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MERRF Syndrome

NORD is very grateful to Salvatore DiMauro, MD, Lucy G. Moses Professor of Neurology, Columbia University Medical Center, for assistance in the preparation of this report.

Synonyms of MERRF Syndrome

  • Fukuhara syndrome
  • MERRF
  • myoclonus epilepsy associated with ragged red fibers
  • myoencephalopathy ragged-red fiber disease

Disorder Subdivisions

  • No subdivisions found.

General Discussion

MERRF (Myoclonus Epilepsy with Ragged-Red Fibers) syndrome is an extremely rare disorder that begins in childhood and affects the nervous system and skeletal muscle as well as other body systems. The distinguishing feature in MERRF is myoclonus, consisting of sudden, brief, jerking spasms that can affect the arms and legs or the entire body. In addition, individuals with MERRF syndrome may have muscle weakness (myopathy), an impaired ability to coordinate movements (ataxia), seizures, and a slow deterioration of intellectual function (dementia). Short stature, degeneration of the optic nerve (optic atrophy), hearing loss, cardiomyopathy and abnormal sensation from nerve damage (peripheral neuropathy) are also common symptoms. Abnormal muscle cells are present and appear as ragged red fibers (RRF) when stained with the modified Gomori trichrome and viewed microscopically. MERRF is caused by mutations in mitochondrial DNA (mtDNA).

Symptoms

Symptoms of MERRF syndrome can begin in childhood, adolescence or early adulthood after a period of normal development. Symptoms and physical findings associated with MERRF syndrome vary greatly between affected individuals in the same family and between different families. Myoclonus is usually the first symptom followed by seizures, ataxia, muscle weakness and dementia. Short stature, degeneration of the optic nerve (optic atrophy), hearing loss, and altered sensation (pins-and-needles or pain) from nerve damage (peripheral neuropathy) are also common symptoms. Cardiomyopathy and the heart rhythm abnormality known as Wolff-Parkinson-White syndrome are frequently present. Occasional symptoms include benign fat cell tumors (lipomas), especially around the neck, and eye abnormalities involving melanin in the retina (pigmentary retinopathy).

People with MERRF syndrome have an accumulation of lactic acid in the blood (lactic acidosis) and often complain of vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing.

Causes

MERRF syndrome is caused by mutations in mitochondrial DNA (mtDNA).
Mutations affecting the genes of mtDNA are inherited from the mother. MtDNA in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass it on to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, carry the blueprints for regulating energy production.

Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mtDNAs may be out-numbered by the number of normal mtDNAs. Symptoms may not appear in any given generation until the mutation affects a significant proportion of mtDNAs. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.

Mutations in the mtDNA gene MT-TK are associated with MERRF in approximately 90% of cases. One particular MT-TK mutation, m.8344A>G, accounts for 80% of cases. Mutations in MT-TL1, MT-TH, MT-TS1, MT-TS2 and MT-TF have also been associated with MERRF.

A few cases of MERRF syndrome appear to occur as the result of a new spontaneous mutation in a mitochondrial gene and are not inherited.

Affected Populations

MERRF syndrome is a rare disorder that affects males and females in equal numbers. Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like MERRF syndrome.

Related Disorders

Kearns-Sayre syndrome is a rare neuromuscular disorder characterized by three primary findings: progressive paralysis of eye muscles (chronic progressive external ophthalmoplegia); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart block (less frequently, heart disease (cardiomyopathy)) . Other findings may include muscle weakness, short stature, hearing loss, inability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). (For more information on this disorder, choose "Kearns Sayre" as your search term in the Rare Disease Database.)

MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome is a disorder that begins in childhood and affects mostly the nervous system and muscle. The most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. MELAS is caused by mutations in mitochondrial DNA. Diabetes mellitus and paralysis of eye muscle (chronic progressive external ophthalmoplegia) are often present in isolation or in association with other symptoms. (For more information on this disorder, choose "MELAS" as your search term in the Rare Disease Database.)

Leigh syndrome (LS) is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, with impairment of respiratory and kidney function.

There are several different genetically determined enzyme defects that can cause Leigh syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain (most commonly complex I or complex IV) or of the pyruvate dehydrogenase complex. In most cases, Leigh syndrome is inherited as an autosomal recessivedisorder. However, some forms are inherited as X-linked recessive or mitochondrial (maternal)disorders. (For more information on this disorder, choose "Leigh" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
MERRF is diagnosed based on clinical findings and molecular genetic testing.

Clinical testing may include measurement of lactate and pyruvate concentrations in blood and CSF. CSF protein may also be elevated in MERRF syndrome. Brain imaging techniques such as magnetic resonance imaging (MRI) may be used to look for stroke-like lesions and magnetic resonance spectroscopy (MRS) is used to look for lactate in the brain. Electrocardiogram may be used to diagnose heart rhythm abnormalities. Muscle biopsy will usually show ragged red fibers.

The mtDNA mutations associated with MELAS can usually be detected in white blood cells, but due to heteroplasmy (see Causes), other tissue samples may be necessary such as skin, saliva, hair follicles, urinary sediment and skeletal muscle.

Treatment
No specific treatment is available for MERRF syndrome. Anti-convulsant drugs are used to help prevent and control seizures associated with MERRF syndrome. Levetiracetam has been effective in controlling myoclonus in a small number of patients. Therapies are sometimes used to increase energy production by the mitochondria and slow the effects of the condition. Coenzyme Q10 and L-carnitine have been beneficial in some patients.

Physical therapy and aerobic exercise may help to improve muscle weakness, stiffness and motor function.

Genetic counseling is recommended for affected individuals and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about MERRF syndrome:

Salvatore DiMauro, MD
Lucy G. Moses Professor of Neurology
4-424B College of Physicians & Surgeons
630 West 168th Street
New York, NY 10032
Telephone: 212-305-1662
FAX: 212-305-3986
sd12@columbia.edu

MERRF Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS.
Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2478.

Adams, RD, et al, eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:986.

Fauci AS, et al, eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2454, 2480.

Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:2167.

Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1715.

Lyon G, et al, eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:256-57.

Scriver CR, et al, eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:1560-62.

Menkes JH, au, Pine JW, et al, eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:852.

Buyse ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1190.

JOURNAL ARTICLES
Nissenkorn A, et al, Neurologic presentations of mitochondrial disorders. J Child Neurol. 2000;15:44-48.

Stratilova L, et al. Various manifestations of the A8344G mt DNA heteroplasmic mutation in 4 families with the MERRF syndrome. Cas Lek Cesk. 1999;138:401-05.

Fukuhara N. MERRF. Ryoikibetsu Shokogun Shirizu. 1999;27:188-90.

Chinnery PF, et al. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain. 1998;121:1889-94.

Noer AS, et al., A tRNA (lys) mutation in the mtDNA is the causal genetic lesion underlying myoclonic epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet. 1991;49:715-22.

Palca J. The other human genome. Science. 1990;249:1104-05.

Berkovic SF, et al. Myoclonus epilepsy and ragged-red fibers (MERRF). A clinical pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study. Brain. 1989;112:1231-60.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:545000; Last Update:5/5/10.

Genetics Home Reference-U.S. Library of Medicine. http://ghr.nlm.nih.gov/condition/myoclonic-epilepsy-with-ragged-red-fibers Updated 12/09. Accessed 9/10.

DiMauro S and Hirano M. (Updated 8/18/09). MERRF. In GeneReviews at Genetests: Medical Genetics Information resource (database online). Copyright, University of Washington, Seattle. 1997-2010. Available at http://www.genetests.org. Accessed 9/10.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2010/09/30 00:00:00 GMT+0

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