eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

MELAS Syndrome

Author: Fernando Scaglia, MD, FACMG, Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital
Contributor Information and Disclosures

Updated: Jul 23, 2009

Introduction

Background

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome is a progressive neurodegenerative disorder. Patients may present sporadically or as members of maternal pedigrees with a wide variety of clinical presentations. The typical presentation of patients with MELAS syndrome includes features that comprise the name of the disorder, such as mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. Other features, such as seizures, diabetes mellitus, hearing loss, cardiac disease, short stature, endocrinopathies, exercise intolerance, and neuropsychiatric dysfunction are clearly part of the disorder.

Pathophysiology

Strokelike episodes and mitochondrial myopathy characterize MELAS syndrome. Multisystemic organ involvement is seen, including the CNS, skeletal muscle, eye, cardiac muscle, and, more rarely, the GI and renal systems.

Approximately 80% of patients with the clinical characteristics of MELAS syndrome have a heteroplasmic A-to-G point mutation in the dihydrouridine loop of the transfer RNA (tRNA)^{Leu (UUR)} gene at base pair (bp) 3243 (ie, 3243 A → G mutation).¹ However, other mitochondrial DNA (mtDNA) mutations are observed, including the m.3244 G → A, m.3258 T → C, m.3271 T → C, and m.3291 T → C in the mitochondrial tRNA^Leu(UUR) gene.

The pathogenesis of the strokelike episodes in MELAS syndrome has not been completely elucidated. These metabolic strokelike episodes may be nonvascular and due to transient oxidative phosphorylation (OXPHOS) dysfunction within the brain parenchyma. A mitochondrial angiopathy of small vessel is responsible for contrast enhancement of affected regions and mitochondrial abnormalities of endothelial cells and smooth muscle cells of blood vessels. The multisystem dysfunction in patients with MELAS syndrome may be due to both parenchymal and vascular OXPHOS defects. Increased production of free radicals in association with an OXPHOS defect leading to vasoconstriction may offset the effect of potent vasodilators (eg, nitric oxide).

The unusual strokelike episodes and higher morbidity observed in MELAS syndrome may be secondary to alterations in nitric oxide homeostasis that cause microvascular damage. Nitric oxide can bind the cytochrome c oxidase–positive sites in the blood vessels present in the CNS, displacing heme-bound oxygen and resulting in decreased oxygen availability in the surrounding tissue and decreased free nitric oxide. Furthermore, coupling of the vascular mitochondrial dysfunction with cortical spreading depression might underlie the selective distribution of ischemic lesions in the posterior cortex in these subjects.   

Mutations in this disorder affect mitochondrial tRNA function, leading to the disruption of the global process of intramitochondrial protein synthesis. Measurements of respiratory enzyme activities in intact mitochondria have revealed that more than one half of the patients with MELAS syndrome may have complex I or complex I + IV deficiency. A close relationship is apparent between MELAS and complex I deficiency. The decreased protein synthesis may ultimately lead to the observed decrease in respiratory chain activity by reduced translation of UUG-rich genes such as ND6 (component of complex I).²

In addition, studies revealed that the 3243 A → G mutation produces a severe combined respiratory chain defect in myoblasts, with almost complete lack of assembly of complex I, IV, and V, and a slight decrease of assembled complex III. This assembly defect occurs despite a modest reduction in the overall rate of mitochondrial protein synthesis. Translation of some polypeptides is decreased, and evidence of amino acid misincorporation is noted in others.

Frequency

United States

No estimates concerning the prevalence of the common MELAS mutation are available for the North American population; however, the syndrome has been observed to be less frequent in blacks.

International

The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the m.3243A → G mutation in the adult Finnish population. If the assumption is made that all first-degree maternal relatives of a verified mutation carrier also harbor the mutation, prevalence increases to more than 16.3 per 100,000. This high prevalence suggests that mitochondrial disorders may constitute one of the largest diagnostic categories of neurogenetic diseases among adults. In Northern England, the prevalence of this mutation in the adult population has been determined to be approximately 1 per 13,000.

Mortality/Morbidity

The progressive disorder has a high morbidity and mortality. The encephalomyopathy, associated with strokelike episodes followed by hemiplegia and hemianopia, is severe. Focal and general convulsions may occur in association with these episodes.

Other abnormalities that may be observed are ventricular dilatation, cortical atrophy, and basal ganglia calcification. Mental deterioration usually progresses after repeated episodic attacks. Psychiatric abnormalities and cognitive decline (eg, altered mental status, schizophrenia) may accompany the strokelike episodes. Bipolar disorder is another psychiatric abnormality observed in MELAS syndrome. Autism spectrum disorders (ASDs) with or without additional neurological features can be early presentations of the m.3243 A → G mutation. Myopathy may be debilitating. The encephalopathy may progress to dementia; eventually, the clinical course rapidly declines, leading to severe disability and premature death.

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. Subjects with MELAS syndrome were found to have increased ascending aortic stiffness and enlarged aortic dimensions suggesting vascular remodeling. Aortic root dissection was found in one patient with MELAS syndrome.³ Some patients may develop Leigh syndrome (ie, subacute necrotizing encephalopathy). Patients may develop renal failure due to focal segmental glomerulosclerosis.

More rarely, these patients may exhibit severe GI dysmotility and endocrine dysfunction, including hypothyroidism and hyperthyroidism.

Race

No predilection for a particular ethnic group is noted.

Sex

No sexual predilection is present.

Age

In many patients with MELAS syndrome, presentation occurs with the first strokelike episode, usually when an individual is aged 4-15 years. Less often, onset of disease may occur in infancy with delayed developmental milestones and learning disability. One presentation of the disorder was reported in a 4-month-old infant.

Clinical

History

• Onset of the disorder may be myopathic with weakness, easy fatigability, and exercise intolerance.
• Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome onset may occur early in infancy with a history of developmental delay and learning disabilities. Developmental delay, learning disability, or attention deficit disorder is primarily found in patients prior to the development of the first stroke. An encephalopathic picture that is progressive and leads to dementia may be present. Patients may be apathetic. The level of cognitive functioning worsens over time by Karnofsky score in fully symptomatic patients.
• Failure to thrive may be the presenting feature in some patients with MELAS syndrome.
• Strokelike episodes are the hallmark feature of this disorder. Initially, episodes may manifest with vomiting and headache that may last several days. These patients may also experience episodes of seizures and visual abnormalities followed by hemiplegia. Seizure types may be tonic-clonic or myoclonic.
• Migraine or migrainelike headaches observed in these patients may also reflect the strokelike episodes. Pedigrees of patients with classic MELAS syndrome identify many members whose only manifestations are migraine headaches.
• Patients may have visual complaints due to ophthalmoplegia, and they may experience blindness because of optic atrophy and difficulties with night vision due to pigmentary retinopathy.
• Some patients may experience hearing loss, which may accompany diabetes. It may be observed in association with the classic disorder of MELAS syndrome.
• Polydipsia and polyuria may be the presenting signs of diabetes; diabetes appears to be the most common manifestation of MELAS syndrome. Usually, type 2 diabetes is described in individuals with MELAS syndrome, although type 1 (formerly termed insulin-dependent diabetes) may also be observed. Guidelines for diagnosis and management of type 2 diabetes have been established.⁴
• Palpitations and shortness of breath may be present in some patients with MELAS syndrome secondary to cardiac conduction abnormalities, such as Wolff-Parkinson-White syndrome. Patients may experience shortness of breath secondary to cardiomyopathy, which is usually of the hypertrophic type; however, dilated cardiomyopathy has also been described.
• Acute onset of GI manifestations (eg, acute onset of abdominal pain) may reflect pancreatitis, ischemic colitis, and intestinal obstruction.
• Numbness, tingling sensation, and pain in the extremities can be manifestations of peripheral neuropathy.
• Psychiatric disorders (eg, depression, bipolar disorder) have been associated with the m.3243 A → G mutation. Dementia has been another clinical manifestation. Moreover, autism spectrum disorders (ASD) have been associated with the 3243 A → G mutation.
• Patients may develop features of hypothyroidism and hyperthyroidism
• Some patients may develop apnea and an ataxic gait in association with neuroradiologic features of MELAS syndrome.
• Oliguria can be associated with MELAS syndrome and may indicate the onset of nephrotic syndrome.
• Patients with MELAS syndrome may have functional vascular involvement. Aortic root dissection has been reported in one patient with MELAS syndrome.

Physical

• Patients with MELAS syndrome may exhibit hypertension.
• Myopathy presents with hypotonia and weakness. Proximal muscles tend to be more involved than distal muscles. Musculature is thin, and patients may present with a myopathic face.
• Strokelike episodes may present with convulsions, visual abnormalities, numbness, hemiplegia, and aphasia. Episodes may be followed by transient hemiplegia or hemianopia, which lasts a few hours to several weeks.
• Additional features on neurologic examination may include ataxia, tremor, myoclonus, dystonia, visual disturbances, and cortical blindness. Some patients may present with ophthalmoplegia and ptosis.
• On ophthalmologic examination, patients have presented with pigmentary retinopathy.
• Sensorineural deafness has been reported as part of the disorder in approximately 25% of patients with MELAS syndrome.
• Cardiomyopathy with signs of congestive heart failure (CHF) may also be observed upon physical examination.
• Skin manifestations of cutaneous purpura, hirsutism, and a scaly, pruritic, diffuse erythema with reticular pigmentation may be observed in patients with MELAS syndrome.
• Short stature may be the first manifestation of MELAS syndrome in many patients.

Causes

• MELAS syndrome has been associated with at least 6 different point mutations, 4 of which are located in the same gene, the tRNA^{Leu (UUR)} gene. The most common mutation, found in 80% of individuals with MELAS syndrome, is an A → G transition at nucleotide (nt) 3243 in the tRNA^{Leu (UUR)} gene. An additional 7.5% have a heteroplasmic T → C point mutation at bp 3271 in the terminal nucleotide pair of the anticodon stem of the tRNA^{Leu (UUR)} gene. Moreover, a MELAS phenotype has been observed associated with an m.13513G → A mutation in the ND5 gene and in POLG deficiency.   
• These mutations are heteroplasmic, which reflects the different percentages of mutated mtDNA present in different tissues. Variable heteroplasmy among individuals affected with MELAS syndrome reflects variable segregation in the ovum. Mutations in tRNA^Lys may be expected to have an important effect on translation and protein synthesis in mitochondria. The MELAS disorder–associated human mitochondrial tRNA^{Leu (UUR)} mutation causes aminoacylation deficiency and a concomitant defect in translation initiation.
• Abnormal calcium homeostasis resulting in neuronal injury has been suggested as another mechanism contributing to the CNS involvement observed in MELAS syndrome.
• Patients with MELAS syndrome have been found to have a marked decrease in the activity of complex I. The major effects observed secondary to nt 3243 and nt 3271 mutations have been a reduction in protein synthesis and the activity of complex I. These effects have been demonstrated through studying cybrids in which human cell lines without mtDNA are fused with exogenous mitochondria containing 0-100% of the common m.3243 mutation. Cybrids with more than 95% of mutant DNA had decreased rates of synthesis of mitochondrial proteins, leading to respiratory chain defects.

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