Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem mitochondrial syndrome characterized by progressive myoclonus and seizures. Other features associated with MERRF include cerebellar ataxia, myopathy, cardiac arrhythmia, sensorineural hearing loss, optic atrophy, and dementia. MERRF occurs due to genetic mutations in the mitochondrial DNA (mtDNA) with A8344G mutation in the tRNA (Lys) gene being the most common and present in more than three-fourth of the patients. The pathognomonic red-ragged muscle fibers are seen on muscle biopsy. In 1980, Fukuhara et al. gave the first detailed clinical description of MERRF; hence this condition is also known as Fukuhara syndrome. MERRF is a rare disorder and is included in the National Organization for Rare Disorders (NORD).
Mitochondria are important cellular organelles and contain their own deoxyribonucleic acid (DNA). The mtDNA is a small circular molecule composed of 16,569 base-pairs and consists of 37 genes. These genes encode for 22 transfer RNAs (tRNAs), 13 polypeptides, and 2 ribosomal RNAs (rRNAs). These genes are important for the mitochondrial respiratory chain (MRC) to generate cellular energy in the form of adenosine triphosphate (ATP). The mtDNA does not follow the laws of Mendelian inheritance and has a strict maternal inheritance. During fertilization, the zygote receives mitochondria only from the oocyte. Thus, mtDNA is transmitted vertically from mother to all her male and female offsprings.
Multiple mtDNA mutations have been identified in MERRF. The most common mutation observed is an A-to-G mutation at nucleotide 8344 (m.8344A>G) of the mtDNA lysine tRNA gene (MT-TK). It is present in about 80% of MERRF patients. Some of the other mtDNA mutations identified in MERRF are m.8356T>C, m.8363G>A, m.3243A>G, m.3255G>A, and m.3291T>C. The details of each mutation will be beyond the scope of this review.
The epidemiologic data of MERRF is largely unknown, but it is widely considered that the prevalence of MERRF is probably less than 1:100,000. In Europe, three epidemiologic studies detecting the most common MERRF mutation (m.8344A>G) revealed a prevalence of 0 to 1.5 in northern Finland and 0.39 in northern England per 100,000 adult persons. The prevalence of the same mutation in a pediatric population of western Sweden was 0 to 0.25 per 100,000. MERRF affects both males and females equally. Onset is usually in childhood or early adulthood. The actual prevalence of mitochondrial diseases may be more than the estimated numbers, as most of the cases remain undiagnosed.
Mitochondria are known as the powerhouse of the cells, and mtDNA is required for the MRC to generate ATP. It is proposed that the mutations in mtDNA disrupt MRC resulting in decreased cellular energy, ion-channel dysfunction, and neuronal cell death. Since mitochondria are present in the majority of the cells, hence these disorders involve multiple systems. Further, different tissues have different energy requirements and have a variable threshold of vulnerability to mitochondrial dysfunction, wide phenotypic variations and overlaps exist in clinical presentations among mitochondrial diseases.
Patients with MERRF present with predominant progressive myoclonic epilepsy, a characteristic feature that separates MERRF from other mitochondrial diseases. The onset of MERRF is usually in childhood. Affected children have normal early development. Myoclonus may be intermittent or continuous. It is often photosensitive and aggravated by action and stimuli. Most of these patients also experience other types of seizures in addition to myoclonus. The seizures may be of generalized tonic-clonic, atonic or absence types.
In addition to seizures, patients with MERRF commonly develop cerebellar ataxia, sensorineural deafness, short stature, cutaneous lipomas, and a clinical myopathy that may be indistinguishable from limb-girdle muscular dystrophy. Cardiac arrhythmias, particularly Wolff-Parkinson-White syndrome, and cardiomyopathy are also frequently seen. Cognitive decline and dementia also occur but late in the disease.
Clinical symptoms of MERRF are highly variable among patients, even within the same family. The degree of mitochondrial heteroplasmy (proportion of normal and abnormal mtDNA in each tissue) is one of the reasons for this variability. Occasionally, patients with MERRF also have strokes (MERRF/MELAS overlap) or progressive external ophthalmoplegia and retinopathy ( MERRF/Kearns-Sayre syndrome overlap) making it difficult to diagnose clinically.
The lactic acid levels are typically increased in both blood and cerebrospinal fluid (CSF) in symptomatic as well as the asymptomatic patients with MERRF. The lactic acid is further increased after physical activity and exercise. CSF protein is also raised but often does not exceed 100mg/dl. A raised creatine kinase (CK) often demonstrates myopathy.It is also important to exclude other treatable causes that may mimic mitochondrial disease. These include autoimmune inflammatory disorders, endocrinopathies (diabetes mellitus, adrenal, thyroid, and parathyroid disorders), vitamin B12 deficiency, and disorders of collagen formation.
Magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the brain may reveal early gray matter changes, while the white matter changes occur late in the disease. Other imaging features seen in MERRF are cerebral atrophy, cerebellar atrophy with dentate nucleus calcification, and changes in the red nucleus as a result of progressive neuronal loss. Magnetic resonance spectroscopy (MRS) may be helpful in the diagnosis of MERRF. It reveals a high lactic acid peak.
Electroencephalogram (EEG) may reveal a slow background activity with generalized epileptiform discharges, which may precipitate with photic stimulation. These EEG features may also be seen in MELAS and other progressive myoclonic epilepsies.Electromyography and nerve conduction studies (EMG/NCS) may reveal small polyphasic motor units with early recruitment consistent with a myopathic process. However, a concomitant neuropathy may be present in some patients.
A muscle biopsy is important in the diagnosis of mitochondrial disorders, including MERRF. The typical red-ragged fibers are pathognomonic and are present in more than 90% of patients with MERRF. These stain more strongly with succinate dehydrogenase (SDH) as compared to modified trichrome Gomori (TGM), unlike other mitochondrial diseases. This histological difference may be explained by a deficient cytochrome c oxidase (COX) activity in muscle fibers of patients with MERRF.
Genetic testing is available for the diagnosis of MERRF. The most common mutation observed is an A-to-G mutation at nucleotide 8344 (m.8344A>G) of the mtDNA lysine tRNA gene (MT-TK). It is present in about 80% of MERRF patients. Some of the other mtDNA mutations identified in MERRF are m.8356T>C, m.8363G>A, m.3243A>G, m.3255G>A, and m.3291T>C. If a mutation is present in a family, molecular genetic testing can be used to evaluate the at-risk relatives.
There is no specific treatment for MERRF, similar to other mitochondrial disorders. This condition cannot be cured. Multiple therapeutic agents are tried to decrease the decrease progression with variable results. These therapeutic agents include coenzyme Q10 (CoQ), vitamin B-complex supplementation, and L-carnitine.
The symptomatic management of the complications is the cornerstone in patients with MERRF. Antiepileptic drugs are given for myoclonic seizures and epilepsy. Although sodium valproate is typically the recommended drug for myoclonic epilepsies, it should be used with caution in mitochondrial diseases as it inhibits carnitine uptake and may precipitate liver failure. Carbamazepine, oxcarbazepine, and phenytoin may worsen the myoclonic episodes. No head-to-head clinical drug trials are available for the treatment of epilepsy in patients with MERRF, but some authors recommend levetiracetam, topiramate, clonazepam, or zonisamide. Other complications, e.g., cardiac arrhythmia, deafness, and myopathy, are treated accordingly. It is also important to avoid drugs and toxins with adverse mitochondrial effects, for example, aminoglycoside antibiotics, linezolid, cigarettes, and alcohol.
The myoclonus in MERRF may be clinically indistinguishable from other progressive myoclonus epilepsies, e.g., Unverricht-Lundborg, Lafora body disease, neuronal ceroid lipofuscinosis, or sialidoses. Increased lactic acid, muscle biopsy features of red-ragged fibers, and genetic testing usually confirm the diagnosis.
Sometimes, MERRF may also be difficult to diagnose from other mitochondrial disorders, especially with the overlapping features of multiple strokes (MERRF/MELAS overlap) or progressive external ophthalmoplegia and retinopathy (MERRF/Kearns-Sayre syndrome overlap).
MERRF is a chronic condition, which is slowly progressive. As explained above, different individuals become symptomatic with different phenotypes and at different ages, even within the same family. Hence, the exact prognosis is difficult to ascertain, but usually, it is poor.
Patients with MERRF are at increased risk for cardiac arrhythmia and ventricular dysfunction resulting in cardiac failure and sudden death. They are also at high-risk for head trauma due to seizures, respiratory complications, kyphoscoliosis, diabetes mellitus, and thyroid problems.
Patient and family education is very important regarding the progressive and multisystem nature of this disease. A male with MERRF having a mutated mtDNA cannot transmit the disease to any of his offspring. A female having a mutated mtDNA will transmit the disease to all of her offspring. Further, prenatal diagnosis for MERRF is also possible if MERRF has been detected in the mother.
Affected persons with MERRF and their asymptomatic at-risk relatives should have a regular follow-up (e.g., every 6 to 12 months initially) for disease monitoring and the appearance of new symptoms. It is recommended to have an annual neurologic, ophthalmologic, cardiology, and endocrinologic evaluations to screen for complications.
MERRF is a multisystem disease. It needs a team of specialists for optimal care. Affected persons with MERRF and their asymptomatic at-risk relatives should have a regular follow-up (e.g., every 6-12 months initially) for disease monitoring and the appearance of new symptoms.
It is recommended to have annual neurologic (epilepsy control), ophthalmologic (for vision changes), cardiology (electrocardiogram and echocardiogram), and endocrinologic evaluations (for diabetes and thyroid problems). Physiotherapy, occupational therapy, and rehabilitation are important for improving the quality of life and prevent complications.
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