Mitochondrial disease

Introduction to mitochondrial disease Mitochondrial disorder mitochondrial disease is a group of heterogeneous lesions caused by genetic defects that cause mitochondrial metabolic enzyme defects, resulting in ATP synthesis disorders and insufficient energy sources. Different types of mitochondrial myopathy have different ages of onset. Granulocytes are organelles closely related to energy metabolism. Both cell survival (oxidative phosphorylation) and cell death (apoptosis) are related to mitochondrial function, especially oxidative phosphorylation of the respiratory chain is associated with many human diseases. According to different mitochondrial lesions, it can be divided into mitochondrial myopathy and mitochondrial myopathy. basic knowledge The proportion of illness: 0.001% Susceptible people: no specific population Mode of infection: non-infectious Complications: Spinocerebellar ataxia, epilepsy

Cause of mitochondrial disease

Gene mutation (90%):

Mitochondria are organelles that provide energy in cells. Human mtDNA is a 16569 bp circular double-stranded molecule, divided into light and heavy chains, containing 37 genes, mainly encoding respiratory chains and energy metabolism-related proteins, mtDNA deletions or point mutations. Enzymes or vectors encoding mitochondrial oxidative metabolism process disorders, glycogen and fatty acids cannot enter the mitochondria to fully utilize and produce sufficient ATP, leading to energy metabolism disorders and complex clinical symptoms.

Pathogenesis

Mitochondria are closely related to energy metabolism, and both cell survival (oxidative phosphorylation) and cell death (apoptosis) are related to mitochondrial function, especially oxidative phosphorylation of the respiratory chain is associated with many human diseases.

Since the fertilized egg mitochondria are all from the egg, mitochondrial disease is a maternal inheritance method different from Mendelian inheritance, similar to the autosomal genetic disease, but each generation has more cases than autosomal genetic diseases, and the mother transmits mtDNA to the offspring. Daughters can pass mtDNA to the next generation. Because there are multiple copies of mtDNA in each cell, the mitochondrial coding gene phenotype is related to the relative proportion of intracellular mutants and wild-type mtDNA. Only when the mutant reaches a certain threshold will the patient develop symptoms. .

Pathological changes: Muscle frozen sections were biopsied with modified Gomori trichrome staining. Ragged red fiber (RRF) with abnormal mitochondria was observed under light microscope. Electron microscopy showed a large number of abnormal mitochondrial glycogen and lipid droplets. Mitochondria Disordered, mitochondria are closely related to energy metabolism in organelles, both cell survival (oxidative phosphorylation) and cell death (apoptosis) are related to mitochondrial function, especially oxidative phosphorylation of respiratory chain is associated with many human diseases. .

Luft et al. (1962) first reported a case of mitochondrial myopathy, biochemical studies confirmed oxidative phosphorylation decoupling, Anderson (1981) measured human mitochondrial DNA (mtDNA) full-length sequence, Holt (1988) first discovered mitochondrial disease patients with mtDNA deletion It is confirmed that mtDNA mutation is an important cause of human disease, and a new concept of mitochondrial inheritance different from traditional Mendelian inheritance is established.

According to different mitochondrial lesions, it can be divided into:

1. Mitochondrial myopathy: Mitochondrial lesions are mainly involved in skeletal muscle.

2. Mitochondrial encephalomyopathy: The lesion simultaneously invades the skeletal muscle and central nervous system.

3. Mitochondrial encephalopathy: lesions invade the central nervous system.

Mitochondrial disease 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. At present, there is still no good treatment for mitochondrial diseases, mainly symptomatic treatment. It may be beneficial to supplement the respiratory chain components or their analogues and vitamins, such as coenzyme Q10 and its analogue idebenone. Regular medical treatment can help delay the development of the disease, prevent and timely deal with some serious image quality of life and even life.

Mitochondrial complications Complications, spinocerebellar ataxia, epilepsy

Mitochondrial disease usually occurs in infants, children or early adulthood. It is a progressive or progressive disease course. The common manifestations of infants and young children are stillbirth or stillbirth, progressive encephalopathy, muscle weakness, epilepsy, growth retardation, etc. Performance includes binocular vision loss, young people with stroke-like episodes, myoclonic epilepsy, muscle weakness, eyelid ptosis and visual doubles, diabetes, gastrointestinal diseases, etc. Diseases caused by mtDNA mutations are generally maternally inherited, that is, patients can only obtain defective mtDNA from their mothers, and male patients will never have sick children. However, due to the influence of the proportion of mutant mtDNA in the body and the occurrence of new mutations in mitochondrial disease, a considerable number of patients have no clear family history of maternal. The respiratory chain defect disease caused by nuclear gene mutations is consistent with autosomal dominant, recessive or sporadic patterns. Certain neurodegenerative diseases have also been shown to be associated with respiratory chain defects such as certain Parkinson's syndrome and amyotrophic lateral sclerosis.

Symptoms of mitochondrial disease Common symptoms Fatigue, myopic myoclonus, deafness, mental retardation, hemianopia, conduction block, drooping, ataxia, calcification

1. Mitochondrial myopathy: Most of them start at the age of 20, and there are children and middle-aged onset. Both men and women are affected. The clinical feature is that skeletal muscle is extremely intolerant to fatigue, and mild activity is fatigued. Muscle soreness and tenderness, muscle atrophy are rare, easily misdiagnosed as polymyositis, myasthenia gravis and progressive muscular dystrophy.

2. Mitochondrial encephalomyopathy includes:

(1) Chronic progressive extraocular tendon (CPEO): mostly in childhood, the first symptom is drooping eyelids, slowly progressing to all extraocular tendons, eye movement disorders, bilateral extraocular muscles symmetrically involved, diplopia Uncommon; some patients have muscle weakness in the pharyngeal muscles and limbs.

(2) Keams-Sayre syndrome (KSS): onset before 20 years of age, rapid progression, CPEO and retinitis pigmentosa, often accompanied by heart block, cerebellar ataxia, increased CSF protein, neurological deafness and Intelligent decline, etc.

(3) mitochondrial myopathy with hyperlactosis and stroke-like seizure (MELAS) syndrome: onset before the age of 40, more childhood episodes, sudden stroke-like episodes, such as hemiplegia, hemianopia or cortical blindness, Repeated seizures, migraine and vomiting, the condition gradually worsened, CT and MRI can be seen occipital cerebral softening, the lesion range is inconsistent with the main cerebral vascular distribution, common brain atrophy, ventricular enlargement and basal calcification; blood and cerebrospinal fluid lactic acid increased.

(4) Myoclonic epilepsy with muscle hairy red fiber (MERRF) syndrome: mostly in childhood, mainly manifested in myoclonic epilepsy, cerebellar ataxia and proximal limb weakness, can be associated with multiple Sexually symmetric lipoma.

3. Mitochondrial encephalopathy: including Leber hereditary optic neuropathy (LHON), subacute necrotizing encephalomyelopathy (Leigh disease), Alpers disease and Menkes disease.

Mitochondrial examination

1. Blood biochemical examination: 1 blood lactic acid, pyruvic acid minimum exercise test: about 80% of patients after 10 minutes of exercise, blood lactate and pyruvic acid can not return to normal, positive; mitochondrial myopathy patients CSF lactic acid content also increased; 2 mitochondria Respiratory chain complex enzyme activity is reduced.

2. mtDNA analysis: 1CPEO and KSS are missing mtDNA fragments, which may occur in the egg or embryo formation stage; 280% of MELAS patients are mtDNA, tRNA gene 3243 point mutation; MERRF syndrome is t84 gene locus 8344 point mutation.

3. Muscle frozen section: Gomori staining biopsy revealed mitochondrial accumulation in muscle cells, increased RRF and glycogen.

4. CT or MRI examination: mitochondrial encephalopathy patients with leukoencephalopathy, basal calcification, brain softening, brain atrophy and ventricular enlargement.

5. Electromyography: can be expressed as myogenic damage or neurogenic damage.

Diagnosis and diagnosis of mitochondrial disease

diagnosis

The diagnosis of mitochondrial myopathy relies on typical clinical symptoms: the proximal extremities are extremely intolerant of fatigue, short stature, and neurological deafness, with clinical features of each subtype; serum lactate, pyruvate and muscle biopsy find RRF, As a result of mtDNA deletion or point mutation, mitochondrial myopathy patients with leukoencephalopathy, basal calcification, brain softening, brain atrophy and ventricular enlargement can be seen by CT or MRI.

Differential diagnosis

However, it should be noted that inflammatory myopathy and other myopathy may be associated with the accumulation of mitochondria and glycogen, and to prevent excessive diagnosis of mitochondrial myopathy.

Mitochondrial myopathy needs to be differentiated from polymyositis, myasthenia gravis, periodic paralysis and progressive dystrophy of the eye and pharynx.

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