lysine mutations
  • seen with ataxia and myoclonus and abnormal muscle stains
  • can also develop peripheral neuropathy, optic atrophy, hearing loss
  • short stature and lipomas common
30
Q

NARP

A
  • ATPase 6 mutations (complex V)
  • adult onset, often non-specific lactic acidosis related
  • peripheral neuropathy, cerebellar ataxia, pigmentary neuropathy
31
Q

KSS

A

-mtDNA deletion that presents before 20yo
+sometimes only detectable in CNS and muscle
+mostly de novo
-causes ptosis, progressive external ophthalmoplegia and pigmentary retinopathy
+one of the following also part of diagnosis: CSF protein >100mg/dL, conduction heart block, or cerebellar ataxia
-hormone imbalance may also occur (i.e. DM, hypoparathyroidism), as can short stature, hearing loss, dementia, limb weakness

32
Q

Pearson syndrome

A

-mtDNA deletion that presents and is fatal in infancy
+mutation detectable in blood
-causes anemia, exocrine pancreas dysfunction

33
Q

Progressive external ophthalmoplegia (PEO)

A
  • mtDNA deletion detectable in muscle with onset in adulthood
  • ptosis and inability to move eyes laterally
34
Q

POLG mutations

A

-spectral disorder ranging from severe infantile to adult onset
-gene is the only mtDNA pol that functions in replication and repair
-150+ mutations
+exonuclease activity loss causes PEO
+linker region loss causes ataxia, vasiculations
+replication activity loss leads to severe Alpers phenotype (sz, cortical blindness, dementia, liver dz)

35
Q

suspecting mitochondrial mutation

A
  • more likely to be AR nuclear mutation if infantile onset with lactic acidosis
  • more likely to be mtDNA mutations if later onset-mutations must buildup
36
Q

management

A

-no treatment, but treat symptoms
+no fasting, no febrile periods
+vaccinate, avoid illness, avoid toxic drugs (valproate, statins, etc)
+may give vitamin cocktails and antioxidants
-guidelines with anesthesia due to recovery difficulty
-arginine or citrulline therapy for stroke

37
Q

(Mitochondrial NeuroGastroIntestinal Encephalomyopathy) MNGIE

A
  • fatal AR condition
  • characterized by ptosis with ophthalmoplegia, GI dysmotility, cachexia, peripheral neuropathy, leukoencephalopathy and mitochondrial abnormalities
38
Q

TK2 disease

A

-mt thymine kinase deficiency leads to early onset and average death within 2.5y
-causes progressive skeletal and respiratory muscle failure
+decreased movement, gait abnormalities, tremor
-see elevated CK and lactic acid levels

ABGC (34 decks)

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