Myoclonic epilepsy with ragged red fibers

Alternate names

Merrf syndrome; MERRF; Myoclonic epilepsy associated with ragged red fibers; Fukuhara syndrome; Myoencephalopathy ragged-red fiber disease

Definition

Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem disorder characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia.

Summary

• Myoclonic epilepsy with ragged-red fibers (MERRF) is a disorder that affects many parts of the body, particularly the muscles and nervous system.
• In most cases, the signs and symptoms of this disorder appear during childhood or adolescence.
• The features of MERRF vary widely among affected individuals, even among members of the same family.

Onset

Symptoms usually first appear in childhood or adolescence after normal early development.

Epidemiology

MERRF is a rare condition; its prevalence is unknown. MERRF is part of a group of conditions known as mitochondrial disorders, which affect an estimated 1 in 5,000 people worldwide.

Cause

• Mutations in the MT-TK gene are the most common cause of MERRF, occurring in more than 80 percent of all cases.
• Less frequently, mutations in the MT-TL1, MT-TH, and MT-TS1 genes have been reported to cause the signs and symptoms of MERRF.
• People with mutations in the MT-TL1, MT-TH, or MT-TS1 gene typically have signs and symptoms of other mitochondrial disorders as well as those of MERRF.
• The MT-TK, MT-TL1, MT-TH, and MT-TS1 genes are contained in mitochondrial DNA (mtDNA).
• Mitochondria are structures within cells that use oxygen to convert the energy from food into a form cells can use through a process called oxidative phosphorylation.
• Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA.
• The genes associated with MERRF provide instructions for making molecules called transfer RNAs, which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria. These proteins perform the steps of oxidative phosphorylation.

Gene mutations

• Mutations that cause MERRF impair the ability of mitochondria to make proteins, use oxygen, and produce energy.
• These mutations particularly affect organs and tissues with high energy requirements, such as the brain and muscles. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of MERRF.
• A small percentage of MERRF cases are caused by mutations in other mitochondrial genes, and in some cases the cause of the condition is unknown.

Inheritance

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Mitochondrial inheritance patterns

• MERRF is inherited in a mitochondrial pattern, which is also known as maternal inheritance.
• This pattern of inheritance applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.
• In most cases, people with MERRF inherit an altered mitochondrial gene from their mother, who may or may not show symptoms of the disorder. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MERRF.

Signs and symptoms

• Because muscle cells and nerve cells have especially high energy needs, muscular and neurological problems are common features of diseases that affect the mitochondria.
• MERRF is a progressive multi-system syndrome with symptoms that begin during childhood, but onset may occur in adulthood.
• The rate of progression varies widely.
• Onset and extent of symptoms can differ widely from individual to individual and among affected siblings.

The classic features of MERRF include:

• Myoclonus (brief, sudden, twitching muscle spasms) – the most characteristic symptom
• Epileptic seizures
• Ataxia (impaired coordination)
• Ragged-red fibers (a characteristic microscopic abnormality observed in muscle biopsy of patients with MERRF and other mitochondrial disorders)
• Additional symptoms may include: hearing loss, lactic acidosis (elevated lactic acid level in the blood), short stature, exercise intolerance, dementia, cardiac defects, eye abnormalities, and speech impairment.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of movement(Movement disorder)
• Ataxia
• EMG abnormality
• Generalized myoclonic seizure
• Myopathy(Muscle tissue disease)
• Ragged-red muscle fibers
• Sensorineural hearing impairment

30%-79% of people have these symptoms

• Cognitive impairment(Abnormality of cognition)
• Multiple lipomas(Multiple fatty lumps)
• Optic atrophy
• Short stature(Decreased body height)

Diagnosis

• In some individuals, the clinical picture is characteristic of a specific mitochondrial disorder , and the diagnosis can be confirmed by identification of a pathogenic mtDNA variant on molecular genetic testing of DNA extracted from a blood sample.
• In many individuals, such is not the case, and a more structured approach is needed, including family history, blood and/or CSF lactate concentration, neuroimaging, cardiac evaluation, and molecular genetic testing for a mtDNA or nuclear gene pathogenic variant.
• Approaches to molecular genetic testing of a proband to consider are serial testing of single genes, multigene panel testing (simultaneous testing of multiple genes), and/or genomic testing (e.g., sequencing of the entire mitochondrial genome, genome sequencing, or exome sequencing to identify a pathogenic variant in a nuclear gene).
• In many individuals in whom molecular genetic testing does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function.[1].

Treatment

While there is no cure for MERRF, there are various medications and therapies that can be helpful in managing symptoms. This includes: Antiseizure medications, levetiracetam for myoclonus, physical therapy, and aerobic exercise. Standard medication is used to treat cardiac symptoms. Daily use of Coenzyme Q10 and L-carnitine have been of some benefit to individuals. Other supplements that might be utilized include creatinine and lipoic acid.

NIH genetic and rare disease info

• NIH info on Myoclonic epilepsy with ragged red fibers

Myoclonic epilepsy with ragged red fibers is a rare disease.

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