Myoclonic epilepsy associated with ragged red fibers (MERRF)
Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder characterized by a range of neurological and muscular symptoms, including myoclonus (involuntary muscle twitching), seizures, muscle weakness, and cerebellar ataxia (problems with coordination). Additional symptoms may include hearing loss, cardiomyopathy, and intellectual disability. MERRF is caused by mutations in mitochondrial DNA (mtDNA), primarily affecting the tRNA lysine gene (MT-TK), which is inherited maternally. The incidence of MERRF is quite low, with estimates suggesting fewer than 1 in 100,000 individuals are affected. Diagnosis typically involves biochemical analysis and muscle biopsy, where characteristic ragged red fibers can be observed. Currently, there is no known cure for MERRF, and treatment focuses on managing symptoms, including the use of antiepileptic medications and supportive therapies. Prognosis varies widely based on factors such as age of onset and severity of symptoms, highlighting the complex nature of this condition. Research into potential future therapies is ongoing, aiming to address the underlying genetic defects.
Myoclonic epilepsy associated with ragged red fibers (MERRF)
ALSO KNOWN AS: MERRF syndrome; Fukuhara disease; myoencephalopathy ragged-red fiber disease
DEFINITIONMyoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disease characterized by muscle weakness, myoclonus, seizures, intellectual disability, cerebellar ataxia, and abnormal proliferation of mitochondria in the muscle fiber also called ragged red fiber (RRF). Other clinical symptoms include hearing loss, muscle weakness, cardiomyopathy, and multiple lipomas. It is a maternally inherited genetic disease caused by mutations in the mitochondrial DNA (mtDNA). A few sporadic cases are known, and some patients present with clinical symptoms with no mutation.
Risk Factors
The incidence of MERRF in the population is very low, with 2023 estimates placing it at less than 1 in 100,000 people. Age of onset is usually after the first or second decade of life. Early onset is very rare. An onset at two months has been reported in a case with 98 percent of mutation in the muscle, and the patient died at eleven months. MERRF is caused by three documented point mutations in the mitochondrial tRNA lysine gene (MT-TK). Mutations in the MT-TK gene account for more than 80 percent of all cases. Less common causes of MERRF include mutations in the MT-TL1, MT-TH, and MT-TS1 genes, and individuals with mutations in these genes may display symptoms of other mitochondrial diseases in addition to those of MERRF. The mutations are inherited maternally; mothers carry the mutation, and both male and female offspring can be affected. Furthermore, mothers and family members harboring the mutation may be asymptomatic.
MERRF, as with other mtDNA diseases, resembles “recessive” mutations because low levels of mutation may not cause clinical symptoms. The symptoms are manifested only when the level of mutations in the affected tissues is above a threshold value.
Etiology and Genetics
Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disease caused by mutations in the mtDNA. A few sporadic cases have been reported. The mutations are maternally inherited because mtDNA is inherited exclusively from the mother. Three mtDNA mutations in the tRNA lysine gene MT-TK (A8344G, T8356C, G8363A) have been associated with MERRF.
MERRF is mainly characterized by myoclonus (involuntary muscle twitches), seizures, myopathy (muscular weakness), and cerebellar ataxia (difficulty coordinating voluntary movements). Other symptoms include hearing loss, dementia, multiple lipomas, cardiomyopathy, and peripheral neuropathy.
The G8363A mutation is associated with cardiomyopathy, hearing loss, and psychiatric symptoms with no other typical features of MERRF. In most cases, high mutation levels (80 to 90 percent) in the muscle correlate with severity of clinical symptoms. Ragged red fibers due to accumulation of mitochondria in the muscle, a hallmark of MERRF, can be seen microscopically after staining.
Serum levels of pyruvate and lactate are high. Biochemical assays of respiratory chain enzymes have revealed low COX (complex IV) and complex I activities. Histochemical staining has revealed a mosaic pattern of positive and negative staining of COX and complex I fibers. RRFs have all been negative for COX and complex I.
The mutation causes defects in mitochondrial protein synthesis, which in turn results in respiratory chain dysfunction in tissues like the brain and muscle, causing severe clinical symptoms.
Adequate treatment for MERRF is lacking and is largely symptomatic. Antiepileptic drugs are used to control seizures, and physical therapy and aerobic exercise may improve impaired motor function. Therapeutic strategies have involved replacing the mutated mtDNA with normal molecules in cultured cells, which partially restored mitochondrial function. These are promising strategies that may yield results in the future.
Symptoms
The most characteristic symptoms of MERRF are myoclonus (sudden jerky movements and muscle spasms), epileptic seizures, cerebellar ataxia or impaired coordination of movement, muscle weakness, and wasting. Other symptoms may include hearing loss, short stature, dementia, and cardiac, eye, and speech impairments.
Screening and Diagnosis
Biochemical analysis of respiratory chain enzymes shows deficiency of complexes I and IV (cytochrome c oxidase, COX). Histochemical staining of muscle biopsy shows RRF when stained for succinic dehydrogenase. The RRFs are typically COX-negative, which differentiates MERRF from other mitochondrial diseases. Fibroblasts and muscle cells are also usually COX-negative. Neuropathologic changes include degeneration of the brain stem and cerebellum. Magnetic resonance imaging shows cerebellar atrophy in the brain. The level of mutation in tissues is assessed by restriction fragment length (RFLP) analysis. All these clinical and laboratory findings are diagnostic of MERRF.
Treatment and Therapy
Currently, there is no cure for MERRF. Treatment for MERRF in particular, or for mitochondrial diseases in general, is also inadequate. A “mitochondrial cocktail” composed of several compounds such as succinate, riboflavin, coenzyme Q10, vitamins E and C, and alpha lipoic acid is administered to correct mitochondrial dysfunction in patients. Additionally, symptomatic therapy to alleviate seizures, myoclonus, associated cardiomyopathy, or failure to thrive is available. Research into correcting the genetic defect is in progress.
Prevention and Outcomes
Prognosis depends on age of onset, severity of symptoms, organs involved, and other factors. Patients with high levels of the mutation in tissues have poor prognosis due to the progressive myopathy, cardiomyopathy, and brain involvement. Diagnostic criteria are of limited use when counseling parents considering having children. Prenatal testing or preimplantation genetic diagnosis is not possible.
Bibliography
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