Mitochondrial Diseases Flashcards
Mitochondrial DNA characteristics
1) heteroplasmy
Each mitochondrion contains 2–10 copies of mtDNA, and in turn each cell contains multiple mitochondria; therefore, there are hundreds to thousands of copies of mtDNA in each cell.
Alterations of mtDNA may be present in some of the mtDNA molecules (heteroplasmy) or in all of the molecules (homoplasmy).
As a consequence of heteroplasmy, the proportion of a deleterious mtDNA mutation can vary widely
2) tissue distribution of that mutation broadens the clinical spectrum of pathogenic mtDNA mutations
3) tissue threshold effect
Cells with high metabolic activities are severely and adversely affected
by mtDNA mutations (brain and muscles more affected)
4) maternal inheritance
During the formation of the zygote, the mtDNA is derived exclusively from the oocyte.
Thus, mtDNA is transmitted vertically in a nonmendelian fashion from the mother to both male and female progeny
Mitochondrial diseases: Which are most common mtDNA or nDNA mutations?
In children most common mitochondrial diseases caused by nDNA
In adults most common mitochondrial diseases caused by mtDNA
Mitochondrial syndromes (mtDNA mutations)
1) KEARNS-SAYRE SYNDROME & CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
2) MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome
3) MERRF (myoclonus with epilepsy and ragged-red fibers) syndrome
4) NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa Syndrome)
5) LEBER HEREDITARY OPTIC NEUROPATHY
Mitochondrial myopathy muscle biopsy finding
ragged-red fibers
Kearns Sayre syndrome main clinical findings
- Opthalmoparesis and ptosis
- Pigmentary retinopathy
- Cardiac conduction block
- Onset usually before 20 years
Other:
short stature, cerebellar ataxia, raised cerebrospinal fluid protein (>100 mg/dL), anemia, diabetes, deafness, and cognitive deficits or intellectual disability
Συνήθως σποραδικό!!
MELAS syndrome main features
(1) stroke-like episodes occurring at a young age (typically
before age 40)
(2) encephalopathy manifesting as seizures, dementia, or both
(3) mitochondrial dysfunction as evidenced by lactic acidosis, ragged-red fibers
MELAS syndrome pathogenesis
The mtDNA m.3243A>G mutation in the tRNALeu(UUR) gene (MT-TL1) has been identified in about 80% of patients with MELAS syndrome.
Why are the episodes in MELAS called stroke-like
These episodes are different from typical embolic or thrombotic ischemic strokes and thus are called “stroke-like” for several reasons:
● The brain lesions do not respect vascular territories
● The apparent diffusion coefficient (ADC) on MRI is not always decreased (as it would be with tissue infarction) but may be increased or demonstrate a mixed pattern
● The acute MRI signal changes are not static and may migrate, fluctuate, or resolve more quickly and more often than would occur in a typical ischemic stroke
MELAS clinical findings
The hallmark of this syndrome is the occurrence of stroke-like episodes that result in hemiparesis, hemianopia, or cortical blindness.
Other common features include:
- focal or generalized seizures
- recurrent migraine-like headaches
- vomiting
- short stature
- hearing loss
- muscle weakness
MELAS diagnosis
Clinical/ Imaging findings plus
- The presence of lactic acidosis and muscle biopsy showing ragged-red fibers provides evidence of mitochondrial dysfunction
- Usually, the diagnosis can be confirmed by identification of a pathogenic mtDNA mutation in blood
MELAS management
no specific disease-modifying therapy is available
For patients with MELAS who have stroke-like episodes accompanied by seizure, aggressive treatment with antiseizure medication using intravenous levetiracetam (20 to 40 mg/kg, maximum 4500 mg) as first choice is recommended.
Other options are phenytoin (15 to 20 mg/kg with cardiac monitoring), phenobarbitone (10 to 15 mg/kg with respiratory monitoring), or lacosamide (200 to 400 mg)
Arginine supplementation has been used as a strategy to treat patients with MELAS, both as an infusion in the acute phase of the stroke-like episodes and as an oral daily therapy.
However, evidence of efficacy is lacking!
MERRF syndrome clinical findings
Myoclonic epilepsy with ragged red fibers (MERRF) is characterized by myoclonus, typically as the first symptom, and is associated with generalized epilepsy, ataxia, and myopathy
Additional features can include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, lipomatosis, and/or cardiomyopathy with Wolff-Parkinson-White syndrome.
Childhood onset after a normal early development is common.
Leber hereditary optic neuropathy: clinical findings
LHON usually presents as subacute to acute loss of central or cecocentral vision as a result of a painless optic neuropathy in one eye followed by loss of vision in the other eye weeks or months later.
The age at onset is typically 18–35 years.
The presence of tortuous blood vessels adjacent to the optic
nerve (peripapillary telangiectasias) can be a clue to the diagnosis.
Wolff-Parkinson-White cardiac preexcitation is often observed in LHON patients.
Skeletal muscle is not affected clinically and, accordingly, ragged-red fibers are not observed!!
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(μόνο 10% γυναικών και 50% ανδρών φορέων)
Leber hereditary optic neuropathy: management
There is no proven effective treatment for LHON.
Idebenone (a synthetic analog of CoQ10) is approved in Europe for the treatment of visual impairment in adolescent and adult patients with LHON.
Where available, a one- to three-year trial of idebenone may be considered for symptomatic patients in conjunction with regular neuro-ophthalmologic testing
Which is most common in Leber hereditary optic neuropathy, homoplasmy or heteroplasmy?
In most LHON patients the mtDNA mutations are homoplasmic
