MELAS

[Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes; Myopathy, Mitochondrial-Encephalopathy-Lactic Acidosis-Stroke]

Clinical Diagnosis

The clinical diagnosis of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) is based on the following features:

• Stroke-like episodes, typically before age 40 years

• Encephalopathy with seizures and/or dementia

• Mitochondrial myopathy, evidenced by lactic acidosis and/or ragged red fibers (RRF) on muscle biopsy

To confirm the diagnosis, two of the following are also required [Hirano et al 1992]:

• Normal early psychomotor development

• Recurrent headache

• Recurrent vomiting

Testing

Lactic acidosis both in blood and in the CSF.   In individuals with MELAS, lactate and pyruvate concentrations are commonly elevated at rest and increase excessively after moderate exercise.

Note: Other situations (unrelated to the diagnosis of MELAS) in which lactate and pyruvate can be elevated are acute neurologic events such as seizure or stroke.

Elevated CSF protein.   The concentration of CSF protein may be elevated but rarely surpasses 100 mg/dL.

Brain imaging.  During stroke-like episodes, brain MRI shows areas of increased T2 signal, typically involving the posterior cerebrum and not conforming to the distribution of major arteries. Slow spreading of the stroke-like lesions in the weeks following the first symptoms can be documented by T2-weighted MRI [Iizuka et al 2003]. In addition, diffusion-weighted MRI shows increased apparent diffusion coefficient (ADC) in the stroke-like lesions of MELAS, in contrast to the decreased ADC seen in ischemic strokes [Kolb et al 2003].

Basal ganglia calcifications are also commonly seen on CT.

Electrocardiogram (ECG) may show evidence of cardiomyopathy, pre-excitation, or incomplete heart block.

Electromyography and nerve conduction studies are consistent with a myopathic process, but neuropathy may coexist. Neuropathy is relatively common (22% in a study of 32 individuals) and is generally mixed axonal and demyelinating [Karppa et al 2003].

Muscle biopsy typically shows ragged red fibers (RRF) with the modified Gomori trichrome stain or "ragged blue fibers" resulting from the hyperintense reaction with the histochemical stain for succinate dehydrogenase (SDH). Most RRFs stain positively for cytochrome c oxidase (COX) activity [DiMauro & Bonilla 1997], unlike in other mtDNA-related disorders such as Kearns-Sayre syndrome (KSS) and MERRF (myoclonic epilepsy ragged red fibers), in which RRFs do not react with the cytochrome c oxidase (COX) histochemical stain. An additional morphologic feature that is characteristic (though not pathognomonic) of MELAS is the overabundance of mitochondria in smooth muscle and endothelial cells of intramuscular blood vessels, best revealed with the SDH stain ("strongly succinate dehydrogenase-reactive blood vessels," or SSVs) [Hasegawa et al 1991].

Respiratory chain studies.   Biochemical analysis of respiratory chain enzymes in muscle extracts usually shows multiple partial defects, especially involving complex I and/or complex IV. However, biochemical results can also be normal.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes

• MT-TL1.   The mitochondrial DNA (mtDNA) gene MT-TL1 encoding tRNA^Leu(UUR) is the gene associated with MELAS in about 80% of cases.

• MT-ND5.  Mutations in the MT-ND5 gene have been reported with increasing frequency in individuals with isolated MELAS or with overlap syndromes [DiMauro & Davidzon 2005].

• Other mtDNA tRNA genes.  Mutations causing MELAS have been identified in other mtDNA tRNA genes including MT-TC,MT-TV,MT-TF, and MT-TS1.

Molecular genetic testing: Clinical uses

• Diagnostic testing

• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• MT-TL1

  
  Targeted mutation analysis.  The most common mutation in MELAS, present in over 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide 3243 in MT-TL1, first described by Goto et al (1990). Mutations included in targeted mutation analysis testing panels vary across laboratories and may include the MT-TL1 mutations A3243G, T3271C, and A3252G as well as additional rare mutations.

  
  Note: (1) Mutations are usually present in all tissues and can be detected in mtDNA from blood leukocytes in individuals with typical MELAS; however, the occurrence of "heteroplasmy" in disorders of mtDNA can result in varying tissue distribution of mutated mtDNA. Hence, in individuals having one or only a few symptoms consistent with MELAS or asymptomatic maternal relatives, the pathogenic mutation may be undetectable in mtDNA from leukocytes and may only be detected in other tissues, such as cultured skin fibroblasts, hair follicles, urinary sediment, or, most reliably, skeletal muscle. Among accessible tissues, urinary sediment has proven the most useful for detecting the A3243G mutation [Shanske et al 2004, McDonnell et al 2004]. (2) A muscle biopsy is recommended in the rare instance in which the MT-TL1 A3243G mutation cannot be detected by standard techniques in mtDNA from leukocytes or urinary sediment from an individual with classic MELAS.

  Sequence analysis/mutation scanning.  Sequence analysis/mutation scanning of the MT-TL1 gene may be an option for individuals in whom a mutation is not detected through targeted mutation analysis. Sixteen additional point mutations and one 4-bp deletion in MT-TL1 have been associated with the MELAS syndrome (Table 5).

• MT-ND5

  
  Targeted mutation analysis.   Targeted mutation analysis for the most common MT-ND5 mutation, G13513A, is available clinically. Some panels include testing for the 12770 A→G mutation.

  Sequence analysis.  Sequence analysis of the MT-ND5 gene is clinically available.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in MELAS

Test Methods	Mutations Detected	Mutation Detection Rate	Test Availability
Targeted mutation analysis	A3243G mutation of MT-TL1	~80%	Clinical
	T3271C mutation of MT-TL1	~7.5%
	A3252G mutation of MT-TL1	<5%
Sequence analysis/mutation scanning	All MT-TL1 sequence alterations	Unknown
Targeted mutation analysis	G13513A and 12770 A→G mutations of MT-ND5
Sequence analysis	MT-ND5 sequence alterations

Genetically Related Disorders

The A3243G mutation of MT-TL1 can also be associated with a variety of mitochondrial disorders including progressive external ophthalmoplegia (PEO), diabetes mellitus, cardiomyopathy, or deafness. See Mitochodrial Disorders Overview.

Natural History

MELAS is a multisystem disorder with protean manifestations.

In typical cases, onset is in childhood. Early psychomotor development is usually normal, but short stature is common. First onset of symptoms is frequently between the ages of two and ten years, with some persons having delayed onset between ten and 40 years. Onset of symptoms before age two years or after age 40 years is uncommon. The most common initial symptoms are seizures, recurrent headaches, anorexia, and recurrent vomiting. Exercise intolerance or proximal limb weakness can be the initial manifestation, followed by generalized tonic-clonic seizures.

Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness that may produce altered consciousness and may recur. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss adds to the progressive decline of these individuals.

Migrainous headaches occur in the majority of affected individuals and are often severe during the acute phase of the stroke.

Less common symptoms include myoclonus, ataxia [Petruzzella et al 2004], episodic coma, optic atrophy, cardiomyopathy [Menotti et al 2004], pigmentary retinopathy, ophthalmoplegia, diabetes mellitus, hirsutism, gastrointestinal dysmotility [Garcia-Velasco et al 2003, Chang et al 2004], and nephropathy.

Some individuals have one presentation — e.g., progressive external ophthalmoplegia (PEO), diabetes mellitus (DM), cardiomyopathy, or deafness — almost exclusively [Hirano & Pavlakis 1994].

The typical age of death ranges from ten to 35 years, but some individuals live into their sixth decade [Ciafaloni et al 1992]. Intercurrent infections or intestinal obstruction are often the terminal events [Hirano & Pavlakis 1994].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been identified.

For all mtDNA mutations, clinical expression depends on three factors:

• Heteroplasmy.  The relative abundance of mutant mtDNAs

• Tissue distribution of mutant mtDNAs

• Threshold effect.  The vulnerability of each tissue to impaired oxidative metabolism

While the tissue vulnerability threshold probably does not vary substantially among individuals, mutational load and tissue distribution do vary and may account for the clinical diversity seen in individuals with MELAS. In one report, a correlation was found between the frequency of the more common clinical features and the level of mutant mtDNA in muscle, but not in leukocytes [Chinnery et al 1997].

Diverse clinical presentations (i.e., progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness) can be associated with the same MT-TL1 mutation, A3243G. This may be the result of the higher abundance of the mutation in muscle in individuals with PEO than in those with typical MELAS, which may in turn explain why ragged red fibers in individuals with PEO are COX negative rather than COX positive [Petruzzella et al 1994].

As-yet-undefined nuclear DNA factors may also modify the phenotypic expression of mtDNA mutations [Moraes et al 1993].

Penetrance

In mtDNA-related disorders, penetrance typically depends on mutation load and tissue distribution, which show random variation within families (see Genotype-Phenotype Correlations.)

Anticipation

No evidence of anticipation has been found. Knowledge of the molecular defect may favor earlier diagnosis in subsequent generations.

Prevalence

An epidemiologic study from northern Finland estimated the prevalence of the A3243G mutation to be greater than or equal to 16.3/100,000 (95% confidence interval 11.3-21.4/100,000) [Majamaa et al 1997]. According to a more recent Finnish study, this estimate may be high [Uusimaa et al 2004].

Evaluations at Initial Diagnosis to Establish the Extent of Disease

• Measurement of height and weight to assess growth

• Audiologic evaluation

• Ophthalmologic evaluation

• Assessment of cognitive abilities

• Physical therapy assessment

• Neurologic evaluation, MRI, MRS [Kaufmann et al 2004], and, if seizures are suspected, EEG

• Cardiac evaluation

• Screening for diabetes mellitus by fasting serum glucose concentration and glucose tolerance test

Treatment of Manifestations

• Sensorineural hearing loss has been successfully treated with cochlear implantation [Sue et al 1998, Sinnathuray et al 2003].

• Ptosis can benefit from eyelid "crutches," blepharoplasty, or frontalis muscle-eyelid sling placement.

• No therapy is available for PEO or retinopathy.

• Aerobic exercise is helpful in MELAS and other mitochondrial diseases [Taivassalo & Haller 2004]. Physical therapy should be implemented in individuals after strokes.

• Seizures respond to traditional anticonvulsant therapy.

• Standard analgesics can be used for migraine headaches.

• Cardiac manifestations can benefit from standard pharmacologic therapy.

• Diabetes mellitus can be managed by dietary modification only, especially in thin individuals, or with oral hypoglycemic agents, but often requires insulin therapy.

Prevention of Primary Manifestations

• No specific treatment for MELAS exists.

• The administration of coenzyme Q10 (50-100 mg 3x/day) and L-carnitine (1000 mg 3x/day) has been of some benefit to some individuals.

• Idebenone, a form of coenzyme Q10 that apparently crosses the blood-brain barrier more efficiently, has also been reported as beneficial in anecdotal reports [Ikejiri et al 1996].

Surveillance

Affected individuals and their at-risk relatives should be followed at regular intervals to monitor progression and the appearance of new symptoms. Annual ophthalmologic, cardiologic, and endocrinologic evaluations are recommended.

Agents/Circumstances to Avoid

Dichloroacetate (DCA) reduces blood lactate by activating the pyruvate dehydrogenase complex. Anecdotal reports of effectiveness f[De Vivo et al 1990] have not been substantiated by a double-blind, placebo-controlled trial, which in fact documented a toxic effect of DCA on peripheral nerves and concluded that individuals with MELAS (who are already at increased risk for peripheral neuropathies) should avoid DCA [Kaufmann et al, in press].

Testing of Relatives at Risk

Molecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutation loads and are thus at risk of developing symptoms. However, no proven disease-modifying intervention exists at present.

Therapies Under Investigation

Oral administration of L-arginine seems to attenuate the severity of strokes when administered in the acute phase [Kubota et al 2004, Koga et al 2005] and to reduce the frequency of strokes when given interictally [Koga et al 2005]; double-blind studies are needed to confirm these data.

Beneficial effects of oral succinate were reported in one individual [Oguro et al 2004].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

MELAS is caused by mutations in mtDNA and is transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

• The father of a proband does not have the disease-causing mtDNA mutation.

• The mother of a proband usually has the mtDNA mutation and may or may not have symptoms. In some mothers, the disease-causing mutation may be undetectable in mtDNA from leukocytes and may be detected in other tissues, such as cultured skin fibroblasts, hair follicles, urinary sediment, or, most reliably, skeletal muscle.

• Alternatively, the proband may have a de novo somatic mitochondrial mutation.

Sibs of a proband

• The risk to the sibs depends on the genetic status of the mother.

• If the mother has the mtDNA mutation, all the sibs of a proband will inherit the disease-causing mtDNA mutation and may or may not have symptoms. One group has reported that women with higher levels of mutant mtDNA in their blood have a greater likelihood of producing affected offspring [Chinnery et al 1998].

Offspring of a proband

• All offspring of females with a mtDNA mutation will inherit the mutation.

• Offspring of males with a mtDNA mutation are not at risk of inheriting the mutation.

Other family members of a proband.   The risk to other family members depends upon the genetic status of the proband's mother. If she has a mtDNA mutation, her sibs and mother are also at risk.

Related Genetic Counseling Issues

Phenotypic variability.  Family members with the MT-TL1 mutation A3243G are more likely to have non-MELAS manifestations (i.e., diabetes, hearing loss) than MELAS.

The phenotype of an individual with a mtDNA mutation results from a combination of factors including the severity of the mutation, the percentage of mutant mitochondria (mutational load), and the organs and tissues in which they are found (tissue distribution). Different family members often inherit different percentages of mutant mtDNA and therefore can have a wide range of clinical symptoms.

Interpretation of testing results of asymptomatic at-risk family members is extremely difficult. Prediction of phenotype based on test results is not possible.

Family planning.  The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that test methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Although results of prenatal diagnosis for MELAS cannot provide additional information, it is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The specific mtDNA mutation in the mother must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Interpretation of prenatal diagnostic results is complex for the following reasons:

• The mutational load in the mother's tissues and in fetal tissues sampled (i.e., amniocytes and chorionic villi) may not correspond to that of other fetal tissues.

• The mutational load in tissues sampled prenatally may shift in utero or after birth as a result of random mitotic segregation.

Prediction of phenotype, age of onset, severity, or rate of progression is not possible.

Molecular Genetic Pathogenesis

The pathogenetic mechanism is not completely clear, but interesting insights were obtained from studies of cybrid cell lines. Cybrids are mtDNA-less human immortal cell lines (rho⁰ cells) repopulated with mitochondria from individuals with MELAS harboring the A3243G or other pathogenic mutations [King & Attardi 1989]. The cybrid cell-line studies showed that high proportions of the MT-TL1 A3243G mutation correlated with decreased mitochondrial protein synthesis, decreased oxygen consumption, and increased amounts of an unprocessed RNA fragment containing the mutant gene and designated RNA-19 [King et al 1992]. High levels of RNA-19 were documented in tissues from individuals with MELAS [Kaufmann et al 1996]. Other studies have demonstrated low levels of the mutant tRNA, decreased aminoacylation, and hypomodification of the D-stem — alterations that may contribute to the observed decreased protein synthesis [Helm et al 1999, Borner et al 2000, Chomyn et al 2000]. An alternative theory, also based on cybrid work, attributes the pathogenesis of the mutation to a misreading of leucine codons as phenylalanine codons [Yasukawa et al 2000] because of lack of methyltaurine modification of the anticodon wobble base [Kirino et al 2004].

Normal allelic variants: Benign polymorphisms are especially frequent in mtDNA and are listed in www.mitomap.org.

For more information, see Table A: locus-specific databases and HGMD above.

Normal gene product: Like the other 21 mtDNA-encoded tRNAs, tRNA^Leu(UUR) is essential for mitochondrial protein synthesis, specifically for the incorporation of leucine into nascent proteins.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 13 October 2005 (me) Comprehensive update posted to live Web site

• 18 June 2003 (ca) Comprehensive update posted to live Web site

• 27 February 2001 (me) Review posted to live Web site

• September 2000 (sdm) Original submission