Where are mitochondria not found

Mitochondrial Diseases

Clinical symptoms

Defects of the mitochondria lead to the failure of the cellular energy metabolism and today they play an important role in pediatric and neurological clinics, although the prevalence of these diseases is still difficult to estimate (approx. 1: 5,000).

Respiratory chain defects are among the classic and best-studied mitochondrial diseases. Primary respiratory chain defects affect either the structural subunits of the respiratory chain themselves or superordinate factors. They cause a primary cellular energy deficiency (deficiency) and in many cases lead to progressive neurodegenerative diseases. Respiratory chain defects are clinically extremely heterogeneous. Organs with a high energy turnover, i.e. skeletal muscles and the heart, are most frequently affected. Frequent symptoms on the part of the muscles are therefore muscle pain when exerted or increased, muscle fiber breakdown (rhabdomyolysis) with dark-colored urine and the risk of kidney damage, but also muscle weakness (paresis) and muscle wasting (atrophy). Frequent additional symptoms are diabetes mellitus, blindness (retinopathy), neuropathy, deafness, cardiac arrhythmias and others.

Thirteen subunits of the respiratory chain complexes are produced in the mitochondria by their own transcription and translation machinery and inserted into the mitochondrial inner membrane with the help of other proteins, while the proteins encoded by the nuclear genome have to be translocated through complex processes across both mitochondrial membranes and guided to their final position ( see picture). This explains that genetic defects in the case of a respiratory chain defect are not limited to the 13 mitochondrially or more than 70 nuclear-coded structural components themselves.

In the last decade, more than 200 different mutations of and defects in numerous nuclear genes have been described, which cause primary respiratory chain defects and sometimes occur sporadically, but can also be inherited maternally, autosomal recessive, autosomal dominant or X-linked. The clinical and genetic heterogeneity therefore poses a particular challenge - both for diagnostics and for genetic counseling.

Some mitochondrial diseases, which are mainly manifested by symptoms in the muscles, should be briefly presented here:

Myoclonus Epilepsy with Ragged Red Fibers (MERRF)

At MERRF, patients experience symptoms such as myoclonic and tonic-clonic epilepsy, mitochondrial myopathy, neurosensory deafness, ataxia, and dementia. A typical histological correlate of this mitochondrial disease in muscles is “ragged red fiber” (RRF). The most common cause of MERRF syndrome is the 8344A> G mutation in the mtDNA - Lys gene. There are also progressive myoclonus epilepsies with or without RRF, which can be associated with other mutations in the mtDNA (e.g. ND5, other tRNA genes). Autosomal mutations of the nuclear-encoded POLG1 gene have also been described in patients with typical MERRF syndrome. Multiple mtDNA deletions in muscle DNA are common in these patients.

Chronic Progressive External Ophthalmoplegia (CPEO)

Isolated ocular symptoms (paralysis of the eye muscles and drooping eyelids) are found in CPEO. If other symptoms are associated with it, one speaks of a CPEO + up to the most severe form, the Kearns-Sayre syndrome (KSS), which in addition to ocular myopathy with retinopathy, lactic acidosis, neurosensory deafness, ataxia, cardiomyopathy, cardiac conduction disorders, increased CSF protein concentration and dementia can be socialized. The onset of the disease is variable (childhood to advanced adulthood). These clinical pictures are often caused by singular deletions of the mitochondrial DNA. The deletions can affect parts of mitochondrial DNA of various sizes; with a few exceptions they occur spontaneously. With these clinical pictures, autosomal dominant (ANT1, Twinkle, POLG1) as well as autosomal recessive inheritance forms (POLG1) must be considered. These are usually associated with multiple deletions of the mtDNA.

Rhabdomyolysis

Rhabdomyolysis is a common clinical syndrome caused by acute muscle fiber necrosis and the release of muscle enzymes into the blood, leading to myoglobinuria. Myoglobinuria can cause acute renal insufficiency in 15% of patients. The background to rhabdomyolysis is very heterogeneous. Genetic diseases, toxins, muscle overload or inflammatory processes can cause rhabdomyolysis. The genetic background in rhabdomyolysis is very heterogeneous. Autosomal recessive mutations in the carnitine palmitoyltransferase gene (CPT2) or in the muscle glycogen phosphorylase gene (PYGM) have been described in patients. Another genetic cause found in patients with mitochondrial myopathy and rhabdomyolysis was mtDNA mutations in the Cytb, ND and tRNA genes.

Leigh Syndrome (LS)

The LS or "subacute necrotizing encephalomyelopathy" goes back to the pathologist D. Leigh, who described the typical brain morphology with symmetrical basal ganglia and brain stem necrosis for the first time in 1951. LS is one of the most common mitochondrial diseases in children. In about 70% of the cases LS is associated with primary respiratory chain defects, in another 15-20% with a pyruvate dehydrogenase deficiency. In addition to the typical Leigh syndrome, there are a number of respiratory chain diseases that are associated with lesions in the basal ganglia, but also the white matter. For example, demyelination symptoms as well as cerebral and cerebellar atrophies can be found. Demyelination of peripheral nerves with subsequent neurogenic muscular atrophy can also be seen. In addition to the CNS changes, other organs are often affected, such as the heart, liver, kidney, etc.As a large number of causative gene mutations can be detected, a targeted molecular genetic prenatal diagnosis is possible. A disease gene, SURF1, should be emphasized, which is affected in relatively many cases by LS and complex IV defects. Mutations in a large number of different genes can cause Leigh syndrome and only biochemical analysis can limit the number of genes in question in individual patients. The molecular causes of Leigh-like syndromes are still partly unknown. As a rule, the determination of the respiratory chain enzymes in the skeletal muscle helps to narrow down the molecular cause of the LS and to connect specific genetic diagnostics.

Diagnosis

Tissue collection / muscle biopsy

In cooperation with genetic institutes, we carry out comprehensive diagnostics for mitochondrial diseases. Performing a muscle biopsy is necessary for most mitochondrial diseases. At the Friedrich Baur Institute, the patient's muscle biopsies are examined histologically and biochemically. To this day, the histological evidence of increased occurrence of “ragged red fibers” in skeletal muscle biopsies is considered characteristic of mitochondrial myopathy. Furthermore, the determination of the activities of the respiratory chain enzymes is necessary in many cases. The histological and biochemical results enable targeted molecular genetic analyzes. DNA (genetic material) is isolated from the muscle. In the case of deletion (s), depletion or some point mutations of the mtDNA, the genetic analysis of the DNA from the muscle is more informative than the DNA obtained from blood cells.

Therapy options

The cause of mitochondrial diseases, i.e. mitochondrial or nuclear gene defects, cannot yet be treated. For many diseases, however, there are symptomatic treatment options. In the case of primary deficiency (see research projects), the patient's condition improves significantly by taking CoQ10 until they are symptom-free. In patients with sporadic mtDNA mutations (only detectable in muscle DNA), aerobic exercise can improve muscle strength. Various symptoms and complications (epilepsy, diabetes mellitus, strokes, cardiac arrhythmias, hormonal disorders, etc.) can be treated or prevented with medication or other measures (pacemakers). The ptosis can be corrected with an operation (blepharoplasty).

Research and clinical studies

The institute's research projects on mitochondrial diseases currently focus on mitochondrial DNA depletion syndrome and primary coenzyme Q10 deficiency.

The institute participates in clinical studies on Friedreich's ataxia and Leber's hereditary optical neuropathy under the direction of Prof. Dr. Thomas Klopstock.

Contact person in the institute

Prof. Dr. Thomas Klopstock
Ira Brandstetter