Melas Syndrome

What is Melas Syndrome?

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare genetic disorder, usually passed on from the mother, that mainly affects the brain and muscles. Typically, children who initially develop normally might start showing signs of MELAS between ages 2 and 15, though symptoms can appear earlier or even later, up to the age of 40. The syndrome’s main features include repeated episodes of brain dysfunction (encephalopathy) and muscle disease (myopathy), headaches, and specific neurological issues. Sometimes these symptoms can be similar to having a stroke, causing partial paralysis, vision loss, or even complete blindness in certain visual fields. Other common symptoms might include localized or widespread seizures, repeated migraines, vomiting, short stature, hearing loss, and muscle weakness.

The most common cause of MELAS is a small change in the genetic material inside the cell’s powerplants (mitochondria), specifically within transfer RNA (tRNA) that is crucial for cell function. The most common of these genetic changes accounts for 80% of MELAS cases. Another less common change accounts for the remaining cases. MELAS tends to worsen over time, leading to increased brain impairment and, eventually, severe cognitive decline or dementia during teenage years or early adulthood.

Diagnosing MELAS depends on various factors. These include the signs and symptoms a patient shows, the findings from imaging scans, and in some instances, the analysis of muscle tissue. During sudden bursts of symptom severity (acute attacks), doctors can observe specific chemical changes in the patient’s blood. Furthermore, MRI scans can show specific types of brain damage not typically linked to any known stroke-causing blood vessels. To be certain of the diagnosis, gene testing of the mitochondria can provide a clear answer.

Currently, there is no known cure for MELAS that can stop or slow its progression. Treatment instead focuses on relieving and managing the symptoms with a team of healthcare professionals. Medication options that are often used work on potentially improving the function of the mitochondria. This includes drugs like L-arginine, carnitine, and coenzyme Q10.

What Causes Melas Syndrome?

MELAS is a genetic condition that’s passed down through families and it affects certain tiny parts of our cells called mitochondria. Interestingly, we only inherit mitochondria from our mothers, not our fathers, which is why disorders like MELAS follow this same maternal line of inheritance. Therefore, MELAS and similar conditions occur when mitochondria get diminished during conception. Though rare, sometimes MELAS can occur spontaneously in a person without any family history. These genetic disorders happen because changes in the order of mitochondria’s DNA components affect its working, especially in energy production.

MELAS disrupts the assembly of protein into something called ‘respiratory chain complexes’. This is thought to be due to changes in a type of RNA called tRNA, though the precise details aren’t fully understood. As mitochondria are the ‘power stations’ of our cells, any conditions affecting them will have a significant impact, especially on energetically demanding parts of our bodies like the brain, eyes, heart, and muscles.

There are several variations in tRNA that can lead to MELAS, with the most common one being found in the MTTL1 mitochondrial gene. An alteration known as m.3243A>G is seen in 80% of people with MELAS, while a second common variant, m.3271T>C, can be observed in about 10%. However, researchers continue finding more genes associated with conditions similar to MELAS.

Risk Factors and Frequency for Melas Syndrome

MELAS is one of the most common diseases related to mitochondria, with about 1 in 4000 people being affected. Research in Finland and Northern England highlights that the m.3243A>G variant exists in about 10.2 per 100,000 and 1 per 13,000 adults respectively. However, these numbers might actually be lower than the true rates. In 2006, a large study of Caucasians found the occurrence of the MELAS m.3242 A>G variant to be as high as 236 per 100,000, which is substantially more than previous estimates.

MELAS is amongst the most common mitochondria-related illnesses.
About 1 in 4000 people are estimated to have this condition.
Studies of adult populations in Finland and Northern England found the incidence of a MELAS variant to be 10.2 per 100,000 and 1 per 13,000 respectively.
These rates might be underestimates; a large 2006 study found a variant’s prevalence to be as high as 236 per 100,000 in Caucasians.
There is no difference in the susceptibility to MELAS between genders.
However, only women can pass the condition onto their children as the disease-carrying mitochondria are present in the father’s sperm, but are usually not incorporated into the fertilized egg.
No clear patterns of the disease affecting any particular race have been observed.

Signs and Symptoms of Melas Syndrome

MELAS is a syndrome that begins to show symptoms in children usually between the ages of 2 and 15, after a period of normal early development. Less common, it can also show up in infancy or adulthood. Initial signs in infants might be delayed development and poor growth. In older children, MELAS often begins by showing signs such as recurring migraines, decreased appetite, vomiting, seizures, and changes in brain function, including loss of consciousness or confusion. Mental decline often begins in childhood and progresses slowly.

Delayed development and growth problems in infants
Recurring migraines
Decreased appetite
Vomiting
Seizures
Changes in brain function leading to confusion or loss of consciousness
Slowly progressing mental decline beginning in childhood

MELAS is characterized by stroke-like episodes, seizures, frequent migraines, vomiting, stunted growth, hearing loss, muscle weakness, high levels of lactic acid, diabetes, heart disease, and problems with the digestive function. Patients often have cycles of worsening and improving symptoms, with worsening brain function and confusion leading to dementia due to stroke-like episodes. Muscle pain or weakness may be an early symptom of MELAS, although it is often not recognized as such.

The stroke-like episodes that characterize MELAS often begin suddenly with neurological symptoms like weakness or vision changes on one side of the body, or complete vision loss. They may also include vomiting and migraines that last several days. Despite their name, these episodes are not like typical strokes because there is no blocked blood vessel and the affected area does not correspond to any specific blood vessel territory.

Seizures can occur in children with MELAS, along with visual abnormalities and hemiplegia (paralysis of one side of the body). Seizures may be tonic-clonic (involving stiffness and jerking) or myoclonic (involving muscle twitching). Children who develop MELAS at a younger age often experience seizures that are resistant to medication, creating more severe symptoms and impairment.

Patients can sometimes experience the stroke-like episodes as migraines or headaches that resemble migraines. These headaches can sometimes be the only symptom of a stroke-like episode.

Other symptoms associated with MELAS include vision loss due to damage to the optic nerve, difficulty with night vision due to a condition called pigmentary retinopathy, excessive thirst and urine production (possible signs of diabetes), feeling your heart beat (palpitations) and shortness of breath (suggesting heart conduction problems such as Wolff-Parkinson-White Syndrome or heart disease), numbness and pain in the limbs associated with peripheral neuropathy, a possible link with mental health disorders like bipolar disorder and depression, hearing loss, and Alzheimer’s disease linked to a specific genetic variant.

Testing for Melas Syndrome

To diagnose MELAS, a condition that affects many of the body’s systems, doctors will check for specific signs and identify changes in certain genes associated with the condition.

One way doctors test for MELAS is by looking at the levels of certain chemicals in your blood and spinal fluid. These include lactic acid and a chemical called pyruvic acid. High levels of lactic acid can sometimes be the first clue in a MELAS diagnosis. This is especially true during an episode that resembles a stroke. If high lactic acid levels are found, doctors may consider other conditions that could be causing it, like tissue damage from low oxygen levels or sugar imbalances or certain metabolic disorders. If these conditions are unlikely, then high levels of lactic and pyruvic acid could indicate MELAS.

However, it’s important to note that despite the high lactic acid levels, MELAS doesn’t always lead to a condition known as metabolic acidosis, which is when the body’s fluid balance is upset. Additionally, some people with MELAS may have normal lactic acid levels in their blood but still have high levels in their spinal fluid.

Other signs include an increase in lactic and pyruvic acid levels with exercise, a possibly higher than normal ratio of lactic acid to pyruvic acid, and normal oxygen levels even while the lactic acid to pyruvic acid ratio is high.

Another important tool in diagnosing MELAS is genetic testing. Doctors can test for changes in mitochondrial DNA (the kind of DNA found in our cells’ energy-making machinery). This testing can be done using samples of blood, muscle, hair follicles, cheek cells, or cells from urine. However, due to the fast rate of blood cell division, it might be difficult to detect certain genetic changes in blood samples. More reliable samples are those from urine, cheek cells or skin cells. If the genetic tests come back normal but doctors are still suspicious of MELAS, they may recommend a muscle biopsy.

Imaging can also help diagnose MELAS. CT scans can show changes in the brain that look like stroke damage. Over time, these changes can lead to brain shrinkage and calcification, which is when calcium builds up in tissue.

MRI can also be used. This type of imaging can show different areas of the brain that appear to have been affected by a lack of oxygen. These areas don’t fall within a specific blood vessel region, which is unusual for stroke patients. Initial lesions often appear in the back part of the brain and can eventually affect other parts including the cerebral cortex, basal ganglia, and thalamus.

Another diagnostic tool is magnetic resonance spectroscopy. This tool can detect abnormalities in the ratios of certain brain and muscle metabolites. It might even show areas of high lactic acid in the brain when blood tests do not.

Lastly, a technology called positron emission tomography can also be used. It can show a decreased use of oxygen in the brain, increased blood flow in certain brain regions, and continued normal use of glucose.

There are a few more tests doctors can do if needed. These include an EEG to look for certain types of electrical activity in the brain, ECG to check for any heart irregularities, and an echocardiogram if they suspect a heart condition called cardiomyopathy. These tools all help to give a comprehensive evaluation and provide valuable information for diagnosing MELAS.

Treatment Options for Melas Syndrome

MELAS syndrome is a type of inherited genetic disorder caused by defects in the energy-producing parts of the cells called mitochondria. Unfortunately, there is currently no cure available that can effectively slow or stop the progression of this disease.

Interestingly, MELAS syndrome is considerably affected by a lack of a substance called nitric oxide. Therefore, doctors may administer substances like arginine and citrulline, which are precursors (building blocks) to nitric oxide. This could improve the availability of nitric oxide and minimize the effects of its deficiency.

During severe episodes similar to strokes, doctors may administer arginine to help reduce brain damage. Brain damage can happen when the blood vessels in the brain can’t dilate properly due to the lack of nitric oxide. For patients with MELAS who are experiencing a severe stroke-like event, a high dose of arginine could be beneficial if given within the first few hours after symptoms start. After that, a continuous dose of arginine may be provided for a few days.

Patients with MELAS syndrome may also have lower than normal levels of citrulline. Some studies have shown that supplementing with citrulline can enhance nitric oxide production more than supplementing with arginine. As citrulline can stimulate the body to produce arginine, it also holds therapeutic potential for MELAS.

There are also other treatments available for MELAS. For instance, vitamins like coenzyme Q10, vitamin K3, vitamin K1, and ascorbate are used in an attempt to boost mitochondrial function. Certain case reports suggest improvement with other substances as well, like riboflavin, dichloroacetate, sodium succinate, and creatinine monohydrate.

Coenzyme Q10 and L-carnitine are vitamins that are believed to boost energy production by mitochondria and potentially slow down the progression of MELAS syndrome. Idebenone, a synthetic version of coenzyme Q10, is also being explored through clinical trials for its potential benefit to neurological function in mitochondrial disorders like MELAS.

Unfortunately, seizures that occur in patients with MELAS can sometimes be difficult to manage with medication. In particular, a medication called valproate is not considered an appropriate treatment for these patients. This is because many reports suggest that valproate can worsen seizures and brain disease in individuals with MELAS syndrome.

If a person comes to the doctor with a family history suggesting they may have inherited a condition from their mother’s side of the family, several illnesses could be the cause. These could include:

Various mitochondrial disorders
Kearns-Sayre syndrome
Myoclonus epilepsy with ragged red fibers (MERRF)
Leigh syndrome
An issue with the mitochondrial DNA polymerase (POLG)
Pearson syndrome
Nutritional issues causing failure to thrive
Medium-chain acyl-coenzyme A dehydrogenase deficiency
Carnitine deficiency
Nephrotic syndrome
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Myoclonus epilepsy with ragged red fibers (repeat)

Kearns-Sayre syndrome is an uncommon disorder affecting nerves and muscles and can cause issues with vision, height, hearing, and coordination. People with this syndrome might also have eye symptoms and more frequent heart problems.

MERRF and MELAS are conditions that can cause seizures, mental deterioration, and muscle problems which can be mistaken for each other due to the appearance of ragged red fibers on a tissue sample. People with MERRF might also have hearing loss, vision problems, and short stature.

However, the distinguishing feature of MERRF is a specific type of seizure, called a myoclonic seizure, though a definitive distinguisher is required genetic testing. Leigh syndrome, on the other hand, causes progressive neurological deterioration, seizures, and vomiting, typically in young children.

What to expect with Melas Syndrome

MELAS is a disease that continues to worsen over time, severely affecting the brain and muscles, which often leads to dementia. Currently, there are no available treatments that can slow down or stop the disease from progressing. On average, the life expectancy after starting to experience seizures or neurological problems is around 17 years.

Possible Complications When Diagnosed with Melas Syndrome

MELAS, a medical condition, can lead to various complications which include:

Difficulty growing and being shorter than typical
Decreasing intellectual abilities that could result in dementia
Development of mental health issues like depression, schizophrenia, or bipolar disorder
Conditions on the autism spectrum
Loss of hearing
Issues with hormones, such as hypogonadism, diabetes, low parathyroid or thyroid hormones, or an overactive thyroid
Heart disease resulting in heart failure
Heart conditions that can cause sudden death
Problems with vision or even blindness
Kidney problems leading to kidney failure
Sudden kidney failure due to muscle breakdown
Digestive tract issues
Inflammation of the pancreas
Potential breakdown or opening in the main blood vessel of the heart, though further research is needed to confirm this

Preventing Melas Syndrome

If a doctor suspects or confirms that a patient has MELAS, which is a rare genetic disorder affecting many of the body’s systems, they should seek advice from a genetics expert. This expert can offer genetic counseling, which is a service that helps patients understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. The patient’s family members may also need to be evaluated because they could also be at risk of having MELAS.

The patient and those caring for them need to understand what to expect as the illness progresses. This includes how to handle sudden neurological episodes (problems related to the brain and nervous system), as well as information on how the disease might advance and what other medical problems could result from it.

Patients and caregivers need to be informed about the possible issues that might arise due to MELAS, including heart disease (cardiomyopathy), a kidney disorder (nephrotic syndrome), loss of hearing, diabetes, progressive neurological decline (gradual loss of brain function), dementia (thinking and memory problems), and gastrointestinal difficulties (problems with the digestive system).

It is also important for patients to understand the need to stay properly hydrated and nourished. Clear communication about what to expect in terms of their health outlook (prognosis) can also be really beneficial. Healthcare professionals may also discuss and share details about ongoing clinical trials, which are research studies that test how well new medical approaches work in people.

Frequently asked questions

MELAS syndrome is a rare genetic disorder that mainly affects the brain and muscles. It is typically passed on from the mother and is characterized by repeated episodes of brain dysfunction and muscle disease, along with symptoms such as headaches, neurological issues, seizures, migraines, and muscle weakness. The syndrome can resemble a stroke, causing partial paralysis, vision loss, or even complete blindness.

About 1 in 4000 people are estimated to have this condition.

The signs and symptoms of MELAS Syndrome include: - Delayed development and growth problems in infants - Recurring migraines - Decreased appetite - Vomiting - Seizures - Changes in brain function leading to confusion or loss of consciousness - Slowly progressing mental decline beginning in childhood Other symptoms associated with MELAS Syndrome include: - Stroke-like episodes characterized by weakness or vision changes on one side of the body, or complete vision loss - Migraines or headaches resembling migraines - Visual abnormalities and hemiplegia (paralysis of one side of the body) - Seizures, which can be tonic-clonic (involving stiffness and jerking) or myoclonic (involving muscle twitching) - Vision loss due to damage to the optic nerve - Difficulty with night vision due to pigmentary retinopathy - Excessive thirst and urine production, possible signs of diabetes - Palpitations and shortness of breath, suggesting heart conduction problems or heart disease - Numbness and pain in the limbs associated with peripheral neuropathy - Possible link with mental health disorders like bipolar disorder and depression - Hearing loss - Alzheimer's disease linked to a specific genetic variant.

MELAS Syndrome is a genetic condition that is passed down through families and affects certain parts of our cells called mitochondria. It can also occur spontaneously in a person without any family history.

The doctor needs to rule out the following conditions when diagnosing MELAS Syndrome: - Kearns-Sayre syndrome - Myoclonus epilepsy with ragged red fibers (MERRF) - Leigh syndrome - An issue with the mitochondrial DNA polymerase (POLG) - Pearson syndrome - Nutritional issues causing failure to thrive - Medium-chain acyl-coenzyme A dehydrogenase deficiency - Carnitine deficiency - Nephrotic syndrome - Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

The types of tests that are needed for MELAS syndrome include: - Blood tests to check for levels of lactic acid and pyruvic acid - Genetic testing to look for changes in mitochondrial DNA - Imaging tests such as CT scans, MRI, magnetic resonance spectroscopy, and positron emission tomography - EEG to look for certain types of electrical activity in the brain - ECG to check for any heart irregularities - Echocardiogram if a heart condition called cardiomyopathy is suspected These tests help doctors diagnose MELAS syndrome and provide valuable information about the condition.

MELAS syndrome is currently incurable, but there are various treatment options available to manage the symptoms and slow down the progression of the disease. Doctors may administer substances like arginine and citrulline, which are precursors to nitric oxide, to improve the availability of nitric oxide and minimize its deficiency. Arginine can also be administered during severe episodes similar to strokes to help reduce brain damage. Supplementing with citrulline has shown potential in enhancing nitric oxide production. Other treatments include the use of vitamins like coenzyme Q10, vitamin K3, vitamin K1, and ascorbate to boost mitochondrial function. Coenzyme Q10 and L-carnitine are believed to slow down the progression of MELAS syndrome by boosting energy production. Clinical trials are also exploring the potential benefits of idebenone, a synthetic version of coenzyme Q10, for neurological function in mitochondrial disorders. However, it is important to note that seizures in MELAS patients can be difficult to manage with medication, and valproate is not considered an appropriate treatment as it can worsen seizures and brain disease in individuals with MELAS syndrome.

When treating MELAS syndrome, there can be potential side effects or complications. These include: - Difficulty growing and being shorter than typical - Decreasing intellectual abilities that could result in dementia - Development of mental health issues like depression, schizophrenia, or bipolar disorder - Conditions on the autism spectrum - Loss of hearing - Issues with hormones, such as hypogonadism, diabetes, low parathyroid or thyroid hormones, or an overactive thyroid - Heart disease resulting in heart failure - Heart conditions that can cause sudden death - Problems with vision or even blindness - Kidney problems leading to kidney failure - Sudden kidney failure due to muscle breakdown - Digestive tract issues - Inflammation of the pancreas - Potential breakdown or opening in the main blood vessel of the heart, though further research is needed to confirm this.

The prognosis for MELAS syndrome is poor. The disease continues to worsen over time, severely affecting the brain and muscles, and often leading to dementia. On average, the life expectancy after starting to experience seizures or neurological problems is around 17 years. Currently, there are no available treatments that can slow down or stop the disease from progressing.

A geneticist or a neurologist would be appropriate doctors to see for MELAS syndrome.