MELAS: Mitochondrial
Encephalopathy with Lactic Acidosis and Strokelike Episodes
MELAS is a rare, progressive, multisystem disorder caused
by mitochondrial dysfunction. It primarily affects the central nervous system
(CNS), muscles, and other organs that rely heavily on mitochondrial energy
production. Below is a comprehensive explanation of MELAS, covering its cause,
etiology, pathophysiology, epidemiology, clinical presentation, imaging
features, treatment, and prognosis.
Cause and Etiology
MELAS is caused by mutations in mitochondrial DNA (mtDNA)
that affect the mitochondrial respiratory chain. The mutation leads to impaired
mitochondrial energy production, which primarily affects high-energy demanding
tissues, such as the brain, muscles, and eyes.
·
Mitochondrial DNA Mutations: The most common mutation associated with MELAS is a point mutation
in the mitochondrial tRNA gene (A3243G) in the MT-TL1 gene, which encodes a
transfer RNA responsible for protein synthesis in mitochondria.
·
Inheritance: MELAS
follows maternal
inheritance, as mitochondria are inherited only through the egg
cell. A mother with a mutation in her mitochondrial DNA can pass it to all of
her children, regardless of gender. The father cannot pass on the mutation
since his sperm does not contribute mitochondria to the offspring.
Pathophysiology
MELAS is primarily a disorder of energy production.
Mitochondria, the "powerhouses" of cells, generate energy in the form
of adenosine triphosphate (ATP) through oxidative phosphorylation in the
electron transport chain. When mutations in mitochondrial DNA impair this
process:
1.
Impaired ATP Production: The mutation in the mitochondrial DNA disrupts the function of the
respiratory chain, leading to inefficient ATP production. As a result, cells in
high-energy tissues (like the brain and muscles) suffer from energy deficits.
2.
Lactic Acidosis:
Due to the reduced ability of cells to generate energy through oxidative
phosphorylation, anaerobic glycolysis is upregulated to compensate. This leads
to the accumulation of lactate in the blood, causing lactic acidosis.
Stroke-like Episodes: The cerebral tissues are particularly vulnerable to energy deficits. The brain is highly dependent on efficient mitochondrial function for normal neuronal activity. The mitochondrial dysfunction in MELAS causes a cascade of events leading to neuronal injury, which manifests as stroke-like episodes (SLEs). These episodes are often transient, but repeated episodes can lead to permanent brain damage.
Epidemiology
·
Prevalence: MELAS
is considered a rare disorder. The exact prevalence is not well established,
but estimates suggest it affects about 1 in 4,000 to 1 in 10,000 individuals
globally.
·
Age of Onset:
Symptoms often begin in childhood or early adulthood, typically between the
ages of 2 and 40.
·
Gender: Both males
and females are equally affected because of the maternal inheritance pattern of
mitochondrial DNA.
Clinical Presentation
The clinical presentation of MELAS is highly variable, but
the hallmark features include:
1.
Stroke-like Episodes: These are sudden-onset neurological deficits that resemble a
stroke, such as hemiparesis, visual disturbances, seizures, and loss of
coordination. They can last for hours or days but often lead to permanent
neurological damage with recurrent episodes.
2.
Lactic Acidosis:
Elevated lactate levels in the blood lead to lactic acidosis, which can cause
symptoms such as nausea, vomiting, fatigue, muscle weakness, and rapid
breathing (tachypnea).
3.
Seizures: Seizures
are common in MELAS and may be associated with stroke-like episodes or may
occur independently.
4.
Muscle Weakness:
Patients with MELAS often have generalized muscle weakness and exercise
intolerance, as the muscles are affected by impaired energy production.
5.
Hearing Loss:
Sensorineural hearing loss is a common feature, typically progressive, due to
mitochondrial dysfunction in the cochlear cells.
6.
Vision Problems:
MELAS can cause vision impairment due to retinal degeneration or optic
neuropathy. This leads to progressive loss of visual acuity.
7.
Other Symptoms:
o
Diabetes Mellitus:
Can develop as a secondary feature due to mitochondrial dysfunction affecting
pancreatic beta cells.
o
Cardiomyopathy: A
heart muscle disease that can lead to heart failure and arrhythmias.
o
Endocrine abnormalities: Thyroid dysfunction and other hormonal disturbances may occur.
Imaging Features
Imaging is essential for diagnosing and monitoring MELAS,
particularly in identifying stroke-like episodes and assessing brain changes.
1.
Magnetic Resonance Imaging (MRI):
o
Cerebral infarcts:
MRI may show stroke-like lesions, often affecting the posterior brain regions,
especially the occipital
lobe. These areas are more vulnerable due to their high energy
demand.
o
Cerebellar and basal ganglia involvement: Stroke-like episodes often involve the basal ganglia and
cerebellum, leading to coordination and movement issues.
o
White Matter Changes: Long-term mitochondrial dysfunction can lead to progressive white
matter changes, often visible on MRI as areas of hyperintensity.
2.
Positron Emission Tomography (PET): PET scans may show decreased cerebral metabolism in regions
affected by stroke-like episodes, reflecting decreased mitochondrial function
and energy production.
3.
Muscle Biopsy:
Muscle biopsies often show ragged-red fibers (abnormal mitochondria aggregates), which
are indicative of mitochondrial disorders.
Treatment
There is no cure for MELAS, but treatment is symptomatic
and supportive:
1.
Management of Stroke-like Episodes:
o
Anti-seizure medications: To control seizures, antiepileptic drugs such as valproate or
levetiracetam may be used.
o
Stroke prevention:
Some patients may benefit from anticoagulant or antiplatelet therapy to prevent
further strokes, but this is controversial and not universally recommended.
2.
Management of Lactic Acidosis:
o
Bicarbonate therapy: In severe cases of lactic acidosis, intravenous bicarbonate may be
administered to correct the acid-base imbalance.
o
Dietary interventions: Some patients benefit from a high-fat, low-carbohydrate diet
(e.g., ketogenic diet) to reduce lactate production by shifting the metabolic
pathway.
3.
Supplements:
o
Coenzyme Q10 (CoQ10): An antioxidant that supports mitochondrial function and may
improve symptoms.
o
L-carnitine: To
enhance mitochondrial fatty acid oxidation and energy production.
o
Vitamin E and other antioxidants: These are sometimes used in an attempt to reduce oxidative damage
to tissues.
4.
Endocrine Management:
o
Insulin therapy:
For those with diabetes mellitus or other endocrine issues, appropriate
hormonal treatment is essential.
o
Thyroid hormone replacement: If hypothyroidism is present, thyroid hormone replacement is
necessary.
Prognosis
The prognosis of MELAS varies greatly depending on the
severity of the disease and the presence of complications:
1.
Life Expectancy:
The disease is progressive, and many patients develop severe neurological
impairments over time. Life expectancy can be reduced, with death often
occurring due to complications like cardiac failure, respiratory failure, or
recurrent stroke-like episodes. Many individuals with MELAS live into their 40s
or 50s, but some may live longer with appropriate management.
2.
Disability: Due to
recurrent stroke-like episodes and progressive neurological damage, MELAS often
leads to significant disability, including cognitive decline, motor deficits,
and loss of vision and hearing.
3.
Quality of Life:
The quality of life can be significantly impacted by muscle weakness, seizures,
and cognitive decline. However, some individuals may experience periods of
stability with proper management of symptoms.
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