MELAS Syndrome

MELAS Syndrome

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Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome is a multisystem and 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 headaches, seizures, neuropsychiatric dysfunction, diabetes mellitus, sensorineural hearing loss, cardiac disease, short stature, endocrinopathies, muscle weakness, exercise intolerance, gastrointestinal dysmotility, and dementia are clearly part of the disorder.

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. [1, 2]

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). [3] 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 tRNALeu(UUR)gene. [4]

The pathogenesis of the strokelike episodes in MELAS syndrome has not been completely elucidated. [5] 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). [6]

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.

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.

MELAS syndrome 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. [7] 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.

MELAS syndrome has no reported racial predilection.

MELAS syndrome has no reported sexual predilection.

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.

MELAS syndrome widely varies in presentation; however, patients in general tend to have a poor prognosis and outcome. The encephalomyopathy tends to be severe and progressive to dementia. The patient with MELAS syndrome may end up in a state of cachexia. Currently, no therapies have proven efficacy.

Once the diagnosis is established, refer the patient and family for genetic counseling and evaluation of other family members who may be at risk of being affected.

Educate the family concerning further deteriorations and complications (eg, cardiomyopathy, nephrotic syndrome, deafness, diabetes, GI difficulties) that may affect the proband. In general, educate the family about maintaining a good nutritional and hydration status, and discuss information concerning current trials (eg, use of dichloroacetate for persistent lactic acidosis in individuals with MELAS syndrome).

For excellent patient education resources, visit eMedicineHealth’s Brain and Nervous System Center. Also, see eMedicineHealth’s patient education article Stroke.

Seidowsky A, Hoffmann M, Glowacki F, Dhaenens CM, Devaux JP, Lessore de Sainte Foy C, et al. Renal involvement in MELAS syndrome – a series of 5 cases and review of the literature. Clin Nephrol. 2012 Aug 21. [Medline].

Meseguer S, Martínez-Zamora A, García-Arumí E, Andreu AL, Armengod ME. The ROS-sensitive microRNA-9/9* controls the expression of mitochondrial tRNA-modifying enzymes and is involved in the molecular mechanism of MELAS syndrome. Hum Mol Genet. 2014 Aug 22. [Medline].

Mehrazin M, Shanske S, Kaufmann P, Wei Y, Coku J, Engelstad K. Longitudinal changes of mtDNA A3243G mutation load and level of functioning in MELAS. Am J Med Genet A. 2009 Feb 15. 149A(4):584-7. [Medline]. [Full Text].

Liu K, Zhao H, Ji K, Yan C. MERRF/MELAS overlap syndrome due to the m.3291T>C mutation. Metab Brain Dis. 2014 Mar. 29(1):139-44. [Medline].

Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Arch Neurol. 2010 Jan. 67(1):19-24. [Medline].

Sasarman F, Antonicka H, Shoubridge EA. The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet. 2008 Dec 1. 17(23):3697-707. [Medline].

Nemes A, Geleijnse ML, Sluiter W, Vydt TC, Soliman OI, van Dalen BM. Aortic distensibility alterations in adults with m.3243A>G MELAS gene mutation. Swiss Med Wkly. 2009 Feb 21. 139(7-8):117-20. [Medline].

Scarpelli M, Zappini F, Filosto M, Russignan A, Tonin P, Tomelleri G. Mitochondrial Sensorineural Hearing Loss: A Retrospective Study and a Description of Cochlear Implantation in a MELAS Patient. Genet Res Int. 2012. 2012:287432. [Medline]. [Full Text].

[Guideline] International Diabetes Center. Type 2 diabetes practice guidelines. 2003. [Full Text].

Primiano G, Plantone D, Forte F, Sauchelli D, Scaldaferri F, Gasbarrini A, et al. Acute refractory intestinal pseudo-obstruction in MELAS: efficacy of prucalopride. Neurology. 2014 May 27. 82(21):1932-4. [Medline].

Singmaneesakulchai S, Limotai N, Jagota P, Bhidayasiri R. Expanding spectrum of abnormal movements in MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Mov Disord. 2012 Oct. 27(12):1495-7. [Medline].

Fayssoil A. Heart diseases in mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome. Congest Heart Fail. 2009 Nov-Dec. 15(6):284-7. [Medline].

Dindyal S, Mistry K, Angamuthu N, Smith G, Hilton D, Arumugam P, et al. MELAS syndrome presenting as an acute surgical abdomen. Ann R Coll Surg Engl. 2014 Jan. 96(1):101E-103E. [Medline].

Betts J, Jarost E, Perry RH et al. Molecular neuropathology of MELAS; level of heteroplasmy in individual neurons and evidence of extensive vascular involvement. Neuropathology and Applied. Neurobiology. 2006. 32:359-373.

Borner GV, Zeviani M, Tiranti V, et al. Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients. Hum Mol Genet. 2000 Mar 1. 9(4):467-75. [Medline].

Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992 Apr. 31(4):391-8. [Medline].

Deschauer M, Tennant S, Rokicka A, He L, Kraya T, Turnbull DM. MELAS associated with mutations in the POLG1 gene. Neurology. 2007 May 15. 68(20):1741-2. [Medline].

Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994 Jan. 9(1):4-13. [Medline].

Hirano M, Ricci E, Koenigsberger MR, et al. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992. 2(2):125-35. [Medline].

Jacobs HT, Holt IJ. The np 3243 MELAS mutation: damned if you aminoacylate, damned if you don’t. Hum Mol Genet. 2000 Mar 1. 9(4):463-5. [Medline].

Joko T, Iwashige K, Hashimoto T, et al. A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes associated with diabetes mellitus and hypothalamo-pituitary dysfunction. Endocr J. 1997 Dec. 44(6):805-9. [Medline].

Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006 Feb 14. 66(3):324-30. [Medline].

Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005 Feb 22. 64(4):710-2. [Medline].

Matsumoto J, Saver JL, Brennan KC, Ringman JM. Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS). Rev Neurol Dis. 2005 Winter. 2(1):30-4. [Medline].

Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol. 1984 Oct. 16(4):481-8. [Medline].

Pons R, Andreu AL, Checcarelli N, Vila MR, Engelstad K, Sue CM. Mitochondrial DNA abnormalities and autistic spectrum disorders. J Pediatr. 2004 Jan. 144(1):81-5. [Medline].

Scaglia F, Northrop JL. The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options. CNS Drugs. 2006. 20(6):443-64. [Medline].

Shanske S, Coku J, Lu J, Ganesh J, Krishna S, Tanji K. The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. Arch Neurol. 2008 Mar. 65(3):368-72. [Medline].

Shimotake T, Furukawa T, Inoue K, Iwai N, Takeuchi Y. Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). J Pediatr Surg. 1998 Dec. 33(12):1837-9. [Medline].

Sue CM, Bruno C, Andreu AL, et al. Infantile encephalopathy associated with the MELAS A3243G mutation. J Pediatr. 1999 Jun. 134(6):696-700. [Medline].

Tanahashi C, Nakayama A, Yoshida M, Ito M, Mori N, Hashizume Y. MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study. Acta Neuropathol. 2000 Jan. 99(1):31-8. [Medline].

Tay SH, Nordli DR Jr, Bonilla E, Null E, Monaco S, Hirano M. Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Arch Neurol. 2006 Feb. 63(2):281-3. [Medline].

Thambisetty M, Newman NJ, Glass JD, Frankel MR. A practical approach to the diagnosis and management of MELAS: case report and review. Neurologist. 2002 Sep. 8(5):302-12. [Medline].

Koenig MK, Emrick L, Karaa A, Korson M, Scaglia F, Parikh S, et al. Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes. JAMA Neurol. 2016 May 1. 73 (5):591-4. [Medline].

El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen. 2017 Jan. 5:[Medline].

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP Chief, Pediatric Neurology, Associate Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Epileptologist, Medical Director, Tulane Center for Autism and Related Disorders, Co-Director, Developmental Neurogenetics Center, Tulane University School of Medicine

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Medical Association, Association of Military Surgeons of the US, Child Neurology Society, Southern Pediatric Neurology Society

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Biomarin; Supernus<br/>Received income in an amount equal to or greater than $250 from: Biomarin; Supernus; American Board of Pediatrics.

Sherry Gu, MD Resident Physician, Department of Pediatrics, Tulane University School of Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Luis O Rohena, MD, FAAP, FACMG Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Fernando Scaglia, MD, FACMG Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital

Fernando Scaglia, MD, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for the Study of Inborn Errors of Metabolism

Disclosure: Nothing to disclose.

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

MELAS Syndrome

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