Melas Syndrome: Symptoms, Types, Causes and Treatment

MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) is a rare but important mitochondrial disorder, affecting multiple body systems and presenting a complex clinical picture. Understanding MELAS is vital not only for medical professionals but also for patients and families navigating its challenges. This article explores the symptoms, types, causes, and treatment options for MELAS syndrome, providing a comprehensive, evidence-based overview.

Symptoms of Melas Syndrome

MELAS syndrome presents a wide array of symptoms, often affecting several organs and systems. The disease most commonly appears in childhood or adolescence but can also manifest in adulthood. Recognizing the breadth and pattern of symptoms is crucial for timely diagnosis and management.

Symptom	Description	Prevalence/Distinction	Source(s)
Stroke-like episodes	Sudden neurological deficits, not confined to vascular territories	Defining, >90% of cases	1 6 8
Seizures	Epileptic events, including status epilepticus	76% of patients	2 3 6 8
Headache	Often migrainous, may be prolonged	50% of patients	2 8
Muscle weakness	Fatigability, myopathy, exercise intolerance	48% of patients	3 8
Hearing loss	Sensorineural, progressive	10-24% of patients	1 3 8
Cognitive decline	Dementia, executive dysfunction, confusion	Variable, sometimes early	1 5 7 8
Diabetes	Impaired glucose metabolism	10-24% of patients	1 3 8
Short stature	Poor growth in childhood	>25% of cases	3 8
Vomiting	Recurrent, often with headache	55% of patients	4 8
Visual loss	Cortical blindness, hemianopia	52% of patients	3 8

Table 1: Key Symptoms

Core Neurological Manifestations

The hallmark of MELAS is the occurrence of stroke-like episodes—acute neurological deficits that mimic strokes but do not correspond to the distribution of major cerebral arteries. These episodes often recur and can involve hemiparesis, cortical blindness, aphasia, or other focal deficits. Seizures, particularly status epilepticus and migrainous headaches, are common and may be prolonged or severe 1 2 6 8.

Cognitive decline and psychiatric features, such as depression, confusion, or even psychosis, can occur, highlighting the syndrome’s impact on higher brain functions. Some patients show executive dysfunction or rapidly progressive dementia, especially after repeated stroke-like episodes 5 7 8.

Multisystem Involvement

Beyond the brain, MELAS affects muscle (causing fatigability and weakness), hearing (sensorineural hearing loss), and metabolism (including diabetes and lactic acidosis). Short stature and growth retardation are often seen in children. Recurrent vomiting, abdominal pain, and gastrointestinal pseudo-obstruction are recognized, sometimes preceding neurological symptoms 3 4 8.

Less Common and Rare Features

MELAS displays remarkable phenotypic variability. Less common manifestations include cardiac conduction defects, pigmentary retinopathy, endocrinopathies (such as hypopituitarism or Addison’s disease), psychiatric symptoms, and even dysmorphic features like hypertelorism or protruding ears. These rare features may greatly affect quality of life and prognosis 3 5 7 8.

Types of Melas Syndrome

While MELAS is unified by its mitochondrial basis and classic symptom triad, it encompasses a spectrum of clinical presentations and genetic variants. Recognizing these types helps tailor diagnosis, management, and family counseling.

Type/Variant	Distinctive Features	Genetic Basis/Notes	Source(s)
Classical MELAS	Early-onset, classic triad (SLEs, lactic acidosis, myopathy)	m.3243A>G in MT-TL1 (80% cases)	1 6 8
Adult-onset MELAS	Onset after age 40, milder course	Usually m.3243A>G mutation	4 8
Atypical variants	Psychiatric, cognitive, or endocrine dominance	Other mtDNA mutations (e.g., MT-ND4, MT-ND6), rare nuclear DNA mutations	7 8 11
Syndromic overlap	Features of other mitochondrial syndromes (e.g., MERRF, autoimmune overlap)	Mixed or novel mtDNA mutations	2 7 8

Table 2: Types and Variants of MELAS

Classical MELAS

The majority of patients present in childhood or adolescence with the classic triad: stroke-like episodes, lactic acidosis, and evidence of myopathy. The m.3243A>G mutation in the mitochondrial MT-TL1 gene is responsible for about 80% of cases 1 6 8.

Adult-Onset and Milder Forms

Though rare (1–6%), MELAS can first manifest after age 40. These cases tend to follow a less aggressive course, sometimes with prominent gastrointestinal symptoms or a greater risk of misdiagnosis due to atypical features 4 8.

Atypical and Variant Presentations

Some patients present primarily with psychiatric symptoms, executive dysfunction, or endocrine abnormalities before neurological symptoms arise. These cases are increasingly recognized as new mitochondrial DNA mutations are discovered (for example, in MT-ND4, MT-ND6 genes), leading to a broader spectrum of presentations 7 8 11.

Syndromic and Genetic Overlap

MELAS can overlap with other mitochondrial disorders such as MERRF (myoclonic epilepsy with ragged-red fibers) or with autoimmune syndromes (e.g., polyglandular autoimmune syndrome). These cases usually involve rare or novel mutations and may present diagnostic and therapeutic challenges 2 7 8.

Causes of Melas Syndrome

At its core, MELAS syndrome is a genetic disorder of mitochondrial function. The causes revolve around defects in the mitochondrial DNA, which impair the cell’s ability to generate energy, especially in organs with high energy demands.

Cause	Mechanism/Effect	Key Genes/Features	Source(s)
mtDNA point mutation	Impaired mitochondrial protein synthesis	m.3243A>G in MT-TL1 (tRNA^Leu(UUR)), >80%	1 6 8 9
Other mtDNA mutations	Defects in respiratory chain complexes	MT-ND4, MT-ND5, MT-ND6, others	7 8 11
Heteroplasmy	Variable mutation load in tissues	Explains phenotypic diversity	4 7 8 11
Nitric oxide (NO) deficiency	Endothelial dysfunction, poor perfusion	Decreased NO precursors, metabolic disruption	1 13 14
Mitochondrial proliferation	Smooth muscle/endothelial angiopathy	Microvasculature dysfunction	1

Table 3: Causes and Mechanisms of MELAS

The Genetic Foundation

MELAS is most often caused by a point mutation (A>G) at position 3243 of the mitochondrial DNA, specifically in the gene encoding mitochondrial tRNA^Leu(UUR) (MT-TL1). This mutation disrupts mitochondrial protein synthesis, compromising the function of the electron transport chain and cellular respiration 1 6 8 9.

Other point mutations—such as those in the MT-ND4, MT-ND5, or MT-ND6 genes (encoding subunits of respiratory chain complex I)—can also cause MELAS, sometimes with different clinical features. The degree of heteroplasmy (the proportion of mutated mtDNA in each cell) determines the severity and variety of symptoms 4 7 8 11.

Pathophysiology: Why Do Symptoms Occur?

• Energy Deficiency: Dysfunctional mitochondria cannot produce enough ATP, especially in energy-demanding organs like the brain, muscles, and endocrine glands. This leads to multi-organ dysfunction and many of the clinical symptoms 1 6 12.
• Lactic Acidosis: Impaired oxidative phosphorylation pushes cells to rely on glycolysis, leading to the accumulation of lactic acid in blood and tissues 1 12.
• Microvascular Angiopathy: Energy deficiency stimulates abnormal proliferation of mitochondria in smooth muscle and endothelial cells, resulting in small vessel disease and impaired blood flow, especially in the brain 1.
• Nitric Oxide Deficiency: Decreased synthesis and availability of nitric oxide impairs vasodilation, contributing to stroke-like episodes and other vascular complications 1 13 14.
• Oxidative Stress and Signaling: Mutant mitochondria increase oxidative stress, disrupt cellular signaling (including via microRNAs), and further impair mitochondrial function 10.

Inheritance

MELAS is almost always maternally inherited, as mitochondria (and their DNA) are passed down from mothers to children. However, new mutations and variable inheritance patterns, including sporadic cases, have also been described 2 6 11.

Treatment of Melas Syndrome

Despite advances in understanding its genetic and molecular basis, MELAS syndrome remains without a definitive cure. However, a combination of supportive, symptomatic, and experimental therapies can improve quality of life and potentially slow disease progression.

Treatment	Purpose/Mechanism	Evidence/Usage	Source(s)
L-arginine & Citrulline	Restore NO production, treat SLEs	Shown to reduce frequency/severity of stroke-like episodes; citrulline may be superior	1 13 14
Coenzyme Q10	Antioxidant, supports mitochondrial function	Commonly used, efficacy unproven	1 6 15
Carnitine	Supports fatty acid metabolism	Commonly used, efficacy unproven	1 15
B vitamins	Support mitochondrial enzymes	Frequently prescribed, limited evidence	6 15
Symptomatic therapies	Seizure control, diabetes management, cardiac support	Individualized, multidisciplinary	1 15
Experimental therapies	Allotopic tRNA import, anti-miR-9 treatments	Early-stage, promising research	9 10

Table 4: MELAS Treatment Options

Symptomatic and Supportive Care

Management of MELAS is primarily symptomatic and involves a multidisciplinary team. Key strategies include:

• Acute stroke-like episodes: Early administration of intravenous or oral L-arginine has been shown in small studies to improve symptoms and reduce recurrence. Citrulline supplementation may have an even greater effect on nitric oxide production, potentially offering additional benefit 1 13 14.
• Seizure management: Standard antiepileptic drugs are used. Status epilepticus may require aggressive intervention 1 2 15.
• Diabetes and endocrine dysfunction: Standard diabetes management applies, with attention to potential endocrine complications 1 8 15.
• Cardiac and hearing support: Regular cardiac monitoring and hearing assessments are recommended, with interventions as needed 1 8 15.
• Nutritional support and growth: Monitoring and supporting growth in children, ensuring adequate calorie and nutrient intake 3 15.

Mitochondrial Supportive Therapies

Several agents are used to support mitochondrial function, although robust evidence is lacking:

• Coenzyme Q10 and antioxidants: Commonly prescribed to support electron transport chain function and reduce oxidative stress 1 6 15.
• Carnitine and B vitamins: Aimed at optimizing mitochondrial metabolism; widely used despite limited evidence for efficacy 1 6 15.

Investigational and Future Therapies

• Allotopic tRNA import: Experimental strategies to introduce correct tRNAs into mitochondria have shown promise in cell models, potentially rescuing mitochondrial function in MELAS 9.
• MicroRNA modulation: Targeting microRNA-9/9*, which regulates mitochondrial tRNA-modifying enzymes, is being explored as a novel therapy 10.

The Importance of Early Recognition

Prompt recognition and initiation of therapy during stroke-like episodes may prevent irreversible neurological damage. Genetic counseling and family screening are essential given the hereditary nature of MELAS 1 6 8.

Conclusion

MELAS syndrome is a complex, multisystem mitochondrial disorder with a wide variability of symptoms, genetic causes, and treatment responses. Understanding its core features and latest management strategies is crucial for improving outcomes.

Key Takeaways:

• Multisystem symptoms include recurrent stroke-like episodes, seizures, muscle weakness, hearing loss, diabetes, and cognitive decline, with significant variability between individuals 1 2 3 8.
• Most cases are due to the m.3243A>G mutation in the MT-TL1 gene, but many other genetic variants are recognized, explaining the diversity of clinical presentations 1 6 7 8 11.
• Pathogenesis involves impaired mitochondrial energy production, lactic acidosis, microvascular dysfunction, and nitric oxide deficiency 1 12 13 14.
• Treatment is supportive and symptomatic, with L-arginine (and potentially citrulline) supplementation for stroke-like episodes, plus mitochondrial support agents and individualized care for organ complications 1 13 14 15.
• Research into experimental therapies offers hope for future advances, but early diagnosis and multidisciplinary support remain the current standard of care 9 10 15.

Understanding MELAS syndrome empowers patients, families, and clinicians to navigate its challenges with greater knowledge, compassion, and hope for ongoing advances.