Rare Disease Database

rarediseases.org/rare-diseases/merrf-syndrome/

MERRF Syndrome

NORD gratefully acknowledges 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

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).

Signs & 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
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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
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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.)

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-

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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.

Standard Therapies
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: [email protected]

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

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4-424B College of Physicians & Surgeons

630 West 168th Street

New York, NY 10032

Telephone: 212-305-1662

FAX: 212-305-3986

[email protected]

NORD Member Organizations

MitoAction
PO Box 51474
Boston, MA 02205
Phone: (888) 648-6228
Email: [email protected]
Website: http://www.MitoAction.org
Muscular Dystrophy Association
161 N. Clark
Suite 3550
Chicago, IL 60601 USA
Phone: (520) 529-2000
Toll-free: (800) 572-1717
Email: [email protected]
Website: http://www.mda.org/
United Mitochondrial Disease Foundation
8085 Saltsburg Road Suite 201
Pittsburgh, PA 15239 United States
Phone: (412) 793-8077
Toll-free: (888) 317-8633
Email: [email protected]
Website: http://www.umdf.org

Other Organizations
Children’s Mitochondrial Disease Network
Mayfield House
30 Heber Walk
England, CW9 5JB United Kingdom
Phone: 440160643946
Email: [email protected]
Website: http://www.emdn-mitonet.co.uk/

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 Epilepsy Foundation
8301 Professional Place
Landover, MD 20785-7223
Phone: (866) 330-2718
Toll-free: (800) 332-1000
Email: [email protected]
Website: http://www.epilepsyfoundation.org
Lactic Acidosis Support Trust
1A Whitley Close
Cheshire, CW10 0NQ United Kingdom
Phone: 160683719
Metabolic Support UK
5 Hilliards Court, Sandpiper Way
Chester Business Park
Chester, CH4 9QP United Kingdom
Phone: 0124420758108452412173
Email: [email protected]
Website: https://www.metabolicsupportuk.org/
NIH/National Institute of Neurological Disorders and Stroke
P.O. Box 5801
Bethesda, MD 20824
Phone: (301) 496-5751
Toll-free: (800) 352-9424
Website: http://www.ninds.nih.gov/
Vereniging voor Kinder met Stofwisselingsziekten
P.O. Box 664
Bloemendalstraat 11
Zwolle, 8000 AR The Netherlands
Phone: 384201764
Email: [email protected]
Website: http://www.stofwisselingsziekten.nl

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.

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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.
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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.

Years Published
1993, 1996, 1998, 1999, 2000, 2001, 2010
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