MERRF syndrome is a rare genetic disease caused by structural and biochemical defects of mitochondria, characterized by severe damage to the central nervous system and muscle tissue. The clinical picture may differ even within the same family. Symptoms include various types of epileptic seizures, impaired coordination, and muscle weakness. The confirming diagnostic methods are histological examination of the muscle biopsy and DNA analysis. There is no specific treatment, symptomatic therapy is carried out with neurometabolic, anticonvulsants, drugs that improve mitochondrial function.
G31.8 Other specified degenerative diseases of the nervous system
MERRF syndrome belongs to the group of hereditary mitochondrial encephalomyopathies. MERRF is an abbreviation meaning “myoclonus (M) epilepsy (E) with torn (R) red (R) fibers (F)”. The disease was first described by Japanese neurologist N. Fukuhara in 1980. According to various epidemiological data, the prevalence of MERRF syndrome ranges from 0.25:100,000 to 1.5:100,000 of the population. Inheritance occurs only on the maternal side, while both sexes suffer with the same frequency.
The occurrence of MERRF syndrome is caused by point mutations of mitochondrial DNA, namely, changes in the nucleotide sequence. The most frequent are the replacement of adenine with guanine at position 8344 of the lysine transport RNA or the replacement of thymine with cytosine at position 8356. This leads to disruption of the formation of mitochondrial proteins.
The clinical development of MERRF syndrome depends on the number of defective DNA, i.e. the more mitochondrial DNA having a mutation, the higher the risk of the disease. Absolutely asymptomatic carriage of mutant genes is also possible. There are no significant risk factors that can provoke the manifestation of this pathology.
As a result of a genetic mutation in mitochondria, the synthesis of respiratory chain enzymes (cytochrome oxidase, succinate dehydrogenase, etc.) fails. The processes of oxidative phosphorylation are disrupted – the most important stage in the energy metabolism of cells, which ensures the formation of the main number of ATP molecules (a universal source of energy for cells).
These phenomena occur in almost all cells of the body. The most severely damaging effect affects organs with a high energy requirement – the central nervous system and muscles. Due to tissue hypoxia, excess lactic acid accumulates in the muscles, which leads to damage to muscle fibers.
In modern neurology, there are no clear official divisions of MERRF syndrome into separate forms. Depending on the number of point mutations and clinical manifestations , the following varieties can be distinguished:
- Asymptomatic – there is a genetic mutation with the possibility of hereditary transmission in the complete absence of symptoms.
- Latent – “soft flow” without involving the nervous system. Patients may be concerned about moderate muscle weakness.
- Manifest – a vivid clinical picture with a severe course and an unfavorable prognosis.
MERRF syndrome can make its debut at almost any age. The onset in childhood is associated with a more unfavorable prognosis. Early signs are considered to be increased muscle fatigue, deterioration of exercise tolerance, aching pains in the calf muscles. Due to the gradual progression of myopathy, muscle weakness becomes more pronounced – the patient experiences difficulties when climbing stairs, walking. In severe cases, the patient can get out of bed with great effort.
Epileptic seizures are typical, which can be diverse – involuntary twitching of the muscles of the face or hands without loss of consciousness (myoclonia), paroxysms like nodding of the head, generalized tonic-clonic seizures with loss of consciousness. Myoclonia is often provoked by sharp sounds or a flash of light. Coordination is disrupted, instability occurs when walking, standing.
Cognitive functions suffer significantly, memory and concentration of attention decrease. Vision and hearing gradually deteriorate. In some cases, peripheral neuropathies are observed, manifested by numbness, burning sensation, tingling (paresthesia) in the extremities. Very rarely there are skin formations – lipomas, hemangiomas, warty nevi.
MERRF syndrome is considered a serious disease with a large number of complications. The most unfavorable of them are epileptic status and cerebral edema. Due to severe myopathy of the pharyngeal muscles, swallowing may be impaired and food may enter the respiratory tract, which will lead to the development of aspiration pneumonia. Also, due to the weakness of the respiratory muscles, respiratory failure occurs.
Optic nerve atrophy and retinal pigment degeneration in some patients causes complete loss of vision. With early clinical manifestation, the child significantly lags behind in physical and neuropsychic development. Imbalance increases the risk of falls and fractures. Very rarely there is chronic pancreatitis and diabetes mellitus.
Patients with MERRF syndrome are supervised by neurologists. Children’s patients are under the joint supervision of pediatric neuropathologists and pediatricians. During the examination, attention is drawn to a general decrease in muscle tone, weakening of tendons and the presence of pathological reflexes (Babinsky, Oppenheim), failure to perform coordination tests – Romberg pose, heel-knee, finger-nasal tests. Additional examination includes:
- Laboratory tests. In the biochemical analysis of blood, an increase in the concentration of lactic acid is noted. A high protein content is detected in the liquor.
- EEG. On the electroencephalogram, it is possible to detect epileptiform activity – generalized spike-wave complexes, diffuse slow waves.
- Tomography. On MRI of the brain, atrophy of the cortical and white matter of the large hemispheres and cerebellum, calcification of the basal ganglia is visible.
- ENMG. During electroneuromyography, there is a decrease in the amplitude and duration of the potentials of motor units, which indicates a lesion of muscle tissue.
- Histological examination. One of the main diagnostic tests of MERRF syndrome. In the muscle biopsy, signs of atrophy are revealed – a decrease in the size of muscle fibers, their pale staining, endomysial and perimysial sclerosis. When histological sections are stained using the Gomori method, the presence of “torn red fibers” is detected in more than 5% of muscle fibers.
- DNA analysis. The main method for verifying the diagnosis. Molecular genetic research finds mutations in mitochondrial DNA – A8344G or T8356C.
MERRF syndrome should be differentiated from other mitochondrial diseases (MELAS syndrome), as well as with hereditary metabolic disorders affecting muscle tissue and the nervous system:
- Myoclonus-Unferricht-Lundborg epilepsy;
- Lafora’s disease;
- accumulation diseases (Gaucher’s disease, leukodystrophy, gangliosidosis).
To date, there are no effective ways to treat this pathology. All measures are symptomatic and palliative in nature, aimed at improving the patient’s condition. To slow down atrophic processes in muscle tissue, physical therapy is mandatory. The regression of symptoms is facilitated by a carbohydrate-restricted diet.
Individual consultations of a speech pathologist, psychologist, speech therapist are recommended for children with mental retardation. Drug therapy is carried out according to the general principles of treatment of mitochondrial diseases and includes 2 main groups of medications:
- Metabolic drugs. In order to improve the processes of cellular respiration, a complex of energotropic drugs (“mitochondrial cocktail”) is used, which includes enzyme cofactors (B vitamins), agents that stimulate electron transfer in the respiratory chain (coenzyme Q10) and antioxidants (ascorbic acid, tocopherol).
- Anticonvulsants. To prevent epileptic seizures, anticonvulsant medications are prescribed – clonazepam, lamotrigine, topiramate. Valproic acid and its derivatives are strictly contraindicated, as they inhibit mitochondrial function. Their use leads to a sharp deterioration of the patient’s condition.
Prognosis and prevention
Life expectancy, the probability of death in MERRF syndrome can vary greatly in different patients. With a low-symptomatic course (absence of damage to the nervous system, moderate myopathy), systematic non-drug and drug treatment, life expectancy may not differ from that in the general population.
With the unfolded flow, the prognosis is extremely unfavorable. The fatal outcome occurs within 10-15 years from the onset of the disease. The main causes of death are epileptic status, aspiration, respiratory failure. The only specific method of prevention is prenatal diagnosis and termination of pregnancy.