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Dementia 40-90%
accumulating cortical injuries
Epilepsy 71-96%
focal or generalized
with or without neuroimaging changes
Recurrent headaches 54-91%
Frequently with vomiting
Peripheral neuropathy 22-77%
axonal and/or demyelinating
chronic and progressive
Hearing impairment 71-77%
Two "Category B"
*High plasma or CSF lactate
*mitochondrial abnormality in muscle biopsy
*MELAS gene mutation
Impaired energy production stimulates mitochondrial proliferation in smooth muscle and endothelial cells of small vessels
Presentation
Variable, multiple manifestations
65-76% before age 20 years
5-8% before age 2 years
1-6% after age 40 years
Pathogenesis
Impaired mitochondrial energy production
abnormal proteins of ETC
Microvascular Angiopathy
secondary to mito proliferation in endothelial cells and smooth muscles of blood vessels
Nitric oxide deficiency
NO produced by vascular endothelium and needed for small vessel relaxation
Stroke-like episodes 84-99%
Do not follow vascular territories
MRS: decreased NAA, increased Lactate
Reversible aphasia
cortical vision loss
weakness
headaches
AMS
Seizures
Progressive accumulation of deficits
High energy demand tissues are effected with clinical variability
nervous system
skeletal muscle
cardiac muscle
kidney
liver
endocrine system
Other organ system manifestations
Lactic acidemia
CSF lactate may be elevated
Non-specific
Gastrointestinal
Cyclic vomiting
Pancreatitis
FTT
Endocrine
Diabetes
Short statue
Management
largely symptomatic, multi-disciplinary
Screening for mentioned complications
Exercise
L-arginine supplementation and IV infusion during stroke-like episodes (increases NO)
Citrulline supplementation less studied but theoretically beneficial (increases NO)
COQ10 for ETC support to improve weakness/fatiguability
Creatine as phosphate donor for muscle and heart and brain
Avoidance of VPA and other AEDs, metformin, aminoglycosides, alcohol, smoking
"Renal, Pulmonary, dermatologic and hematologic"
Genetics
m.3243A>G mutation in mitochondrial gene MT-TL1 gene found in 80% of MELAS patients
other mutations of MT-TL1 are less common
Mutations of nuclear gene POLG encoding mitochondrial proteins have been associated with MELAS-like phenotype
*phenotypic variability