MELAS patients usually don't seek medical attention before experiencing seizures or stroke-like episodes, events that often occur in late childhood or early adolescence. If queried, patients may report previously noted symptoms like intolerance of exercise, muscle weakness, myalgia and recurrent headaches.

Additional symptoms, e.g., lethargy, tachycardia, hypotension, dyspnea, nausea, vomiting and abdominal pain may be ascribed to lactic acidosis, a diagnosis that requires confirmation by laboratory analysis of blood samples. Severe lactic acidosis may even induce confusion, somnolence or stupor.

During later stages of the disease, these symptoms may overlap with neurological deficits caused by recurrent seizures and stroke-like episodes that provoke neuronal loss. MELAS patients generally suffer from prolonged focal seizures that may lead to status epilepticus, but generalized seizures may also occur [7]. Psychiatric manifestations (behavioral abnormalities, schizophrenia), progressive loss of motor and cognitive function (that may be recognized in dyspraxia, ataxia and aphasia) and eventually dementia result from neuronal cell death.

While the symptoms described above refer to a classical case of MELAS syndrome, a variety of other findings may indicate this disease. In fact, most MELAS patients present several of those pathologies:

• Cardiomyopathy
• Depression
• Bipolar disorder
• Hearing impairment
• Ophthalmoplegia
• Visual impairment or blindness
• Endocrine imbalances, particularly thyroid disorders
• Gastrointestinal problems
• Renal dysfunction [8]

• Epilepsy

  Four months later, he experienced another strokelike episode with continuous partial epilepsy on the left hand. [jamanetwork.com]

  AND ragged red fibers Myoclonus epilepsy and ragged red fibers syndrome Myopathy, mitochondrial Neurogenic muscle weakness, ataxia and retinitis pigmentosa Pearson's syndrome R Kearns-Sayre syndrome Right Kearns-Sayre syndrome 277.87 Excludes Applies [icd9data.com]

  EEG was typical for epilepsy, and the record changed especially in the frontotemporal part of the brain. Based on these findings and clinical history, epilepsy was diagnosed and valproic acid was administered. [practicalneurology.com]

  Myoclonus Epilepsy with Ragged Red Fibers; and a neuromuscular disease called the Kearns-Sayre syndrome. [medicinenet.com]

• Short Stature

  The patient presented with diabetes mellitus, sensorineural deafness, short stature, and mental disorientation. All her three children died in early adolescence. [ncbi.nlm.nih.gov]

  Early development is usually normal except for short stature. Other features include sensorineural hearing loss, headache, nausea and vomiting, seizures and basal ganglia calcifications by CT. [pediatricneurologybriefs.com]

  stature, vomiting, headache, cortical blindness, deafness and dementia. [e-arm.org]

• Anemia

  We described, for the first time, a diabetic patient with MELAS syndrome, autoimmune hemolytic anemia, and antiphospholipid syndrome. During routine health examination, a 38-year-old man was diagnosed with diabetes. [care.diabetesjournals.org]

  3243A>G, 3271T>C, 3252T>C). 22) deficiency (n = 10) among young relatives of patients; (b) Marfan phenotype (n = 5); (c) stroke [(n = 53): ischemic infarct and (or) thrombosis (n = 38); hemorrhage (n = 13) and MELAS syndrome (n = 2)]; (d) megaloblastic anemia [medical-dictionary.thefreedictionary.com]

  P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias [icd10data.com]

• Vomiting

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. [ghr.nlm.nih.gov]

  Affected individuals tend to be normal at birth through early childhood, then experience growth failure, episodic vomiting, and recurrent cerebral insults resulting in visual loss and hemiparesis. [finto.fi]

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. [sites.google.com]

  The family survey revealed no abnormal findings except for headache and episodic vomiting in her mother. [ncbi.nlm.nih.gov]

• Abdominal Pain

  Symptoms of MELAS syndrome can include difficulty breathing, vomiting, extreme fatigue, abdominal pain, and muscle weakness. Muscle spasms, diabetes, and heart and kidney problems can occur. [mitochondrialdiseasenews.com]

  Stroke-like episodes, multihormonal hypopituitarism, sensorineural hypoacusis, pigmentary retinal degeneration, intracranial calcification, heart involvement, recurrent vomiting or abdominal pain were seen only in individual cases. [ncbi.nlm.nih.gov]

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. [sites.google.com]

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. [ghr.nlm.nih.gov]

• Nausea

  Mitochondrial myopathy, encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the mitochondrial encephalomyopathies that has distinct clinical features including stroke-like episodes with migraine-like headache, nausea [ncbi.nlm.nih.gov]

  Other features include sensorineural hearing loss, headache, nausea and vomiting, seizures and basal ganglia calcifications by CT. [pediatricneurologybriefs.com]

  Avoidance of lactate in intravenous fluids, hypothermia, prolonged fasting, and postoperative nausea vomiting, all can decrease the metabolic burden in MELAS patients. Varied anesthetic techniques have been used in multiple case reports. [anesthesiaejournal.com]

  The resulting digestive problems include feelings of fullness (satiety) after eating only a small amount, trouble swallowing (dysphagia), nausea and vomiting after eating, episodes of abdominal pain, diarrhea, and intestinal blockage. [medlineplus.gov]

  Specific treatments may include drug therapies for nausea and vomiting and for symptoms secondary to nerve dysfunction (neuropathy) such as pain. [rarediseases.org]

• Episodic Vomiting

  Affected individuals tend to be normal at birth through early childhood, then experience growth failure, episodic vomiting, and recurrent cerebral insults resulting in visual loss and hemiparesis. [finto.fi]

  The family survey revealed no abnormal findings except for headache and episodic vomiting in her mother. [ncbi.nlm.nih.gov]

  There is progressive episodic vomiting, seizures, and recurrent cerebral insults mimicking strokes and causing hemiparesis, hemianopsia, or cortical blindness. The most frequent symptom is episodic sudden headaches with vomiting and convulsions. [accessanesthesiology.mhmedical.com]

  vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia, or cortical blindness. [uniprot.org]

• Failure to Thrive

  However, infants and young children may present with failure to thrive, developmental delay, and learning disabilities. Neurosensory deafness is often seen and peripheral neuropathy is usually evident. [disorders.eyes.arizona.edu]

  Though less common, infantile onset may occur and may present as failure to thrive, growth retardation and progressive deafness. [statpearls.com]

  Failure to thrive may be the presenting feature in some patients with MELAS. Strokelike episodes are the hallmark feature of this disorder. Episodes initially may manifest with vomiting and headache that may last up to several days. [markalewis.com]

• Hypertension

  The former four pregnancies ended at term with vaginal deliveries of normal weight newborns, but all were complicated by gestational hypertension and diabetes. [omicsonline.org]

  Of note, the changes were recorded before the onset of proteinuria and in the absence of hypertension, both at nephrectomy and over the follow-up. [bmcnephrol.biomedcentral.com]

  Hypertensive encephalopathy is caused by an increase in blood pressure. "If the patient has had long-term exposure, he should be treated as a potential case of encephalopathy ." [diki.pl]

  Another cause of high mortality is the less common feature of cardiac involvement, which can include hypertrophic cardiomyopathy, hypertension, and conduction abnormalities, such as atrioventricular blocks, long QT syndrome, or Wolff-Parkinson-White syndrome [emedicine.medscape.com]

  They may or may not cause specific clinical symptoms, and it is currently assumed that diseases like hypertension and diabetes mellitus may be related to mtDNA gene defects. [symptoma.com]

• Heart Failure

  We report that the pathognomonic symptom in MELAS syndrome caused by this newly observed mtDNA mutation may be rapid progression of cardiomyopathy and severe heart failure. [ncbi.nlm.nih.gov]

  After 5 years of follow-up in cardiology consulting offices, ventricular function has remained normal (EF >55%) with no new signs of heart failure. [revespcardiol.org]

  Herrmann G, Decherd GM (1939) The chemical nature of heart failure. Ann Intern Med 12:1233–1244 CrossRef Google Scholar 11. Marin-Garcia J, Goldenthal MJ (2008) Mitochondrial centrality in heart failure. [link.springer.com]

• Hearing Impairment

  He presented with visual disturbance, hearing impairment, continuous partial epilepsy on the right aspect of the face, and right hemiparesis since the age of 13. [jamanetwork.com]

  Clinically, the proband had a stroke-like episode with right hemiparesis, hemianopsia and mental dysfunction as well as short stature, hearing impairments, and elevated lactate levels. [ncbi.nlm.nih.gov]

  Over the years, diabetes and hearing impairment developed and his functional status deteriorated progressively. It took the quarter of a century to arrive at the correct diagnosis. [academic.oup.com]

• Hirsutism

  Dermatological involvement includes purpura, hirsutism, and erythema. The course is often progressive, with gradual cognitive decline, disability, and early demise. Etiology The exact pathogenesis has not been fully elucidated. [orpha.net]

  Alterations of the skin (purpura and hirsutism) occur in 45% of cases. The clinical diagnosis is based on five cardinal manifestations: clinical stroke, seizures, lactic acidosis, ragged-red fibers, and exercise intolerance. [accessanesthesiology.mhmedical.com]

  Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS. Short stature may be the first manifestation of MELAS in many patients. [markalewis.com]

• Myopathy

  Homepage Rare diseases Search Search for a rare disease MELAS Disease definition MELAS (Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) syndrome is a rare progressive multisystemic disorder characterized by encephalomyopathy, lactic [orpha.net]

  Most commonly patients have myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. [disorders.eyes.arizona.edu]

  MELAS syndrome, MELAS, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, lactic acidosis, stroke-like episode, Myopathy, mitochondrial-encephalopathy-lactic acidosis-stroke Symptoms - Mitochondrial [checkorphan.org]

  MELAS MELAS syndrome mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes mitochondrial myopathy, lactic acidosis, stroke-like episode myopathy, mitochondrial-encephalopathy-lactic acidosis-stroke Betts J, Jaros E, Perry RH [ghr.nlm.nih.gov]

• Muscle Weakness

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. [ghr.nlm.nih.gov]

  Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. [sites.google.com]

  Clinical manifestations vary from asymptomatic to progressive muscle weakness; with lactic acidosis, cognitive dysfunction, seizures, stroke-like episodes, mitochondrial encephalopathy and premature death. [oatext.com]

• Hemianopsia

  Clinically, the proband had a stroke-like episode with right hemiparesis, hemianopsia and mental dysfunction as well as short stature, hearing impairments, and elevated lactate levels. [ncbi.nlm.nih.gov]

  Hemianopsia, cortical blindness and ophthalmoplegia may be present. The ERG can show reduced b-wave amplitudes and VEPs may be absent. [disorders.eyes.arizona.edu]

  The main feature of this syndrome is the occurrence of stroke-like episodes that result in hemiparesis, hemianopsia, or cortical blindness. [oatext.com]

  […] mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, a genetically heterogeneous disorder, characterized by episodic vomiting, seizures, and recurrent cerebral insults resembling strokes and causing hemiparesis, hemianopsia [uniprot.org]

  There is progressive episodic vomiting, seizures, and recurrent cerebral insults mimicking strokes and causing hemiparesis, hemianopsia, or cortical blindness. The most frequent symptom is episodic sudden headaches with vomiting and convulsions. [accessanesthesiology.mhmedical.com]

• Night Blindness

  More than one-third of carriers had exercise intolerance and hearing loss, about 40 percent had gastrointestinal disturbance, and ten to twenty percent had short stature, ptosis, diabetes, or night blindness. [journals.lww.com]

• Stroke

  […] acidosis, and stroke-like episodes. [orpha.net]

  MELAS syndrome, MELAS, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, lactic acidosis, stroke-like episode, Myopathy, mitochondrial-encephalopathy-lactic acidosis-stroke Symptoms - Mitochondrial [checkorphan.org]

  Abstract Mitochondrial myopathy encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is a type of mitochondrial disease characterized by recurrently stroke-like episodes. [jstage.jst.go.jp]

  MELAS MELAS syndrome mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes mitochondrial myopathy, lactic acidosis, stroke-like episode myopathy, mitochondrial-encephalopathy-lactic acidosis-stroke Betts J, Jaros E, Perry RH [ghr.nlm.nih.gov]

• Seizure

  Neurol India 2007;55:82-4 Sir, Seizures are sometimes seen in pregnancy. However, rarely do we come across an underlying etiology, which is at least partially treatable. We here report an infrequent cause of seizures precipitated by pregnancy. [neurologyindia.com]

  We present an acute case of recurrent seizures and severe lactic acidosis precipitated by cocaine use in a patient with MELAS syndrome. The triad of lactic acidosis, seizures, and stroke-like episodes focus on the diagnosis. [omicsgroup.org]

  After two years without seizures, the non-enhanced hyperintense parieto-temporo-occipital lesion had disappeared, being attributed to consequent seizure control. The caudate heads, however, remained hyperintense throughout the observational period. [ncbi.nlm.nih.gov]

  After applying high doses of Hydrocortisone in combination with antiepileptic drugs clinical improvement was achieved as well as the return of muscle strength and collective seizures disappeared. [endocrine-abstracts.org]

• Headache

  The onset of symptoms is usually in the first two decades of life, most commonly consisting of headaches of sudden onset accompanied by vomiting and seizures. The headaches may simulate migraines. Weakness, lethargy, and apathy may be present early. [disorders.eyes.arizona.edu]

  These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. [ghr.nlm.nih.gov]

  VASCULAR HEADACHE is frequently associated and the disorder tends to be familial. (From Joynt, Clinical Neurology, 1992, Ch56, p117) URI http://www.yso.fi/onto/mesh/D017241 [finto.fi]

  We report a 27-year-old woman who presented with partial seizure, stroke-like episodes including hemiparesis, hemianopia and hemihypethesia, sensorineural hearing loss, migraine-like headache, and lactic acidosis. [ncbi.nlm.nih.gov]

• Myoclonus

  […] epilepsy AND ragged red fibers Myoclonus epilepsy and ragged red fibers syndrome Myopathy, mitochondrial Neurogenic muscle weakness, ataxia and retinitis pigmentosa Pearson's syndrome R Kearns-Sayre syndrome Right Kearns-Sayre syndrome 277.87 Excludes [icd9data.com]

  MERRF includes myoclonus and ataxia. MELAS has cortical blindness and hemiparesis as distinctive features. [pediatricneurologybriefs.com]

  Association of myoclonus and ataxia. Cerebellar ataxia with proprioceptive sensory disturbances. Muscle weakness and exercise intolerance associated with a neurological syndrome. [oatext.com]

  Maternal transmission previously found in myoclonus epilepsy and ragged-red fibers (MERRF), another mitochondrial disease, is suggested in this disorder as well. [ncbi.nlm.nih.gov]

• Ataxia

  Association of myoclonus and ataxia. Cerebellar ataxia with proprioceptive sensory disturbances. Muscle weakness and exercise intolerance associated with a neurological syndrome. [oatext.com]

  […] metabolism disorder Mitochondrial mutation Mitochondrial myopathy Mitochondrial respiratory chain disorder Myoclonus epilepsy AND ragged red fibers Myoclonus epilepsy and ragged red fibers syndrome Myopathy, mitochondrial Neurogenic muscle weakness, ataxia [icd9data.com]

  K-S syndrome includes ophthalmoplegia, retinal degeneration and cerebellar ataxia. MERRF includes myoclonus and ataxia. MELAS has cortical blindness and hemiparesis as distinctive features. [pediatricneurologybriefs.com]

  Depending upon the degree and location of brain damage, patients may have hemiparesis, lethargy, ataxia, myoclonic jerks, cognitive decline, and dementia. Morbidity and mortality are high. [disorders.eyes.arizona.edu]

A familial history of myopathy, encephalopathy, lactic acidosis and stroke-like episodes is highly suspicious for MELAS syndrome. However, because the age at symptom onset and the severity of the disease largely depend on the ratio of normal to mutated mtDNA, clinical presentation may vary largely even within one single family.

Thus, MELAS syndrome is rarely listed as a differential diagnosis after first presentation of an affected individual. A variety of diagnostic measures are usually applied to check for other diseases. In this context, magnetic resonance imaging or computed tomography scans may be realized to identify the extent of "cerebral infarction". In MELAS patients, multiple vascular territories are affected and findings may even be symmetrical. Further common results of brain imaging are cortical and cerebellar atrophy as well as basal ganglia calcification [9]. Magnetic resonance spectroscopy may reveal enhanced concentrations of lactic acid in brain parenchyma and cerebrospinal fluid.

Diagnosis of MELAS syndrome needs to be confirmed by genetic screens and determination of the underlying mutation. Molecular biological analysis of urinary sediment has been proven to be the most sensitive method to this end and false-negative results have to be expected when using other samples in heteroplasmic patients with low shares of mutated mtDNA.

Of note, even if patients don't present symptoms of cardiomyopathy, they should be submitted to a thorough cardiological examination since cardiac complications are a common cause of death in MELAS patients.

• Muscle Biopsy showing Ragged-Red Fibers

  Diagnostic laboratory findings include demonstration of lactic acidosis, brain imaging during stroke not conforming to the vascular territory, muscle biopsy showing ragged red fibers, and respiratory chain analysis showing multiple partial defects. [orpha.net]

  MR spectroscopy may show an elevated lactate peak in affected and even unaffected brain areas. Muscle biopsy shows ragged red fibers. However, genetic evaluation should be done first, which eliminates the need for muscle biopsy in most cases. [statpearls.com]

Causative treatment for MELAS syndrome is not available, although recent studies regarding dietary supplementation have yielded promising results:

• Rodriguez et al. suggested supplementation of creatine monohydrate, coenzyme Q10 and lipoic acid. The authors observed increased muscle strength and reduced serum lactate levels in three MELAS patients who partook in their study [10].
• Similar effects may be achieved by application of nicotinamide.
• L-arginine may be administered in an effort to improve cerebral blood flow and to diminish frequency and severity of stroke-like episodes in MELAS patients [11].

Little to no adverse effects have been reported for the above mentioned dietary supplements. Thus, although scientific evidence regarding the efficacy is still lacking, patients may benefit from those therapeutic approaches.

Otherwise, symptomatic treatment is indicated during episodes of acute decompensation.

Unfortunately, there is no causative treatment for MELAS syndrome; supportive treatment may merely relieve symptoms and improve life quality. Current research is focused on finding new therapeutic options and preliminary studies regarding dietary supplements have yielded promising results. However, clinical trials have yet to be conducted.

Despite all efforts, the disease takes a progressive course, leads to severe disability and is generally fatal before the age of 40. Early onset of severe symptoms corresponds to large shares of mutated mtDNA in heteroplasmic individuals and is associated with even lower life expectancy.

As has been indicated above, MELAS syndrome results from genetic disorders of the mtDNA. Human mtDNA measures about 17 kbp in length and encodes for a variety of proteins, primarily enzymes, but also for ribosomal and transfer RNA (rRNA and tRNA, respectively) [2]. Despite its small size, several mutations in the mitochondrial genome have been described. They may or may not cause specific clinical symptoms, and it is currently assumed that diseases like hypertension and diabetes mellitus may be related to mtDNA gene defects [3]. Besides MELAS syndrome, MIDD syndrome, Pearson syndrome and Kearns-Sayre syndrome shall be mentioned as examples for clinical disorders triggered by mtDNA mutations.

mtDNA is inherited maternally and consequently, a mother suffering from MELAS syndrome will pass the defect to all her children. Only her daughters will inherit the disease to their children, though. De novo mutations of mtDNA have been described and do indeed account for the majority of cases of Pearson syndrome or Kearns-Sayre syndrome, but are rarely related to MELAS syndrome.

Mutation m.3243A>G is the most common cause of MELAS syndrome [4]. Additionally, mutations m.3244G>A, m.3258T>C, m.3271T>C and m.3291T>C have been associated with MELAS [5]. All of them affect the same gene, the one that encodes for tRNA-Leu(UUR). Loss of its function impedes correct mitochondrial protein biosynthesis and reduces the activity of respiratory chain complexes.

Of note, heteroplasmy, i.e., the presence of more than one type of mtDNA within the same organelle, can be observed in many people. In this situation, gene expression based on copies of normal DNA may partially compensate for defects present on mutated DNA circles. The ratio of normal to mutated DNA to be encountered in an individual patient presumably accounts for age of onset and severity of clinical symptoms.

Mutations of mtDNA are rather frequently observed [3]. Due to heteroplasmy, a precise assessment of disease prevalence is often difficult. Low shares of mutated mtDNA suffice to yield positive findings in molecular biological tests, but such results don't necessarily imply that affected individuals will develop symptoms at one point in their lifes.

With regards to MELAS syndrome, most reliable epidemiological data refer to mutation m.3243A>G, which is assumed to account for the majority of cases. Here, prevalence rates of up to 18 per 100,000 inhabitants have been reported [6]. These numbers are considered trustworthy because encephalomyopathic symptoms may be provoked even though large parts of a patient's mtDNA are unaltered.

Virtually all cells of the human body contain mitochondria and depend more or less on aerobic carbohydrate catabolism, with erythrocytes being the one important exception. Consequently, mtDNA mutations alter mitochondrial metabolism in a plethora of tissues and symptoms associated with MELAS syndrome vary widely. The most common complaints are triggered by the following pathophysiological events:

• Muscles and nerve tissue are most severely affected and functional impairment of these tissues typically dominates the clinical presentation. Myopathy and encephalopathy are direct results of mitochondrial function impairment, and it has been reported that even very low shares of mutated mtDNA in heteroplasmic individuals suffices to induce severe dysfunction of the respiratory chain [6]. Furthermore, cardiac myocytes and neurons are largely unable to sustain their metabolism by anaerobic glycolysis.
• Glycolysis is the transformation of glucose to pyruvate and under anaerobic conditions, i.e., if the respiratory chain is rendered ineffective due to defective mitochondrial protein biosynthesis, pyruvate is converted into lactic acid. This process is catalyzed by the enzyme lactate dehydrogenase and aims at recovering substrates required for continued anaerobic glycolysis. Subsequently, efflux of lactic acid is mediated by monocarboxylate transporter 1. These events lead to an abnormal accumulation of lactic acid in MELAS patients, a condition referred to as lactic acidosis.
• Stroke-like episodes resemble cerebral infarction only in terms of clinical symptoms. Indeed, MELAS-related stroke-like episodes are definitely not induced by thromboembolism, but their precise pathogenesis is incompletely understood. One hypothesis states that metabolic alterations and mitochondrial proliferation in smooth muscle cells of the tunica media of cerebral vessels lead to vasoconstriction and transient ischemia. Of note, such mitochondrial angiopathies may be visualized by means of diagnostic imaging.

Affected families may benefit from genetic counseling. Otherwise, no specific measures can be recommended to prevent MELAS syndrome and symptom onset.

Certain lifestyle decisions may delay disease progress: It is recommended to maintain a healthy diet and sufficient hydration, possibly ingest the above mentioned dietary supplements, realize light aerobic exercises to increase one's aerobic capacity and restrict vigorous exercise to avoid cardiac failure and rhabdomyolysis.

MELAS syndrome is an encephalomyopathic disease triggered by distinct mutations affecting the mitochondrial DNA (mtDNA). MELAS stands for myopathy, encephalopathy, lactic acidosis and stroke-like episodes, which are the main symptoms associated with this disease.

All mutations that have been associated with MELAS syndrome affect one single mitochondrial gene whose gene product is required for translation of distinct messenger RNAs. Loss of function mutations thus interfere with protein biosynthesis, particularly if certain codons account for significant shares of the sequence. This applies to proteins required for the assembly of respiratory chain complexes and consequently, aerobic glycolysis and oxidative phosphorylation are disturbed in MELAS patients. Because muscle cells and neurons largely depend on aerobic metabolism, they are most severely affected by the disease.

Symptom onset typically occurs in childhood, but depending on the severity of mitochrondrial dysfunction, first symptoms may be detected at any age. Patients may report muscle weakness and myalgia, headaches and epileptic seizures. The latter may be related to increased serum levels of lactic acid. First stroke-like episodes are generally experienced in adolescence and rarely after the fourth decade of life. They are associated with hemiparesis, reduced consciousness, visual impairment and exacerbated headaches. During initial stroke-like episodes, these symptoms are generally transient. However, they may become permanent in subsequent fits. These events progressively destroy nerve tissue and cause patients to lose motor and cognitive abilities and to develop dementia [1].

There is no causative treatment for MELAS syndrome. Therapy is supportive and should involve a multidisciplinary team of physicians. Despite all efforts, MELAS syndrome significantly reduces the life expectancy of affected individuals.

MELAS syndrome is a genetic disorder triggered by mutations of mitochondrial DNA (mtDNA). MELAS is an abbreviation for myopathy, encephalopathy, lactic acidosis and stroke-like episodes. These are the main symptoms of the disease.

Causes

Mitochondria are cell organelles that can be found in virtually all cells of the human body, with red blood cells being the one important exception. Most cells depend on mitochondrial function since these organelles use oxygen to create ATP, the cellular currency of energy. If mitochondrial function is impaired - as is the case in MELAS patients - cellular metabolism is strongly disturbed. Muscle cells and neurons are most severely affected.

Of note, inheritance of mtDNA differs from that of nuclear DNA. In detail, a mother inherits her mtDNA to every child, but only her daughters will pass their mtDNA to the next generation.

Symptoms

Because so many different cell types depend on mitochondrial function, the clinical presentation of MELAS syndrome varies between individual patients, even if they pertain to the same family. Most patients experience intolerance of exercise, muscle weakness, muscle pain and recurrent headaches in childhood or adolescence. Before the age of 20, they may suffer epileptic seizures or stroke-like episodes that manifest in acute hemiparesis, reduced consciousness, visual impairment and exacerbated headaches. During initial stroke-like episodes, these symptoms are generally transient. However, the may become permanent in subsequent fits.

Diagnosis

Anamnesis, family history and clinical presentation may prompt a suspicion for MELAS syndrome. In order to confirm that diagnosis, genetic screens have to be performed. This way, the causative mutation in mtDNA can be identified.

Additionally, MELAS patients should undergo thorough cardiological examinations to evaluate if heart muscle involvement constitutes a vital risk.

Treatment

Unfortunately, no causative treatment is available. Dietary supplementation of creatine, coenzyme Q10, lipoic acid, nicotinamide and L-arginine have been recommended, but clinical trials have yet to be conducted.

Supportive treatment is provided during episodes of acute decompensation.

1. Isozumi K, Fukuuchi Y, Tanaka K, Nogawa S, Ishihara T, Sakuta R. A MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) mtDNA mutation that induces subacute dementia which mimicks Creutzfeldt-Jakob disease. Intern Med. 1994; 33(9):543-546.
2. Capt C, Passamonti M, Breton S. The human mitochondrial genome may code for more than 13 proteins. Mitochondrial DNA A DNA MappSeq Anal. 2016; 27(5):3098-3101.
3. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005; 6(5):389-402.
4. Karicheva OZ, Kolesnikova OA, Schirtz T, et al. Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria. Nucleic Acids Res. 2011; 39(18):8173-8186.
5. Kirino Y, Goto Y, Campos Y, Arenas J, Suzuki T. Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. Proc Natl Acad Sci U S A. 2005; 102(20):7127-7132.
6. Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008; 17(23):3697-3707.
7. Demarest ST, Whitehead MT, Turnacioglu S, Pearl PL, Gropman AL. Phenotypic analysis of epilepsy in the mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes-associated mitochondrial DNA A3243G mutation. J Child Neurol. 2014; 29(9):1249-1256.
8. Seidowsky A, Hoffmann M, Glowacki F, et al. Renal involvement in MELAS syndrome - a series of 5 cases and review of the literature. Clin Nephrol. 2013; 80(6):456-463.
9. Kim IO, Kim JH, Kim WS, Hwang YS, Yeon KM, Han MC. Mitochondrial myopathy-encephalopathy-lactic acidosis-and strokelike episodes (MELAS) syndrome: CT and MR findings in seven children. AJR Am J Roentgenol. 1996; 166(3):641-645.
10. Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007; 35(2):235-242.
11. Koga Y, Akita Y, Nishioka J, et al. MELAS and L-arginine therapy. Mitochondrion. 2007; 7(1-2):133-139.