MELAS syndrome

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Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes
A computed tomography brain scan showing bilateral basal ganglia calcification.jpg
Basal ganglia calcification, cerebellar atrophy, increased lactate; a CT image of a person diagnosed with MELAS
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Frequency1 in 4000 [1]

MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) is one of the family of mitochondrial diseases, which also include MIDD (maternally inherited diabetes and deafness), MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. [2] A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. [3] The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Contents

Signs and symptoms

MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development. [4] Children with MELAS often have normal early psychomotor development until the onset of symptoms between 2 and 10 years old. Though less common, infantile onset may occur and may present as failure to thrive, growth retardation and progressive deafness. Onset in older children typically presents as recurrent attacks of a migraine-like headache, anorexia, vomiting, and seizures. Children with MELAS are also frequently found to have short stature. [1]

Most people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, epilepsy, and hormonal imbalances. [5]

Differential diagnosis

The presentation of some cases is similar to that of Kearns–Sayre syndrome. [6] [1]

Myoclonus epilepsy associated with ragged red fibers (MERRF) may be confused with MELAS as they both involve seizures, mental deterioration, and myopathy with ragged red fibers on biopsy. MERRF patients may also have hearing loss, visual disturbance secondary to optic atrophy, and short stature. The characteristic myoclonic seizure in MERRF may help to narrow diagnosis, but genetic testing should be considered to distinguish the two conditions. [1]

Leigh syndrome may also present with progressive neurological deterioration, seizures, and vomiting, mainly in young children. [1]

Genetics

Muscle biopsy of a person diagnosed with MELAS but carrying no known mutation. (a) Modified Gomori trichrome stain showing several ragged red fibers (arrowhead). (b) Cytochrome c oxidase stain showing Type-1 lightly stained and Type II fibers, darker fibers, and a few fibers with abnormal collections of mitochondria (arrowhead). Note cytochrome c oxidase negative fibers as usually seen in mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). (c) Succinate dehydrogenase staining showing a few ragged blue fibers and intense staining in the mitochondria of the blood vessels (arrow). (d) Electron microscopy showing abnormal collection of mitochondria with paracrystalline inclusions (arrowhead), osmiophilic inclusions (large arrowhead) and mitochondrial vacuoles (small arrowhead). Modified Gomori trichrome stain showing several ragged red fibers.jpg
Muscle biopsy of a person diagnosed with MELAS but carrying no known mutation. (a) Modified Gomori trichrome stain showing several ragged red fibers (arrowhead). (b) Cytochrome c oxidase stain showing Type-1 lightly stained and Type II fibers, darker fibers, and a few fibers with abnormal collections of mitochondria (arrowhead). Note cytochrome c oxidase negative fibers as usually seen in mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). (c) Succinate dehydrogenase staining showing a few ragged blue fibers and intense staining in the mitochondria of the blood vessels (arrow). (d) Electron microscopy showing abnormal collection of mitochondria with paracrystalline inclusions (arrowhead), osmiophilic inclusions (large arrowhead) and mitochondrial vacuoles (small arrowhead).

MELAS is mostly caused by mutations in the genes in mitochondrial DNA, but it can also be caused by mutations in the nuclear DNA. [5]

NADH dehydrogenase

Some of the genes (MT-ND1, MT-ND5) affected in MELAS encode proteins that are part of NADH dehydrogenase (also called complex I) in mitochondria, that helps convert oxygen and simple sugars to energy. [8]

Transfer RNAs

Other genes (MT-TH, MT-TL1, and MT-TV) encode mitochondrial specific transfer RNAs (tRNAs).[ citation needed ]

Mutations in MT-TL1 cause more than 80 percent of all cases of MELAS. They impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain. [9]

Inheritance

This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance and heteroplasmy. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.[ citation needed ]

Although first recognised and described in 1984 the condition occurred well before that date. Josiah Wedgwood gave detailed description of this illness in his youngest daughter, Mary Ann Wedgwood (1778–1786). [10] Her illness may provide a link to the illnesses that afflicted her elder brother, Thomas Wedgwood, her eldest sister Susannah Darwin, and Susannah's second son, the famous naturalist, Charles Darwin. The illnesses that afflicted the Wedgwood-Darwin families have a well defined matrilineal inheritance pattern.

Diagnosis

MRI: Multifocal infarct-like cortical areas in different stages of ischemic evolution, areas that do not conform to any known vascular territory. Initial lesions often occur in the occipital or parietal lobes with eventual involvement of the cerebellum, cerebral cortex, basal ganglia, and thalamus.[ citation needed ]

Lactate levels are often elevated in serum and cerebrospinal fluid. 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. Diagnosis may be molecular or clinical: [9]

Due to mitochondrial heteroplasmy, urine and blood testing is preferable to blood alone. [1] PCR and ARMS-PCR are commonly used, reliable, rapid, and cost-effective techniques for the diagnosis of MELAS. [9]

Hearing loss and mitochondrial diabetes are common features. Eyes may have a distinctive speckled pigment in the retina, referred to as a maculopathy. Family members may present differently.

Treatment

There is no curative treatment. The disease remains progressive and fatal. [11] [12]

Patients are managed according to what areas of the body are affected at a particular time. Enzymes, amino acids, antioxidants and vitamins have been used. Treatment for MELAS currently is 1. support the good mitochondria that is left with a mito cocktail and 2. avoid known mito toxins.

Also the following supplements may help:

Epidemiology

The exact incidence of MELAS is unknown. [18] It is one of the more common conditions in a group known as mitochondrial diseases. [18] Together, mitochondrial diseases occur in about 1 in 4,000 people. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Mitochondrial disease</span> Disorders caused by mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

<span class="mw-page-title-main">Leigh syndrome</span> Metabolic disease

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Muscle disorders caused by mitochondrial dysfunction

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">MERRF syndrome</span> Mitochondrial disorder

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

<span class="mw-page-title-main">Mitochondrial neurogastrointestinal encephalopathy syndrome</span> Medical condition

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudoobstruction. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene.

Chronic progressive external ophthalmoplegia (CPEO) is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows. It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the diagnosis. In other people suffering from mitochondrial disease, CPEO occurs as part of a syndrome involving more than one part of the body, such as Kearns–Sayre syndrome. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

Mitochondrially encoded tRNA leucine 1 (UUA/G) also known as MT-TL1 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL1 gene.

Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.

<span class="mw-page-title-main">MT-ND5</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in human MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).

Mitochondrially encoded tRNA valine also known as MT-TV is a transfer RNA which in humans is encoded by the mitochondrial MT-TV gene.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA isoleucine also known as MT-TI is a transfer RNA which in humans is encoded by the mitochondrial MT-TI gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.

Mitochondrially encoded tRNA arginine also known as MT-TR is a transfer RNA which in humans is encoded by the mitochondrial MT-TR gene.

Mitochondrially encoded tRNA threonine also known as MT-TT is a transfer RNA which in humans is encoded by the mitochondrial MT-TT gene.

Mitochondrially encoded tRNA tryptophan also known as MT-TW is a transfer RNA which in humans is encoded by the mitochondrial MT-TW gene.

References

  1. 1 2 3 4 5 6 Pia S, Lui F (2020). "Melas Syndrome". Statpearls. Treasure Island (FL): StatPearls Publishing. PMID   30422554. CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  2. ↑ Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP (October 1984). "Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome". Annals of Neurology. 16 (4): 481–488. doi:10.1002/ana.410160409. PMID   6093682. S2CID   41412358.
  3. ↑ Hirano M, Pavlakis SG (January 1994). "Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts". Journal of Child Neurology. 9 (1): 4–13. doi:10.1177/088307389400900102. PMID   8151079. S2CID   31329972.
  4. ↑ MELAS syndrome at NLM Genetics Home Reference
  5. 1 2 Valiente-Pallejà, Alba; Tortajada, Juan; Bulduk, Bengisu K.; Vilella, Elisabet; Garrabou, Glòria; Muntané, Gerard; Martorell, Lourdes (2022). "Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review". eBioMedicine. 76. doi:10.1016/j.ebiom.2022.103815. PMC   8790490 . PMID   35085849.
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  7. ↑ Abu-Amero KK, Al-Dhalaan H, Bohlega S, Hellani A, Taylor RW (October 2009). "A patient with typical clinical features of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report". Journal of Medical Case Reports. 3: 77. doi: 10.1186/1752-1947-3-77 . PMC   2783076 . PMID   19946553.
  8. ↑ Tranchant C, Anheim M (2016). "Movement disorders in mitochondrial diseases". Revue Neurologique. 172 (8–9): 524–529. doi:10.1016/j.neurol.2016.07.003. PMID   27476418.
  9. 1 2 3 Bulduk, B. K., Kiliç, H. B., Bekircan-Kurt, C. E., Haliloğlu, G., Erdem Özdamar, S., Topaloğlu, H., & Kocaefe, Y. Ç. (2020). A Novel Amplification-Refractory Mutation System-PCR Strategy to Screen MT-TL1 Pathogenic Variants in Patient Repositories. Genetic testing and molecular biomarkers, 24(3), 165–170. https://doi.org/10.1089/gtmb.2019.0079
  10. ↑ Hayman, John; Pavlakis, Steven; Finsterer, Josef (2022-02-17). "Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) in the 18th Century: Mitochondrial Disorders Are Not of Recent Origin". Cureus. 14 (2): e22314. doi: 10.7759/cureus.22314 . ISSN   2168-8184. PMC   8856639 . PMID   35198337.
  11. ↑ Quinn NM, Stone G, Brett F, Caro-Dominguez P, Neylon O, Lynch B (September 2016). "MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke) - a Diagnosis Not to be Missed". Irish Medical Journal. 109 (8): 455. PMID   28124854.
  12. ↑ Muñoz-Guillén N, León-López R, Ferrer-Higueras MJ, Vargas-Vaserot FJ, Dueñas-Jurado JM (August 2009). "[Arreflexic coma and MELAS syndrome]" [Arreflexic coma and MELAS syndrome]. Revista Clinica Espanola (in Spanish). 209 (7): 337–341. doi:10.1016/s0014-2565(09)71818-1. PMID   19709537.
  13. ↑ Rodriguez MC, MacDonald JR, Mahoney DJ, Parise G, Beal MF, Tarnopolsky MA (February 2007). "Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders". Muscle & Nerve. 35 (2): 235–242. doi:10.1002/mus.20688. PMID   17080429. S2CID   28962906.
  14. ↑ Ogle RF, Christodoulou J, Fagan E, Blok RB, Kirby DM, Seller KL, et al. (January 1997). "Mitochondrial myopathy with tRNA(Leu(UUR)) mutation and complex I deficiency responsive to riboflavin". The Journal of Pediatrics. 130 (1): 138–145. doi:10.1016/S0022-3476(97)70323-8. PMID   9003864.
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  16. ↑ Koga Y, Akita Y, Nishioka J, Yatsuga S, Povalko N, Katayama K, Matsuishi T (2007). "MELAS and L-arginine therapy". Mitochondrion. 7 (1–2): 133–139. doi:10.1016/j.mito.2006.11.006. PMID   17276739.
  17. ↑ Hirata K, Akita Y, Povalko N, Nishioka J, Yatsuga S, Matsuishi T, Koga Y (April 2008). "Effect of L-arginine on synaptosomal mitochondrial function". Brain & Development. 30 (4): 238–245. doi:10.1016/j.braindev.2007.08.007. PMID   17889473. S2CID   46238939.
  18. 1 2 3 "MELAS". Genetics Home Reference. December 2013. Retrieved 11 April 2017.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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