What is Mitochondrial Myopathy?

Mitochondrial encephalomyopathy (ME) is a group of rare multi-system diseases mainly caused by brain and muscle involvement caused by abnormal mitochondrial structure and / or function. Its muscle damage is mainly manifested by extreme intolerance of skeletal muscle fatigue. The nervous system mainly includes extraocular muscle paralysis, stroke, recurrent seizures, myoclonus, migraine, ataxia, mental retardation, and optic neuropathy. Other systems Manifestations may include cardiac block, cardiomyopathy, diabetes, renal insufficiency, pseudo-intestinal obstruction, and short stature.

Basic Information

English name

mitochondrial encephalomyopathy

Visiting department

Neurology

Common causes

Genetic defects

Common symptoms

Extraocular muscle paralysis, stroke, recurrent seizures, myoclonus, migraine, ataxia, mental retardation, and optic neuropathy

Causes of Mitochondrial Encephalomyopathy

From the current research on this disease, it is believed that this disease is due to genetic defects, and patients have various dysfunctions in mitochondria, which leads to diversified clinical manifestations.

Clinical manifestations of mitochondrial encephalomyopathy

Because muscles and brain tissues are highly dependent on metabolism such as oxidative phosphorylation, whether nDNA or mtDNA is defective or both are affected at the same time, clinical symptoms are often systemic, but the clinical manifestations have different focuses due to the different degrees of involvement of each enzyme system. Mitochondrial diseases are artificially divided into two categories, namely mitochondrial myopathy and mitochondrial encephalomyopathy.

Among them, mitochondrial encephalomyopathy includes: MELAS syndrome; MERRF syndrome; KSS syndrome; Pearson syndrome; Alpers disease; Leigh syndrome; Menke disease; LHON; NARP; Wolfram syndrome. The clinical characteristics of the main syndromes are summarized as follows:

1. MELAS syndrome

That is, a group of clinical symptoms such as mitochondrial encephalomyopathy with lactic acidemia and stroke-like episodes are mostly maternally inherited. Normal development before 10 years of age. Onset from the age of 10 to 40 years old, the first symptoms are exercise intolerance, stroke-like attacks, paraparesis, aphasia, blindness or deafness. He also had limb weakness, convulsions or paroxysmal headaches, mental retardation, dementia, and lactic acidemia. RRF, abnormal mitochondria, and lattice-like inclusions were found on muscle biopsy. CT showed 30% to 70% of pale bulb calcification, and the MRI cortex was characterized by lamellar abnormal signals. Genetic testing showed 3243 or 3271 nucleotide point mutations. The acute phase of MELAS patients mainly involves the temporal parietal or temporal occipital lobe, and the lesions can involve the cortex and deep white matter. Unlike ischemic cerebral infarction, the distribution of MELAS infarcts and cerebral arterial perfusion blood supply areas is inconsistent, mainly concentrated in the microvascular area with strong metabolism, and the surrounding edema is not obvious, accompanied by astrocyte proliferation. Other common symptoms of nervous system involvement in MELAS patients include neurological deafness, migraine, impaired cognitive function, peripheral neuropathy, depression, and some mental symptoms. Recessive onset of neurological deafness is often an early manifestation of MELAS, often inherited by families, and can also occur in relatives of patients who have not developed the disease. Follow-up studies found that more than half of MELAS patients had varying degrees of hearing loss and maternal inherited diabetes and / or deafness (MIDD). Secondly, the occurrence of irregular migraine before the onset is also a common symptom in the early stage of MELAS patients. Headaches often occur during the intermittent period of the disease. It is speculated that the mitochondrial energy metabolism may be impaired, which increases the excitability of neurons on the one hand and reduces the other. Caused by the threshold of induced headache. Thirdly, patients with MELAS may have different degrees of cognitive impairment, including language, memory, and disorientation. The most common is impaired executive function of the prefrontal lobe. MRI manifests ischemia-like changes in the back of the brainstem and cingulate gyrus, which may be related to degeneration of cerebral cortical neurons. In addition, a small number of patients may develop peripheral neuropathy, showing mild paresthesia, sock-like numbness, etc., which are mainly occult and progressive, and often involve distal limbs.

2.MERRF syndrome

That is, myoclonic seizures, cerebellar ataxia, lactic acidemia, and RRF. A few have mental retardation, dementia, and other deformities such as neurodeafness, shortness, and arched feet. The electroencephalogram showed a spine-slow wave synthesis, and a muscle biopsy showed RRF, abnormal mitochondria, and inclusions. CT and MRI showed cerebellar atrophy and white matter lesions. Genetic testing showed 8344 or 8356 nucleotide mutations.

3.KSS syndrome

Retinitis pigmentosa, cardiac block, and paralysis of extraocular muscles. It usually develops before the age of 20, and other symptoms may include headache attacks, limb weakness, short stature, and low intelligence. A few have low endocrine function, low parathyroid function, pale ball calcification, MRI cortical and white matter abnormal signals. Muscle biopsy showed a few patients with RRF and abnormal mitochondria, and CT and MRI showed basal ganglia calcification and white matter lesions. Genetic testing is characterized by mtDNA deletions or massive rearrangements.

4.CPEO syndrome

Onset can occur at all ages, mostly in children or early adulthood. In addition to the paralysis of extraocular muscles, a few may be accompanied by limb weakness, weight loss or atrophy. Muscle biopsy for RRF, abnormal mitochondria, and inclusions. The genetic testing has a large variation, which shows that mtDNA is deleted or rearranged a lot.

5.Leigh disease

Namely, it is mainly subacute necrotizing cerebrospinal myelopathy caused by complex cytochrome oxidase deficiency, and most of them have a genetic history of the maternal line, and they develop the disease from 2 months to 3 years old. The more common clinical manifestations are feeding difficulties, ataxia, low muscle tone, and pyramidal signs. If the brainstem is involved, it can cause ocular muscle paralysis, vision, and hearing loss. A few may have psychomotor seizures, and pathology shows bilateral symmetrical basal ganglia and brain stem gray matter nucleus damage. The imaging MRI has characteristic features. RRF and mitochondrial inclusions are rare in muscle biopsies. Visible cytochrome C oxidase deficiency.

6.Alpers disease

Familial Primary Progressive Cerebral Grey Atrophy. Onset is usually a few months after birth, a few also occur after the age of 8, and most have a family history. The first symptoms are seizures, vision, hearing loss, and cortical blindness and deafness. Hemiplegia, aphasia, and mental retardation can be seen-dementia. Pathological features: degeneration and degeneration of gray matter neurons in the cortex, proliferation of small blood vessels and stellate cells, lamellar degeneration, and characteristic laminar abnormal signals on MRI. A few muscle biopsies show RRF and abnormal mitochondria.

7.Menke disease

It usually occurs within a few months after birth and dies at the age of three. There are also reports of late childhood onset. Clinical manifestations: curly hair, seizures, ataxia, extrapyramidal or pyramidal tract signs, mental retardation, and stunting. Pathological characteristics: Loss of cerebral atrophy neurons with white matter lesions, and characteristic changes in Purkinje cells of the cerebellum are thick dendrites, longer, and more bifurcation. The blood copper content decreased and the intestinal mucosa copper content increased. Muscle biopsy shows RRF and abnormal mitochondria.

8.Leber Hereditary Optic Neuropathy (LHON)

Sudden bilateral vision loss and loss. The peak age of onset is 20 to 24 years, and the minimum age is 5 years. Most bilateral vision is lost. A few develop the disease in one eye first, and in another eye after a few weeks or months. Blindness, macular edema, and retinal small vessel disease are mostly caused by damage to the posterior optic nerve. More common in males, at least 85% are young males, with X-linked genetic characteristics. The disease is mostly caused by optic nerve injury, and is rarely accompanied by other neurological symptoms and signs. Only a few cases have been reported with ataxia, hypertendinosis, pathological signs and hereditary peripheral neuropathy (CMT). CT, MRI imaging and muscle biopsy were mostly not characteristic.

9. Retinitis pigmentosa ataxia peripheral neuropathy (NARP)

Holt reported three generations of four family cases in 1990. Its clinical characteristics are a combination of different symptoms such as retinal pigment degeneration, ataxia, dementia with developmental delay, convulsions, weakness of the proximal limbs with sensory peripheral neuropathy. It usually develops around 3 years of age. It is reported that it is a combination of maternal inheritance and Leigh disease. It has characteristic changes of CT and MRI. Muscle biopsy has not confirmed RRF.

10. Other

(1) Wolfram syndrome is diabetic with neurological deafness. The mtDNA point mutation of the gene test is the same as that of MELAS, which is nt3243.

(2) mtDNA deletion was detected by mitochondrial peripheral neuropathy and gastrointestinal encephalopathy (MNGIE) genes. The clinical features are childhood onset, extraocular muscle paralysis, sensory motor neuropathy, and often gastrointestinal symptoms of pseudointestinal obstruction.

Mitochondrial encephalomyopathy examination

Electrophysiological examination

Electromyography is one of the most commonly used tests. Electromyography is especially important when there are clinical manifestations of myasthenia such as muscle weakness and atrophy. Most of them are myogenic changes, and a few cases also show neurogenic changes or both. Occasionally, patients with mitochondrial encephalopathy have normal EMG. In some patients with encephalopathy as the main manifestation, neurogenic or myogenic changes can also be seen in the EMG. This is an electromyogram characteristic of mitochondrial disease. Various evoked potential examinations also have auxiliary diagnostic effects on the lesions of various encephalopathy syndromes. EEG is of great significance in mitochondrial encephalopathy with convulsions and epileptic seizures. Among them, MELAS, MERRF, and Alpers disease, which are mainly cortical lesions, not only have diffuse whole brain EEG rhythm, but also have focal changes. In particular, the spike-slow-wave synthesis and sharp-wave slow-wave synthesis unique to epilepsy EEG can be seen. EEG changes in Leigh's disease, KSS, and Menke's disease were relatively mild, with fewer focal or characteristic changes. At the beginning of some patients, although there is a paroxysmal headache, no brain damage has occurred. EEG not only shows diffuse whole brain arrhythmia, but also obvious focal lesions, while CPEO EEG is less common. Positive see. Electrocardiogram examination has important diagnostic significance for KSS. It also has important auxiliary diagnostic significance for maternal genetic mitochondrial myopathy with heart disease.

2. Serum lactic acid test

Elevated serum lactic acid value of mitochondrial disease is also an important diagnostic screening indicator. If the lactic acid value in the quiet state is greater than 1.8nm to 2.0nm, it is abnormal. Especially the increase in lactic acid value after exercise is more meaningful. The abnormal ratio of serum lactic acid to pyruvate is considered as an indicator of intracellular redox metabolism. It is normal for this ratio to be less than 20, which increases when the respiratory chain is defective. Under normal circumstances, the cerebrospinal fluid lactic acid value is lower than the serum value, which can be increased under pathological conditions. It is only found in diseases such as MELAS and other brain tissue damage. Other types of mitochondrial diseases can increase serum lactic acid and cerebrospinal fluid lactic acid value.

3. Imaging (CT, MRI) examination

Some features of imaging (CT, MRI) can play an important role in the clinical diagnosis of mitochondrial encephalomyopathy. In MELAS, multiple stroke-like abnormal signals in the posterior hemispheres, namely the temporal, parietal, and occipital cortex, can be seen, but their characteristics are not distributed according to anatomical blood vessels, involving the cortex and subcortical white matter. The above signs. The CT and MRI characteristics of Leigh's disease are abnormal signals of gray matter nucleus damage such as symmetrical bilateral basal ganglia, thalamus, and brainstem. KSS has scattered abnormal signals that are seen in both gray matter and white matter.

4. Advances in molecular biology and genetic testing methods

With the rapid development of genetics and molecular biology in recent years, significant progress has been made in exploring the pathogenesis of mitochondrial encephalomyopathy. ^[1]

Mitochondrial encephalomyopathy treatment

Although the understanding of the molecular basis of this disease has advanced by leaps and bounds in recent years, treatment options are still limited, and currently rely mainly on supportive therapies rather than correcting fundamental deficiencies.

Drug treatment

Combined medication, the drugs currently used are roughly divided into the following 4 areas:

(1) scavenge oxygen free radical coenzyme Q10, idebenone, vitamin C, vitamin E, etc .;

(2) Reduce the toxic products dichloroacetic acid, dimethylglycine, etc .;

(3) Passing electron coenzyme Q10, idebenone, succinate, vitamin K, etc. by bypass;

(4) Supplement the metabolism of coenzymes creatine, carnitine, nicotinamide, thiamine, riboflavin, etc. Coenzyme Q10 and vitamin C can keep vitamin E active, and coenzyme Q10 can promote energy metabolism; dichloroacetic acid and vitamin B1 act on pyruvate dehydrogenase complex from different aspects. The combined use can accelerate oxidative metabolism and reduce lactic acid production Coenzyme Q10 and succinic acid can be used as electron carriers to directly transfer electrons to complex enzymes and , so patients with complex enzyme I deficiency can use them in combination; antioxidants act on all links of the respiratory chain to protect various complex enzymes from being Oxygen free radicals are destroyed. Therefore, the combination treatment of ME began many years ago. In addition, ME is a disease caused by the oxidative phosphorylation of the integrity of the respiratory chain, so various drugs that improve energy metabolism can help patients with symptoms. However, it is very difficult to determine the lack of a certain factor in the mitochondrial oxidative phosphorylation chain. Therefore, the "cocktail" therapy composed of various coenzymes, vitamins and other drugs that improve energy metabolism has become the main method for treating ME in recent years.

2.L-Arginine

Being a precursor of nitrous oxide (NO) can induce vasodilation, thereby reducing stroke-like episodes in patients with MELAS signs. Kubota's study shows that the symptoms of MELAS are improved after L-arginine treatment in the acute phase of stroke. The magnetic resonance spectroscopy analysis shows that the parietal cortical lactate peak is reduced and the N-acetylaspartate (NAA) peak is normal. These all indicate that L -Arginine can improve mitochondrial energy status and cell viability. Other studies have shown that L-arginine can regulate the excitability of neurons by affecting the absorption of glutamic acid and the release of -aminobutyric acid. Although the safety and exact role of L-arginine need to be confirmed by long-term randomized controlled trials, it brings hope for clinical work. ^[2]

3. Exercise Therapy

Exercise training as a promising treatment option for ME includes resistance and endurance training.

(1) The theory of resistance training is the theory of gene drift. When mtDNA is mutated, it will cause both wild-type and mutant mtDNA in the cell, that is, heterogeneity. However, the proportion of mtDNA mutations must exceed a threshold for lesions to occur. Two studies on patients with specific mtDNA mutations in muscle confirmed this theory. These patients have no detectable mutations in mtDNA in skeletal muscle satellite cells, and resistance training can activate fusion to skeletal muscle fibers. In static satellite cells, it increases the ratio of wild-type mtDNA / mutant mtDNA and corrects some biochemical defects in skeletal muscle fibers.

(2) Aerobic endurance training for endurance training can increase the density of tissue capillaries, increase the permeability of blood vessels and the enzyme activity of the mitochondrial respiratory chain. Aerobic endurance exercise can improve muscle strength in patients with ME whose main manifestation is myopathy.

4. Diet Therapy

Apply different diet therapies to ME patients with different deficiencies:

(1) Patients with pyruvate dehydrogenase deficiency, given a ketogenic diet (lower carbohydrates, increased fat content), can increase patients' mitochondrial biosynthesis and increase heterogeneity to wild-type mtDNA;

(2) Fatty intake should be restricted in patients with carnitine deficiency

(3) In patients with pyruvate carboxylase deficiency, a high protein, high carbohydrate, and low fat diet is recommended. All of the above can improve the clinical symptoms of patients to varying degrees.

5. Gene therapy

Gene therapy strategies include reducing the ratio of mutant mtDNA / wild-type mtDNA, using misplaced and heterogeneous expression, importing other homologous genes, and using restriction enzymes to repair mutant mtDNA. For example, human cytoplasm (including normal mitochondrial acellular nuclei) can be used to repair defective cells (including defective mtRNA and cells with reduced respiratory chain function), which can successfully restore the normal function of the respiratory chain of defective cells; Mitochondrial gene defects also have a certain therapeutic effect. Importing specific nucleic acid peptides into defective cells allows the nucleic acid peptides to specifically inhibit the replication of mutant mtDNA, while allowing normal mtDNA to be replicated. New genetic mutations have been identified in recent years that may be helpful for potential treatment strategies.

6. Cell transplantation

Myoblast transplantation is a treatment method that has emerged in recent years. Cell biology studies have shown that myoblasts fuse into myotubes and develop into mature muscle fibers. If the patient's muscle cells are fused with normal muscle cells in vitro and then imported into the patient, multi-point intramuscular injection is generally used, and there may be more wild mtDNA in the patient. Perhaps it can be applied to clinical treatment in the future.

7. Genetic Therapy

Nuclear transfer is the transfer of nuclear DNA from an oocyte carrying a mutant mtDNA to an enucleated oocyte containing normal mtDNA, which is implanted into the uterus after in vitro fertilization. Due to ethical and safety issues, this method needs to be confirmed by further research.

8. Activated peroxisome proliferators

Activated receptor gamma (PPAR) / peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) signaling pathway to regulate the PPAR / PGC-1 signaling pathway is a potential therapeutic option. PPARs are members of the nuclear receptor superfamily that regulate metabolic pathway gene expression programs. They regulate mitochondrial biosynthesis through PGC-1, and PPAR- activation can increase the ability of cells to maintain mitochondrial potential, thus activating the PPAR / PGC-1 pathway It can exert a therapeutic effect by increasing mitochondrial biosynthesis. In addition, fibrates can induce PGC-1 expression in the heart and skeletal muscle.

9. Remove toxic metabolites

Mitochondrial gastrointestinal encephalomyopathy (MNGIE) is caused by mutation of thymine nucleotide phosphorylase (TP) gene, which basically disappears the activity of the enzyme, and the substrates deoxythymidine and deoxyuridine that are catalyzed appear to increase significantly, making the mitochondrial nucleus The glycoside library is imbalanced, and high concentrations of deoxythymidine and deoxyuridine can cause mtDNA replication disorder in patients with MNGIE, resulting in loss, multiple fragment deletions, and point mutations.

references

1.Jia Jianping. Neurology [M]. Beijing: People's Medical Publishing House, 2008: 378-379.

2.PulkesT, EunsonL, PattersonV, etal. ThemitochondrialDNAG13513AtransitioninND5isassociatedwithaLHON / MELASoverlapsyndromeandmayafrequentcauseofMELAS: AnnNeurol, 1999: 46: 916-919.