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MELAS syndrome: Clinical manifestations, pathogenesis and treatment options

El-Harrab, A. Molecular Genetics and Metabolism 6/2015

Neurologic Manifestations

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%

Diagnostic Criteria

and

Two "Category B"

*High plasma or CSF lactate

*mitochondrial abnormality in muscle biopsy

*MELAS gene mutation

Two "Category A"

*HA with vomiting

*seizures

*hemiplegia

*cortical blindness

*acute focal lesions

on imaging

Other organ system manifestations

Myopathy: exercise intolerance, weakness, motor delay in children

Ragged red fibers that stain with cytochrome C oxidase stain

Vacuolated muscle fibers

Cardiomyopathy: dilated and hypertrohic and conduction abnormalities

Impaired energy production stimulates mitochondrial proliferation in smooth muscle and endothelial cells of small vessels

multiorgan disease caused by mutations in mitochondrial genes or nuclear genes coding proteins in the electron transport chain of mitochondria

Presentation

Variable, multiple manifestations

65-76% before age 20 years

5-8% before age 2 years

1-6% after age 40 years

Neurologic manifestations

"Other" neurologic manifestations

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

Leading to angiopathy of microvasculature

LD, myoclonus, ataxia, episodic AMS, basal ganglia calcifications, elevated CSF proteing, optic atrophy, ophthamoloplegia,

psychiatric illness

Mitochondrial encephalomyopthylactic acidosis, and stroke-like epsiodes

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

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