MERRF syndrome is a maternally inherited mitochondriopathy. The disorder manifests predominantly as encephalopathy with muscle weakness and epilepsy. A causal therapy is not yet available.
What is MERRF syndrome?
Mitochondria are cell organelles that are known as the powerhouse of the cell. They are responsible for providing energy in the form of ATP. In mitochondriopathies, there is damage to or malfunction of these power plants. All mitochondriopathies have weakness in common as a leading symptom. Medicine distinguishes between inherited primary and acquired secondary mitochondriopathies. MERRF (Myoclonic Epilepsy with Ragged Red Fibers) syndrome is a primary or inherited mitochondriopathy with atypical, oligo- and asymptomatic mutation carriers. The disease manifests clinically as mitochondrial encephalopathy. It is a progressive disease that usually begins in early adulthood. The disease often overlaps with other diseases from the group of mitochondriopathies. Most frequently, there is an overlap with the MELAS syndrome. The complex of MELAS and MERRF syndrome is called MERRF/MELAS overlap syndrome. The prevalence of mitochondriopathies for children is 1:5000 or 17 per 100000 population. The exact proportion of MERRF syndrome remains unclear to date.
Causes
MERRF syndrome is caused by a mutation. Most commonly, patients suffer from a point mutation that causes tRNA misexpression. In a large proportion of cases, the point mutations occur on the tRNA Lys gene at position 8344 and thus affect mitochondrial DNA. The mutation is a maternally inherited mutation. The point mutation of A8344G causes disorders in codon-anticodon recognition. Unperturbed codon-anticodon recognition is all-important for post-transcriptional modification. Due to the mutation, the modification of tRNA-Lys at the wobble base U34 is disturbed for patients of MERRF syndrome. As a consequence, the synthesis of mitochondrial proteins is impaired. Since mitochondrial proteins are responsible for oxidative phosphorylation, patients suffer from disturbed phosphorylation processes. Cell deaths are the consequence. In addition, there is usually a reduced activity of respiratory chain complexes. Heteroplasmy is also characteristic. In addition to the mutated DNA, a certain amount of normal DNA is also present. The ratio between these components changes in the progressive course of the disease.
Symptoms, complaints, and signs
Neuromuscular complaints are the leading symptom of MERRF syndrome. These complaints include myoclonias and muscle weakness. Myoclonias manifest as involuntary twitching of single muscle groups or muscles. Central nervous deficits of various kinds may also occur. Epileptic seizures that develop progressively are also characteristic. The frequency and severity of the seizures increase accordingly in the course of the disease. Hearing loss may be present as an accompanying symptom. Cerebellar ataxias and other movement impairments are also conceivable. Fine motor skills as well as gross motor skills and balance are disturbed. In addition to polyneuropathies, short stature, cardiac insufficiency, and decreased respiratory drive may be present. Accompanying symptoms may include endocrine disorders or lipomas. In addition, the affected persons often suffer from mental retardation or demential brain changes. The musculature of the patients is affected by the characteristic changes in the form of “ragged red fibers”. Ragged red fibers appear in individual muscle groups. As an encephalopathy, MERRF syndrome affects the brain in its entirety. This is especially true for the degenerative mitochondrial cell deaths. If there is overlap with MELAS syndrome, other symptoms may be added.
Diagnosis and disease progression
Diagnosis of MERRF syndrome is a complex process. In addition to a family history, the patient’s neurologic status is obtained. Laboratory findings reveal an elevated lactate level with increase in the exercise test. The MRI image may show lesions or atrophy in the cerebellum, brainstem, or basal ganglia. Muscle biopsy can detect diffusely circumscribed, reddish muscle fibers. Definitive certainty is provided by genetic diagnostics using molecular genetic testing.PCR amplification and gel electrophoretic sequence analyses are used for molecular genetic diagnostics. Molecular genetic testing enables particularly early diagnosis. Prenatal diagnoses are conceivable. For a postnatal diagnosis, the physician estimates the overlap with other mitochondriopathies and obtains an overview of the previously affected brain regions. For prenatal diagnosis, prognosis is often difficult. However, MERRF syndrome is generally associated with severe disability or even lethal outcome. The exact prognosis depends strongly on the individual patient’s disease course.
Complications
Primarily, MERRF syndrome results in severe muscle weakness. As a result, affected individuals can no longer easily perform certain activities of daily living or various sports and are also dependent on the help of other people for some activities. The quality of life is considerably reduced by the MERRF syndrome. Likewise, the ability to cope with stress decreases. Most patients also suffer from epilepsy due to the syndrome. In the worst case, this can lead to the death of the patient. Furthermore, restrictions in movement and balance disorders occur. Those affected also suffer from heart defects and short stature. Not infrequently, MERRF syndrome also causes mental disorders, so that the affected persons usually also suffer from severe mental retardation. Also for the relatives and for the parents the syndrome can lead to psychological discomfort or to depressive moods. A causal treatment of the MERRF syndrome is not possible. The symptoms themselves are limited with the help of medication and therapy. In most cases, MERRF syndrome does not lead to a reduction in life expectancy. However, not all symptoms can be cured either.
When should you see a doctor?
If the affected person suffers from problems with the muscles, this is considered unusual. If the complaints persist or increase in intensity, a doctor is needed. If there are twitches in the muscle fibers, impaired muscle strength, or pain, a doctor’s visit is needed. If muscle weakness is noticed or if there is an untraceable reduction in muscle strength, action is required. A doctor should be consulted to determine the cause of the disorders. If there are limitations in mobility, gross motor movements or disturbances in balance, a doctor should be consulted. If the affected person suffers from hearing loss, changes in memory or a decrease in mental capacity, a doctor should be consulted. A loss of memory is a warning signal of the organism for a present illness, which must be clarified. Short stature, problems with the heart rhythm and disturbances of the respiratory activity are further indications of an irregularity. Medical examinations must be initiated to determine the cause. If breathing stops, sleep disturbances or anxiety occur due to the existing health impairments, a doctor is needed. If epileptic seizures occur, an ambulance should be alerted immediately. Until their arrival, first aid measures are to be taken to ensure the survival of the affected person. A loss of consciousness and disturbances in voluntary movements are signs of a seizure disorder that requires medical attention as soon as possible.
Treatment and therapy
To date, MERRF syndrome is incurable. No causal therapy exists. Supportive and symptomatic treatments are available. The goal of these treatments is predominantly to improve quality of life. The main aim is to reduce the patients’ epileptic seizures. The administration of antiepileptic drugs and muscle relaxants is mandatory. Muscular symptoms can be improved especially by administration of high-dose coenzyme Q10. For mitochondrioathies, various general treatments are considered recommended. For example, drugs such as carbamazepine, levetiracetam, and oxcarbazepine are recommended in this context. Drugs such as valproate may increase the symptoms of mitochondriopathies and are therefore controversial. MERRF syndrome patients are also often advised physical therapy and early intervention. Physical therapy interventions ideally reduce movement limitations. Early intervention is intended to counteract cognitive impairments.Affected families can also seek psychotherapy to help them cope with the disease. Various therapies for MERRF syndrome are currently the subject of medical research. Through gene therapy, medicine will likely be able to positively influence the causative mutation in the future.
Outlook and prognosis
In MERRF syndrome, patients cannot expect a cure for the disease given the current medical as well as legal standards. The cause of the disorder can be traced to a mutation of a gene. The congenital disorder is treated symptomatically by doctors. Since human genetics may not be altered for legal reasons, doctors and physicians have no other option to improve the situation so far. Despite all efforts, the affected person experiences a severe impairment of his quality of life. In addition to physical abnormalities, depending on the intensity of the existing irregularities, there may also be cognitive losses. Despite early intervention programs, in most cases a complete cure is not achieved or the mental level of an average person is reached. The established treatment plan consists of administration of medications as well as support of the muscular system. The patient must undergo long-term therapy for this disease. The course of the disease is considerably improved when self-help measures are applied independently in everyday life. Physiotherapeutic exercises are intended to achieve an optimized range of motion. The results show a significant improvement if the training sessions are also carried out outside the session taking place. Due to the multitude of possible disorders, it can lead to a strong emotional strain. Therefore, in MERRF syndrome, the risk of developing a mental illness is increased.
Prevention
So far, MRRF syndrome can be prevented only in the context of family planning. Thus, if necessary, a couple at increased risk can decide against having children of their own. After prenatal diagnosis, the option of abortion is available for consideration.
Follow-up
As a rule, MERRF syndrome can cause various complications and discomforts that can significantly complicate the life of the affected person and thus reduce the patient’s quality of life. Since the disease is a congenital condition, follow-up care focuses on managing the symptoms well. Most affected individuals can no longer manage their daily lives on their own and are therefore dependent on constant assistance. Due to the mental retardation, the child’s development is usually also severely delayed. Due to the heavy mental burden, the parents and relatives of the patient often also suffer from psychological complaints or depression. Professional psychological help can alleviate the suffering and offer strategies to better understand and accept the situation. Since MERRF syndrome cannot be completely cured, those affected are dependent on treatment that is therefore purely symptomatic.
What you can do yourself
In MERRF syndrome, the most important self-help measure is to have all symptoms and complaints clarified immediately by a specialist. The individual complaints can be very acute, which is why close medical monitoring is indicated. This must be accompanied by measures to improve the quality of life, such as exercise and diets, but also the administration of medications. Physiotherapeutic measures support the drug treatment. If possible, support should begin in childhood, as this can effectively counteract cognitive impairments. Parents and relatives often need therapeutic support. The responsible physician can refer the parents to a suitable psychologist and, if necessary, also establish contact with other affected persons. If a seizure or epileptic attack occurs, the emergency physician must be called immediately. Until medical help arrives, the affected person should be reassured and, if possible, placed in a lying position. To ensure smooth treatment, the emergency physician must be informed immediately of the condition. After hospitalization, rest and recuperation are necessary. A doctor must determine the causes of the symptoms to reduce the risk of further seizures.
