Melas Syndrome

Etiology

MELAS is a mitochondrial inherited genetic disorder caused by alterations in mitochondrial DNA. Paternal mitochondria are present only in the tailpiece of sperm, which proves that mitochondrial inheritance is maternal. Maternally inherited mitochondrial disorders, including MELAS, result from the loss of mitochondria during fertilization. In rare instances, MELAS may result from a sporadic variation without a familial history. Mitochondrial genetic disorders stem from sequence variations that impair mitochondrial function, including oxidative phosphorylation (OXPHOS) and energy production.

Experts believe that alterations in tRNA cause impairment of protein assembly into respiratory chain complexes in patients with MELAS. However, the exact mechanisms remain unclear. Mitochondria are the powerhouse of cells, and any mitochondrial disorder will affect the most metabolically active organs of the body, especially the brain, eyes, heart, and skeletal muscles.

Numerous tRNA variations can contribute to the development of MELAS, with the most prevalent variant found in the MTTL1 mitochondrial gene. A single-nucleotide variation, m.3243A>G, is detected in 80% of affected patients, whereas a second common variant, m.3271T>C, is observed in 10%.[4][5] However, ongoing research is uncovering many other genes, such as POLG and BCS1L, which are being identified and linked to similar phenotypic syndromes.

Epidemiology

MELAS stands out as one of the most prevalent mitochondrial diseases, with an estimated incidence of 1 in 4000. A study conducted on the adult Finnish population indicates a prevalence of 10.2 per 100,000 for the m.3243A>G variant. In Northern England, the prevalence of this variant in the adult population has been determined to be approximately 1 per 13,000. These figures might be underestimates. A comprehensive study of a large Caucasian population in 2006 revealed a prevalence of the MELAS m.3242 A>G variation to be 236 per 100,000, significantly higher than previously reported.[6]

Although both genders are equally susceptible to the condition, only women can transmit MELAS as mitochondria are carried in the tails of sperm cells and are consequently shed outside the zygote during fertilization. No apparent racial predilection exists.

Pathophysiology

Each somatic cell possesses multiple and variable copies of the same mitochondrial DNA or genome. The aging of cells results in varying degrees of damage to this mitochondrial DNA. Similar to other mitochondrial disorders, MELAS displays heteroplasmy, indicating a variation in the types of mitochondrial DNA found in different tissues within the same individual. As both normal and abnormal mitochondria may coexist in tissues, there is a variable appearance of diseased mitochondria in other tissues within the same person.

The organs, cells, and clinical presentation affected by MELAS can be heterogeneous. This phenomenon accounts for the broad variability in the presentation of different tissues within an individual and among patients with the same diagnosis. The varied effect on different mitochondria also has diagnostic implications, as serum and urine studies may occasionally yield negative results if those cell lines remain unaffected. In such cases, a muscle biopsy becomes necessary to examine the affected tissue.

The 2 significant theories regarding the underlying pathophysiology of MELAS syndrome are listed below.

The Cytopathic Theory 

The cytopathic theory suggests that abnormal OXPHOS due to mitochondrial variation leads to neuronal dysfunction and cell death during periods of high metabolic activity. The earlier and increased involvement of brain areas, particularly the visual cortex, can be explained by their higher metabolic activity.[7][8]

The Angiopathic Theory

The angiopathic theory proposes vascular endothelial dysfunction due to the mitochondrial disorder causing impaired autoregulation and neuronal ischemia.[7][8] Mitochondrial disorders, including MELAS,  primarily impact tissues with the highest metabolic activities, such as skeletal and heart muscles, as well as the brain, the eye, and the inner ear. The impaired function of the mitochondrial respiratory chain and OXPHOS results in heightened anaerobic glycolytic activities, leading to increased lactic acid levels during acute attacks.[7]

Researchers believe that the neurological symptoms of MELAS syndrome arise from transient OXPHOS dysfunction within the brain parenchyma. Both parenchymal and vascular OXPHOS abnormalities may be responsible for the multisystem involvement observed in patients with MELAS. An OXPHOS defect leads to an increased production of free radicals, which may result in vasoconstriction, thus offsetting vasodilators such as nitric oxide. Individuals with MELAS also exhibit impaired nitric oxide production and postproduction nitric oxide sequestration, contributing to the nitric oxide deficiency associated with MELAS syndrome. Nitric oxide deficiency, combined with impaired mitochondrial energy production and microvascular angiopathy, may cause impaired cerebral vasodilation.[9]

Histopathology

The pathological hallmark of mitochondrial disease is the accumulation of mitochondria in muscle fibers, observed through the Gomori trichrome stain. In an attempt to compensate for inadequate energy production, the diseased mitochondria proliferate and exhibit a bright red appearance in contrast to the blue myofibers, a characteristic referred to as "ragged red fibers." In MELAS syndrome, succinate dehydrogenase–reactive blood vessels are also evident, attributed to mitochondrial proliferation in perivascular smooth muscle and endothelial cells.[10]

History and Physical

Children with MELAS usually experience normal early psychomotor development until symptoms emerge between the ages of 2 and 15. Although less frequent, infantile- and adult-onset are possible. Initial indicators in infants may include developmental delay and failure to thrive. Developmental delay, learning difficulties, and attention-deficit disorder precede the first stroke-like episode in individuals with MELAS. In older children, the onset commonly involves recurrent episodes of a migraine-like headache, anorexia, vomiting, seizures, and encephalopathy with focal neurological findings and impaired awareness. Mental deterioration begins during childhood and progresses slowly.

The characteristic features of MELAS include stroke-like episodes, seizures, recurrent migraine-like headaches, vomiting, short stature, hearing loss, muscle weakness, lactic acidosis, diabetes, cardiac disease, and gastrointestinal dysmotility. The course typically follows a relapsing-remitting pattern, with neurological dysfunction and encephalopathy progressing to dementia due to stroke-like episodes. The onset of MELAS may manifest as myopathy or exercise intolerance, easy fatigability, or proximal muscle weakness. Despite the severity of other neurological features, myopathy is often underrecognized in MELAS and may not cause a significant functional disturbance.

Stroke-Like Episodes

The stroke-like episodes associated with MELAS are a hallmark feature of the disease. Typically, patients exhibit an acute onset of neurological symptoms, such as hemiparesis, hemianopia, or cortical blindness. Initial episodes may also involve vomiting and headaches that can last for several days. These episodes are considered "stroke-like" because there is no vascular occlusion, and the involvement does not correspond to any specific vascular territory.[3] The apparent diffusion coefficient on MRI in individuals with MELAS may be increased or reveal a mixed pattern. Patients with an ischemic stroke show a decreased apparent diffusion coefficient on MRI. Acute MRI findings may also migrate and often resolve more quickly than changes of an ischemic stroke.[11] 

Seizures

Children with MELAS syndrome may experience seizures and visual abnormalities followed by hemiplegia. Seizure types may be tonic-clonic or myoclonic. Children with younger age of onset tend to have higher rates of drug-resistant epilepsy, leading to more severe clinical dysfunction.[12]

Migraine-Like Headaches

The stroke-like episodes may manifest as migraine or migraine-like headaches. These headaches may be the only manifestation of stroke-like episodes in some patients.

Additional Findings

Additional findings associated with MELAS include vision loss due to optic atrophy, difficulties with night vision due to pigmentary retinopathy, polydipsia and polyuria as potential signs of diabetes, palpitations and shortness of breath indicating cardiac conduction abnormalities such as Wolff-Parkinson-White syndrome or cardiomyopathy, numbness, tingling, and pain in the extremities accompanying peripheral neuropathy, a potential association with psychiatric illnesses like bipolar disorder, depression, autism spectrum disorders, hearing loss, and Alzheimer dementia linked to the m.3243 A>G variant.

Evaluation

Clinicians confirm the diagnosis by verifying clinical diagnostic criteria and identifying a pathogenic variant in one of the genes associated with MELAS.

Laboratory Testing

Laboratory testing for MELAS involves assessing serum lactic acid, serum pyruvic acid, cerebrospinal fluid (CSF) lactic acid, and CSF pyruvic acid.

An elevated lactate level is frequently the initial indicator in diagnosing MELAS during an acute stroke-like episode. Lactic acidosis prompts clinicians to explore alternative diagnoses, including tissue hypoxic–ischemic injury, hyperglycemia, hypoglycemia, and amino acid and fatty acid metabolic disorders.[13] If these alternative diagnoses are unlikely, assessing lactic acid and pyruvate levels is an effective screening test for detecting MELAS syndrome. Notably, lactic acidosis does not result in systemic metabolic acidosis. In addition, it is essential to recognize that some affected patients may exhibit normal serum lactic acid levels while showing elevated CSF levels.

Expected findings include elevated arterial lactate and pyruvate, elevated CSF lactate, substantial increases in lactate and pyruvate levels with exercise, and a potentially elevated lactate-to-pyruvate ratio. The elevated lactate-to-pyruvate ratio occurs alongside normal O₂ saturations in patients with MELAS syndrome. In contrast, patients experiencing lactic acidosis due to tissue injury exhibit an increased ratio associated with decreased O₂ saturation.

Genetic Evaluation

Mitochondrial DNA variant analysis can be conducted on various samples, including blood, skeletal muscle, hair follicles, buccal mucosa, and urinary sediment. However, due to the rapid division of hematopoietic cells, detecting the m.3243A>G variation in the blood may be challenging, as it may segregate into very low levels. Preferred samples for genetic diagnosis include those from urinary sediment, skin fibroblasts, and buccal mucosa, given their easy access and ample supply. A skeletal muscle biopsy is warranted if genetic testing yields normal results and suspicion remains high. This biopsy can reveal the presence of ragged red fibers.[14]

Imaging Studies

Computed tomography: Computed tomography scans of the brain may reveal lucencies consistent with an infarction in individuals with MELAS. As time progresses, these changes may include cerebral atrophy and calcifications. 

Single-photon emission computed tomography: Single-photon emission computed tomography uses the tracer N-isopropyl-p-[123-I]-iodoamphetamine to identify strokes and monitor disease progression in individuals with MELAS.

Magnetic resonance imaging: The most common MRI findings are cortical areas resembling multifocal infarcts in various stages of ischemic evolution, characterized by acute diffusion restriction, followed by subacute cortical laminar necrosis, and eventual chronic volume loss. Notably, these findings do not conform to any known vascular territory. Initial lesions often manifest in the occipital or parietal lobes, eventually affecting the cerebellum, cerebral cortex, basal ganglia, and thalamus.

The well-described preferential distribution of lesions with restricted diffusion in the occipital cortical areas of individuals with MELAS syndrome is attributed to the high metabolic demand of these regions. The primary somatosensory cortex represents the second most common area of involvement associated with MELAS syndrome. The relatively symmetric cortical involvement observed on imaging in MELAS syndrome patients sets it apart from common stroke syndromes, reflecting symmetric areas of high metabolic demand.[2]

Magnetic resonance spectroscopy: Magnetic resonance spectroscopy can detect metabolic abnormalities, including the lactate-to-creatine ratio in the muscle or brain and the decreased N-acetylaspartate-to-creatine ratio in stroke regions in the central nervous system. This technique may reveal regions of elevated lactate in the central nervous system, even when serum levels remain normal, and may identify an elevated lactate peak in both affected and unaffected brain areas.[13]

Positron emission tomography: Positron emission tomography may reveal a reduced cerebral metabolic rate for oxygen, an increased cerebral blood flow in cortical regions, and the preservation of the cerebral metabolic rate for glucose.

Additional Testing

Additional testing for MELAS includes electroencephalography, which typically reveals epileptiform spike discharges, an electrocardiogram to assess for cardiac conduction abnormalities, and an echocardiogram if cardiomyopathy is suspected.

Treatment / Management

In the management of MELAS syndrome, there is currently no treatment available that can effectively slow or stop the progression of the disease.

Arginine and Citrulline

MELAS syndrome is a mitochondrial inherited genetic disorder that is significantly impacted by a deficiency in nitric oxide. Administering nitric oxide precursors, such as arginine and citrulline, may increase nitric oxide availability and reduce the effects of nitric oxide deficiency. During an acute stroke-like episode, clinicians may administer arginine to reduce brain damage due to impaired vasodilation in intracerebral arteries caused by nitric oxide depletion.[9][15][16]

Patients experiencing an acute stroke-like event should receive a loading dose of intravenous arginine hydrochloride at 0.5g/kg within 3 hours of symptom onset, if feasible. Following the bolus, a continuous infusion of 0.5g/kg arginine hydrochloride should be continued for 24 hours for 3 to 5 days.

Patients with MELAS may experience hypocitrullinemia. Researchers have observed that short-term supplementation with citrulline enhances nitric oxide production more than arginine. A substantial de novo arginine synthesis occurs in response to citrulline supplementation. Consequently, in addition to arginine, citrulline administration holds therapeutic potential for MELAS. However, controlled studies assessing the effects of citrulline supplementation on the clinical aspects of MELAS are required to establish its use as a therapeutic

Additional Treatment Options

Other treatment options for MELAS include coenzyme Q10, menadione or vitamin K3, phylloquinone or vitamin K1, and ascorbate, which are used to donate electrons to cytochrome c. Furthermore, several case reports suggest improvement with riboflavin, dichloroacetate, sodium succinate, and creatinine monohydrate.

Vitamins such as coenzyme Q10 or L-carnitine are believed to aid in boosting energy production by mitochondria and may potentially decelerate the progression of the disease. Ongoing phase I and II trials of Idebenone, a synthetic coenzyme Q10, are being conducted for MELAS, showing promise in improving neurological function in other mitochondrial disorders (Scaglia, ClinicalTrials.gov Identifier: NCT00887562).

Seizure Management

Seizures in patients with MELAS syndrome may be refractory to treatment. Notably, valproate is not an appropriate treatment for patients with MELAS syndrome. Many reports exist of valproate aggravating encephalopathy and seizures in patients with MELAS syndrome. Numerous reports document valproate exacerbating encephalopathy and seizures in individuals with MELAS syndrome. The primary mechanism of valproate toxicity involves interference with mitochondrial β-oxidation or direct mitochondrial toxicity, explaining the frequently observed elevated ammonia levels in patients taking valproate.[17](B3)

Differential Diagnosis

When patients present with a family history indicative of maternal mitochondrial inheritance,[18] it is essential to consider potential differential diagnoses, including other mitochondrial disorders, Kearns-Sayre syndrome, Myoclonus epilepsy associated with ragged red fibers (MERRF), Leigh syndrome, mitochondrial DNA polymerase (POLG) deficiency, Pearson syndrome, nutritional causes of failure to thrive, medium-chain acyl-coenzyme A dehydrogenase deficiency, carnitine deficiency, nephrotic syndrome, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, and myoclonus epilepsy associated with ragged red fibers (MERRF).

Kearns-Sayre is a rare neuromuscular disorder that may also present with visual disturbances, short stature, hearing loss, and ataxia. The characteristic visual findings of Kearns-Sayre, including chronic progressive external ophthalmoplegia, atypical retinitis pigmentosa, and pigmentary degeneration of the retina, distinguish it from MELAS. Furthermore, patients with Kearns-Sayre syndrome often exhibit more frequent cardiac manifestations in addition to the visual symptoms.

MERRF and MELAS present similar symptoms, such as seizures, mental deterioration, and myopathy, which can be confused due to the presence of ragged red fibers on biopsy. Patients with MERRF may also experience hearing loss, visual disturbance due to optic atrophy, and short stature. Although the presence of characteristic myoclonic seizures in MERRF can aid in narrowing the diagnosis, definitive differentiation between the 2 conditions requires genetic testing. In contrast, Leigh syndrome presents with progressive neurological deterioration, seizures, and vomiting, predominantly affecting young children.

Prognosis

MELAS is relentlessly progressive, and the encephalomyopathy is usually severe and progresses to dementia. No available therapies slow or halt the progression of the disease. The average survival is 17 years following the onset of seizures or neurological deficits.[19]

Complications

Potential complications of MELAS are listed below.

• Failure to thrive and short stature
• Progressive intellectual deterioration possibly leading to dementia
• Development of psychiatric conditions such as depression with psychotic features, schizophrenia, or bipolar disorder
• Autism spectrum disorders
• Sensorineural hearing loss
• Endocrine dysfunction such as hypogonadism, diabetes, hypoparathyroidism, hypothyroidism, and hyperthyroidism
• Cardiomyopathy causing congestive heart failure
• Cardiac conduction defects causing sudden cardiac death
• Visual difficulties or cortical blindness 
• Focal segmental glomerulosclerosis leading to renal failure
• Acute renal failure due to rhabdomyolysis
• Intestinal pseudoobstruction
• Pancreatitis
• Aortic root dissection (although the relationship with the latter is currently unclear and requires further studies)