Questions and answers

The term "mitochondriopathy" covers a large group of diseases in which the function of the mitochondria is disturbed. Mitochondria are the energy power plants of the cell, which convert the nutrients (carbohydrates, fats, protein) absorbed through the intestine into the body's own "energy currency" ATP. With this ATP, the body can then carry out all kinds of processes that involve energy consumption, e.g. the movement and strength development of the muscles, the functioning of the glands, the sensory and internal organs, thinking and much more, i.e. all the processes that we call "life".

Every day, the body converts approximately its own weight of ATP, which is constantly recovered from ADP by the mitochondria. Each cell contains hundreds to thousands of mitochondria. Mitochondria are very efficient, so in everyday life we only use about 20-30% of their maximum capacity. Only during competitive sports and extreme exertion do we reach a maximum of 80% exhaustion. In children and adults with reduced mitochondrial function, the mitochondria may already be working at their performance limits during normal everyday life and their performance cannot be increased any further. If the energy demand of the body then exceeds the energy supply of the mitochondria, a metabolic crisis (metabolic acidosis = over-acidification of the blood) can occur, damaging the internal organs and the brain. Such critical situations include infections with fever, food refusal, gastroenteritis and prolonged periods of starvation.

In addition to ATP production, mitochondria also play an important role in calcium metabolism, which is crucial for the communication between cells, especially between nerve cells in the brain. Depending on their stimulation, the nerve cells release waves of calcium, which are used to transmit information inside the cells. If there are irregularities in this process, the cells can die.

The mitochondrion is composed of many different proteins, estimated to be about 1500 in number, and mutations in the blueprints (genes) of each of these proteins can potentially lead to mitochondrial dysfunction. It is a great challenge for geneticists to find, among the numerous genes that are important for mitochondrial function, exactly the one gene whose disruption causes the disease in a particular patient. This search has become much easier in recent years due to new gene sequencing methods (next generation sequencing, exome sequencing and genome sequencing). But still, with today's methods, the underlying mutations are found in only 50-60% of patients.

Leigh syndrome is typically a disease of the brain in which certain areas are particularly at risk of damage. These are primarily the basal ganglia, nerve structures inside the cerebrum that play an important role in coordinating movement and muscle tension. We have found that certain nerve cells (also called "dopaminergic neurons") of the basal ganglia are particularly sensitive to disruption of calcium signals. Furthermore, the brainstem can be damaged, leading to dysphagia, vomiting & nausea, and breathing disorders.

Children with Leigh syndrome may initially develop normally, but others may have muscle weakness and developmental disabilities from birth. Children may develop epilepsy at an early age, primarily with myoclonic seizures, i.e., seizures with "muscle tremors". In most cases, however, a sudden deterioration of muscle strength, respiration and accumulation of lactic acid (lactate) in the blood occurs only in the context of an infection or febrile illness, so that only then is Leigh syndrome suspected. Confirmation of Leigh syndrome is then done by MRI of the brain, in which the typical changes in the basal ganglia and brainstem are found. In more than 50% of children, the underlying genetic defect can also be identified.

The aim of supportive therapy should be to avoid above all the metabolic crises mentioned above. Among other things, this means treating bacterial infections with antibiotics as soon as they are suspected and, if possible, not bringing the child into contact with feverish children. If a metabolic crisis occurs, parents should consider it an emergency at an early stage and immediately go to the emergency department of a pediatric clinic. It is favorable if the parents receive an emergency plan from the attending physicians, which they can show in an emergency at a pediatric emergency outpatient clinic, in which it is stated exactly how such a metabolic crisis can be countered in order to end it as quickly as possible.

During such metabolic crises, children can deteriorate rapidly. It may then take a very long time for them to regain the developmental state they had before the crisis, but it may also be that they never reach it again. Analysis of numerous medical case histories has shown that the prognosis of mitochondriopathy depends essentially on how to protect children from infections and metabolic crises.

Parents should pay attention to a calorically balanced and sufficient diet. The children can eat anything. Often there is underweight, so parents should seek nutritional counseling in order to work out an enrichment of the diet together (e.g. with Maltodextrin®). It is important to give small meals more often during the day to avoid prolonged periods of hunger and hypoglycemia under all circumstances. If the children do not want to eat due to diarrhea or gastrointestinal problems, the parents should go to a clinic for infusion therapy.

If the children cannot be fed adequately by mouth for a prolonged period of time and lose weight or do not gain enough weight, tube feeding or placement of a PEG (Percutaneous Endoscopic Gastrostomy) tube, through which high-calorie "astronaut food" can be administered directly into the stomach, might be indicated.

A ketogenic diet is only useful in very specific mitochondrial diseases in which the metabolism of fatty acids can partially replace that of carbohydrates. This applies to pyruvate dehydrogenase deficiency and, with limitation, to complex I deficiency. In special cases, the ketogenic diet may be used to treat severe epilepsy or epileptic encephalopathy, if necessary, regardless of the biochemical defect.

Dietary supplements: substances that are prescribed therapeutically for mitochondriopathies, but for which there is no study-based evidence of efficacy are: Coenzyme Q10 (10 mg/kg/d; improves electron transport along the inner mitochondrial membrane), L-carnitine (100 mg/kg/d; improves fatty acid uptake into mitochondria), and biotin (10 mg/d; is a cofactor of several carboxylases).

Since children with mitochondriopathies are particularly at risk of infection, good and complete immunization is especially important. To date, there are no scientific studies that vaccines can cause or worsen mitochondrial diseases. It is known that certain diseases, which can be prevented by vaccination (such as influenza), can cause metabolic crisis and developmental regression in vulnerable children.

The usual contraindications to vaccination (e.g., existing infection) apply as they do for healthy children. There have been reports in the media in the past linking worsening of mitochondrial disease to vaccination. WHO has investigated these data and concluded that very likely no such association exists and published these findings in the WHO report of December 17-18, 2008. However, more research needs to be done to determine if there are rare cases where mitochondrial disorders may be triggered by something related to vaccination. However, we do know that vaccinations are a safe and important way to protect most children from life-threatening diseases.

In the course of mitochondriopathies, which particularly affect tissues with a high energy demand (muscle, brain, endocrine organs, sensory organs), epileptic seizures may occur. These must then often be treated with medication (antiepileptic drugs, AEDs). Suitable first-line AEDs for this purpose are levetiracetam (Keppra®) and lamotrigine (Lamictal®). Under no circumstances should valproic acid be used, as this can lead to severe side effects on the liver. The treatment of children with mitochondriopathies and epilepsies belongs in the hands of a specialized center for pediatric epileptology.

Due to the brainstem dysfunction, some children may experience prolonged episodes of vomiting and nausea. This is usually "central vomiting", i.e., excessive stimulation of the vomiting center in the brainstem without a gastrointestinal problem. In such cases, a centrally acting antiemetic (e.g., Ondansetron®) should be used. This drug requires a prescription and should only be prescribed by physicians who are knowledgeable in the treatment of mitochondriopathies.

Since mitochondriopathies are a multi-systemic disease, various organ systems can be affected. Therefore, physicians recommend regular (yearly) examinations of the heart (echocardiography and ECG), blood pressure, metabolism (Hba1c, blood count, liver values, lactate, pyruvate, ammonia), hearing (threshold audiometry), vision (ocular fundoscopy, visual acuity testing, perimetry), and general and motor development of the child. A regular MRI control is not necessary, since no therapeutic consequences result from it without specific questions.

Drugs that impair mitochondrial function or in whose degradation and excretion the mitochondria have an important role should be used only with caution or avoided altogether. These include valproic acid and phenobarbitone (antiepileptic drugs); aminoglycosides, chloramphenicol, tetracyclines (antibiotics); metformin (antidiabetic drugs), and L-DOPA antagonists (e.g., risperidone, sedatives).

If anesthesia is required, it should be trigger-free. Propofol is a narcotic that is usually well tolerated in mitochondriopathies, although care must be taken to avoid metabolic complications (acidosis) and, if possible, do not use it for long-term sedation as it can be mitochondrial toxic if administered over a long period of time and can even lead to propofol infusion syndrome.

With any new drug, you should discuss with your physicians whether it can be given without problems in mitochondriopathies.

Children with mitochondriopathies can have numerous problems that need to be addressed on an individual basis, and you should look to see if there are support options in the appropriate deficient area. Here, occupational therapy and physiotherapy for the promotion of motor skills, muscle strength and balance as well as speech therapy for the promotion of speech development should be mentioned. Regular multidisciplinary care of the child in a social pediatric center is useful.

The proteins of the mitochondrion are encoded on the one hand by the DNA of the cell nucleus and on the other hand by the DNA in the mitochondrion itself, the so-called mitochondrial DNA (mtDNA). Mutations that cause mitochondriopathy can therefore be found in both nuclear DNA or mtDNA.

The most common mutation in the mtDNA is located in the MT-ATP6 gene, a gene that encodes a subunit of ATPase that is directly involved in ATP production in the mitochondrion. Mutations at other positions of the mtDNA can affect mitochondrial protein synthesis and cause, for example, MELAS or MERRF syndrome. MELAS is the acronym for Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like Episodes, MERRF stands for Myoclonus Epilepsy with Ragged-Red-Fibers. Ragged-red fibers are muscle fibers found specifically in muscle biopsy specimens of these patients.

All mutations in the mtDNA are inherited through the mother's oocyte. Each oocyte carries approximately 50,000 mtDNA copies and in carrier women, there is usually a mixture of healthy and mutant mtDNA copies in the oocytes. The percentage of this mixture is called the mutation load or heteroplasmy level. If the degree of heteroplasmy is below a certain threshold, affected individuals have no symptoms. If the degree of heteroplasmy exceeds a certain threshold, only mild symptoms of the disease begin, and with higher mutation load, symptoms are more severe. Each mutation has its own threshold value. This may mean that mothers of children with mtDNA-related mitochondriopathy are themselves clinically healthy. However, their oocytes may have quite different levels of heteroplasmy, from 0 to 100%. The higher the woman's average mutation load, the higher the percentage of her oocytes with high mutation load.

Other mutations that can lead to mitochondriopathy are located on the chromosomes of the cell nucleus. Affected proteins are subunits of the respiratory chain complexes or so-called assembly factors (e.g., SURF1) that help assemble the respiratory chain complexes. These gene defects are mostly inherited in an autosomal recessive manner. This means that parents who have one healthy and one affected gene copy are healthy because the healthy copy can compensate for the function of the affected copy. However, if the child happens to inherit an affected copy from each parent, the disease will appear.

Each time the oocyte is fertilized by a sperm, the gene copies (alleles) are randomly rearranged. With a probability of 25%, the two diseased alleles of both parents can come together and cause the child to develop the disease. The probability of 25% exists regardless of how many healthy or sick children have already been born in the past.

Prenatal diagnostics involves determining the genetic status of the still unborn fetus in the womb.

Prenatal diagnostics by means of chorionic villus sampling is usually performed in the 12th-14th week of pregnancy. Chorionic villi are obtained from the placenta under ultrasound guidance. The chorionic villi are genetically identical to the fetal tissue. It is therefore possible to draw conclusions about the genetic status of the still unborn fetus (e.g. the presence of certain mutations) after molecular genetic examination of the chorionic villi. At the same time, numerical chromosomal aberration can be excluded during chorionic villus examination. However, chorionic villus sampling is associated with a 0.5-4.0% (depending on the study) increased risk of miscarriage.

In the case of a recessive mode of inheritance, if the genetic defect is known, the fetus can be predicted to be affected with a relatively high degree of certainty. However, if the genetic defect is located in the mtDNA, then only an imprecise prediction is possible due to different mutation loads and the distribution of the mutation load to different tissues of the unborn child. Prenatal diagnostics for mtDNA mutations can basically only be offered if the mutation is located on the MT-ATP6 gene. According to the German Genetic Diagnostics Act, genetic counseling is mandatory before and after prenatal diagnostics.