Introduction
Mitochondrial myopathy(mitochondrial myopathy) refers to a group of multisystem diseases in which the structure and function of mitochondria are abnormal due to defects in genetic genes, resulting in cellular respiratory chain and energy metabolism disorders. Mitochondrial myopathy is called with central nervous system symptoms. In 1962, Luft first used modified Gomori Trichrome staining (MGT) to find broken red fiber (RRF) in muscle fibers and diagnosed the first mitochondrial myopathy. Mitochondrial disease can also affect the central nervous system, causing a variety of mitochondrial encephalomyopathy. The disease is a group of clinical syndromes.
Cause
(1) Causes of the disease
From the current research on this disease, it is believed that this disease is caused by genetic defects, and there are various functional abnormalities in the mitochondria of patients, which leads to the diversity of clinical manifestations.
(two) pathogenesis
It is known that different structural parts of mitochondria contain different enzyme systems, such as cytochrome C reductase, fatty acid coenzyme A ligase and monoamine oxidase in the outer membrane; adenylate kinase and nucleoside diphosphate kinase in the outer chamber; The enzymes and respiratory chains of the phosphorylation system (ie, electron transport systems). Oxidative phosphorylation requires electron transport. Enzymes of the oxidative phosphorylation system include adenosine adenosine synthase and succinate dehydrogenase. The respiratory chain is composed of flavoprotein, iron-sulfur protein,Coenzyme QAnd composed of cytochromes. In addition, the inner membrane also contains a carnitine fatty acid acyltransferase. The matrix contains a citrate cycle enzyme, a fatty acid oxidase, a glutamate dehydrogenase, and a protein structural component that synthesizes DNA and RNA. In addition, mitochondrial DNA (mtDNA) in human matrices is also a genetic material. It is precisely because of the complex structure and function of mitochondria that it is not difficult to understand the heterogeneity and clinical manifestations of mitochondrial diseases in terms of pathogenesis. Jackson et al (1995) analyzed 51 cases of mitochondrial myopathy and brain myopathy, the clinical manifestations of which are the clinical manifestations of a syndrome or mitochondrial myopathy, but biochemical analysis and molecular biology studies revealed patients on the mitochondria The defects can vary.
The pathological changes of the muscles showed RRF on the modified Gomori trichrome stained sections, succinate dehydrogenase (SDH) staining was positively stained, and SDH and cytochrome C oxidase (COX) stained blue fibers. SDH staining also showed strong SDH-reactive vessel (SSV), which reflects a large number of mitochondrial accumulation in vascular endothelial cells or smooth muscle cells. COX staining indicates partial or total loss of enzyme activity. Under electron microscope, a large number of mitochondria were accumulated under the submucosa or myofibrils, and the size and morphology of mitochondria were abnormal. The lattice-like inclusion bodies appeared in the mitochondria and arranged into a parking lot-like structure. In addition, mitochondria can be arranged in a lamellar or concentric pattern, and the latter looks like an "annual ring". The basic pathological changes of the brain are sponge-like tissue, degeneration of neurons, focal necrosis of brain tissue, astrocyte hyperplasia, secondary myelin degeneration and basal ganglia iron deposition.
symptom
The common clinical syndromes of mitochondrial myopathy are described as follows:
1. Mitochondrial myopathy (mitochondrial myopathy) is mainly characterized by muscle weakness associated with proximal limbs with exercise tolerance. It can occur at any age, and children and young people are more common. Myasthenia progression is very slow and may relieve recurrence. After decades of illness, patients can still take care of themselves. Infant mitochondrial myopathy has two types of infantile lethality and benign. Fatal infant myopathy occurs more than 1 week after birth and is characterized by muscle strength, hypotonia, dyspnea, lactic acidosis and renal insufficiency, and death within 1 year of age. Benign infant myopathy is characterized by muscle strength, low muscle tone and dyspnea during the infant's period. After 1 year of age, the symptoms are relieved and gradually return to normal.
The most common genetic abnormality is a mutation at the mtDNA3250 site. Biochemical defects are mainly due to the lack of enzyme complex I, but also the lack of complex II, III. A large amount of RRF was seen in the muscle biopsy, and the serum muscle enzyme was normal or slightly elevated. There may be hyperlactemia.
2. Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS)
It is a group of mitochondrial diseases with stroke as the main clinical feature, which is maternal inheritance, and more than 80% of patients are ill before the age of 20. The characteristic clinical manifestations are recurrent headaches and/or vomiting, cortical blindness (hemenosis), and partial sensory disturbances. Headaches are migraine or unilateral craniofacial pain, and repeated vomiting may or may not be accompanied by migraine. Cortical blindness is a very important symptom of this syndrome. Of the patients under 30 years of age with occipital stroke, 14% are MELAS. Localized epilepsy is sometimes a precursor to MELAS stroke and is one of the characteristics of this syndrome. Other accompanying symptoms are short stature, mental retardation, decreased muscle strength, sensorineural deafness, and seizures.
Enzyme complex I deficiency is the most common (50%) biochemical defect in MELAS, in addition to complex III and IV deficiency. 80% of MELAS had translocation mutations at the mtDNA3243 locus, and some patients also found shift mutations at the 3271, 3252, 3260, and 3291 loci. The main brain pathological changes of MELAS are cavernous degeneration of the brain and cerebellar cortex, dentate nucleus, multifocal necrosis of cerebral cortex, basal ganglia, thalamus, cerebellum and brainstem. False stratified necrosis of the cerebral cortex is also seen as a pathological feature of hypoxic encephalopathy in MELAS, and diffuse calcification of the brain is also common. Since a large number of abnormal mitochondrial accumulations are observed in cerebral vascular smooth muscle, endothelial cells, and neuronal cells, it is unclear whether stroke-like episodes are caused by cerebrovascular disease or neuronal dysfunction. Muscle biopsy showed RRF and strong SDH-reactive vessel (SSV). Brain CT is characterized by white matter, especially multiple low-density lesions in the subcortical white matter, basal symmetry or diffuse calcification of the whole brain.
3. Myoclonus epilepsy with ragged red fiber (MERRF) is a maternal inheritance. It can be diagnosed before the age of 40, and it is more common when it is around 10 years old. Its main clinical features are cerebellar ataxia, myoclonus or myoclonic epilepsy. Maternal relatives may present partial phenotypes, such as only deafness or epilepsy (including absence seizures, seizures, and forced clonic seizures). Symptoms may include short stature, mental retardation, neurological deafness, optic atrophy, ophthalmoplegia, neck lipoma, peripheral neuropathy, heart disease, and diabetes.
Most of the biochemical defects of MERRF are enzyme complex IV deficiency, followed by enzyme complex I and IV deficiency. 80% of MERRF patients have a shift mutation at the mtDNA8344 locus. Brain pathological changes mainly involve the cerebellar dentate nucleus, red nucleus, putamen and Luys body. The main pathological changes in muscle are: RRF and SSV, which reflect the accumulation of mitochondria in vascular endothelium and smooth muscle cells. Blood or cerebrospinal fluid lactate levels can be elevated. Brain atrophy can be seen in the brain CT.
4.Kearns-Sayre syndrome (KSS) and Pearson syndrome KSS mostly occur before the age of 20, mostly sporadic, in addition to extraocular tendon with retinitis pigmentosa and / or heart block, can also appear short stature , neurological deafness and cerebellar ataxia. Pearson syndrome is a group of infants with non-neurological disorders, including complete blood cell decline, pancreatic exocrine dysfunction, abnormal liver function, renal failure, and KSS manifestations in the late survivors. The genetic basis of this syndrome is a large number of mtDNA repeats.
5. Chronic progressive external ophthalmoplegia (CPEO) may be familial or sporadic, and the inheritance of familial morbidity is currently not completely defined, partly maternal inheritance, or autosomal dominant inheritance. . It can occur at any age, but it is more common before the age of 20 years. Clinical manifestations include ocular dyskinesia, drooping eyelids, and short-term diplopia, often accompanied by fatigue and weakness of the proximal limb. A large number of RRF and cytochrome oxidase (COX) deletions were seen in the muscle biopsy pathology. Under electron microscope, a large number of abnormal mitochondrial accumulation, mitochondrial sputum abnormalities and intraorbital crystal-like inclusion bodies were observed. Cerebrospinal fluid examination can have increased lactic acid and elevated protein. Domestic scholars have confirmed that mtDNA has a heterozygous deletion, and DNA sequencing confirmed that a new PvuII restriction site was generated at the mtDNA10909 site and was replaced by a single base, which is considered to be a new point mutation (Chen Qingyi et al., 1996). Protein A colloidal gold (PGA) labeling and immunoelectron microscopy revealed that the gold particles bound to the mitochondrial enzyme complex I, II, III and IV in muscle tissue were reduced to a lesser degree, suggesting the activity of the enzyme complex in the mitochondrial respiratory chain. Lower (Song Donglin et al., 1996).
6. Leigh disease is also known as subacute necrotizing encephalomyelopathy. For familial or sporadic mitochondrial myopathy. Part of the maternal inheritance, part of the autosomal recessive inheritance. It occurs within 6 months to 2 years after birth. Typical symptoms are difficulty in feeding, ataxia, low muscle tone, psychomotor seizures, and drooping of the eyelids caused by brain stem damage, ocular paralysis, decreased vision, and deafness. Clinically, children with recurrent ataxia, decreased muscle tone, symptoms of hand, foot and vomiting should be considered. The 5% genetic abnormality of this disease is the same as MERRF, which is a mutation of mtDNA8344 and 8993. The distribution and pathological features of brain damage are very similar to those of Wernicke encephalopathy, but they are more extensive than Wernick encephalopathy. They are characterized by bilateral symmetrical spongiform changes with myelin loss, colloidal and synaptic in the thalamus, basal ganglia, midbrain, pons, medulla and spinal cord. Angiogenesis, peripheral nerves may have demyelinating changes. Unlike Wernicke's encephalopathy, the nipple is rarely affected. Muscle biopsy showed no abnormalities other than mitochondria after electron microscopy. Bone nucleus and brainstem lesions are often found in brain CT and MRI. Blood and cerebrospinal fluid lactic acid levels are almost increased.
7.Leber hereditary optic neuropathy(Leber hereditary optic neuropathy, LHON) refers to acute or subacute hereditary optic atrophy in adolescent or adult onset. First reported by Leber in 1871. Males are prone to develop at any age, usually 20 to 30 years old. The clinical manifestations are acute or subacute central visual field defects. At first, the monocular vision is unclear. After several weeks or months, both eyes are involved. Visual impairment is usually heavier and can cause blindness. In the early stage, there may be optic disc edema, and the optic disc becomes pale after the contraction period. A striking feature of LHON is that pupils react to light even in the event of a severe central visual field defect. Vision loss is mostly persistent, but a significant proportion of patients may have objective vision improvements, some of which are even dramatic. In addition to visual symptoms, there may be symptoms and signs of the central nervous system, peripheral neuropathy, and heart block.
The main biochemical defect of LHON is the deficiency of complex I, which is a translocation mutation at the mtDNA11778 locus, in addition to the 14484 and 3460 point mutations. The main pathological changes of LHON are optic nerve and ganglion cell degeneration without obvious inflammatory process, and the 6 layers of lateral geniculate body have obvious trans-degenerational degeneration. Muscle biopsy has no RRF and SSV and other enzyme histochemical abnormalities.
8. The main clinical manifestations of Wolfram syndrome are diabetes and deafness in adolescents. The disease has an age of onset, varying degrees, involving multiple organs and maternal genetic characteristics. The genetic basis is the A→G base substitution at the 3243 site of the tRNA leucine (1eu) gene in mtDNA. This patient is consistent with a phenotypic mutation in MELAS syndrome.
Some characteristic changes in clinical syndrome, brain CT and MRI, and family history of maternal inheritance based on specific combinations of symptoms and signs are important clues to mitochondrial diseases. Muscle biopsy is another important means of diagnosing mitochondrial diseases. Pathological changes of diagnostic value include RRF, cytochrome oxidase loss, and SSV. Determination of lactic acid and pyruvate levels in blood and cerebrospinal fluid is an important laboratory test for screening for mitochondrial diseases.
mtDNA analysis is the most reliable method for diagnosing mitochondrial diseases. More than 30 mtDNA mutations have been discovered. Multiplex PCR/allele-specific oligonucleotide probe dot blot hybridization and long fragment PCR methods can be used to detect multiple known one-time. Site mtDNA mutation. Some patients can also use biochemical methods to detect abnormal changes in mitochondrial biochemistry, which plays an important role in further investigation of changes in the activity of this disease, such as mitochondrial enzyme complex, but mtDNA analysis is not easy to promote, in the conditional molecular biology laboratory. get on.
diagnosis
For simple mitochondrial myopathy, attention should be paid to lipid deposition myopathy,Glycogen storage disease, polymyositis and muscular dystrophy are differentiated; those with extraocular tendon should beMyasthenia gravisAnd cancerous eye muscle disease differentiation; muscle pain is more obvious, similar to polymyositis; muscle weakness with episodes, but also like periodic paralysis, need to pay attention to identification; other various syndromes such as MELAS and MERRF, etc. Both should be carefully distinguished from those with similar clinical manifestations.
Timely examination of muscle biopsy can help to confirm the diagnosis.
complication
With the development of the disease, a variety of symptoms and signs can appear (see the clinical manifestations of this disease).
treatment
(a) treatment
There are currently no particularly effective treatments for mitochondrial diseases. Generally available:
1. Coenzyme Q10, intramuscular injection or oral administration.
2. Large doses of B vitamins, such as vitamin B1, vitamin B2Vitamin B6Etc. can improve symptoms.
3. Energy preparations, such asAdenosine triphosphate (ATP),Coenzyme AWait.
4.Sodium dichloroacetate, 12.5 ~ 100mg / (kg · d), oral.
5. Respiratory chain enzyme complex II + III defects, can be treated with vitamin K3 plus vitamin C.
(two) prognosis
Different types of prognosis are different, and the duration of the disease varies (see clinical presentation). Symptomatic treatment can improve the quality of life of patients.
prevention
The treatment of genetic diseases is difficult, the efficacy is not satisfactory, and prevention is more important. Preventive measures include avoiding the marriage of close relatives, conducting genetic counseling, genetic testing of carriers, prenatal diagnosis and selective abortion to prevent the birth of children.
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