Introduction
Autosomal recessive cerebellar ataxia(autosomal recessive cerebellar ataxias) Among these diseases, the more important ones are Friedreich ataxia,Ataxia telangiectasiaEtc. This section focuses on the former. Friedreichs ataxia (FA) is an autosomal recessive disorder characterized by childhood onset, progressive ataxia, cardiomyopathy, deep sensory loss of the lower extremities, loss of tendon reflexes, and pyramidal tract signs, often With skeletal deformities. It is known that this disease involves multiple systems and the clinical manifestations are complex and diverse. As the disease-causing gene is cloned and the gene is found to have GAA trinucleotide repeat extension, a new understanding of the pathogenesis of the disease has been made.
Cause
(1) Causes of the disease
The disease is autosomal recessive, and a few are sporadic. The disease-causing gene (FRDA) is located at 9q13. A mutated form of FRDA, a few are point mutations, and 98% exhibit a GAA trinucleotide repeat extension. The number of GAA extensions in normal people varies from 7 to 22 or from 5 to 10. The number of GAA extensions in patients with FA can reach 200-900, which does not overlap with the number of repetitions of normal people. The number of GAA repeats was negatively correlated with the onset age. For those who are 3 to 20 years old, the number of repetitions is 800 to 900; for those who start from 30 years old, the number of repetitions is 201 to 734. Those with diabetes or hypertrophic cardiomyopathy have more repetitions. There have been recent reports of exceptions: some typical clinical symptoms without GAA expansion; and some GAA extensions but no typical clinical symptoms of FA (McCabe et al., 2000).
(two) pathogenesis
Mutations in the gene result in a decrease in the gene product, the mitochondrial protein frataxin. The spinal cord and myocardium are the tissues with the highest expression of frataxin; the expression of liver, skeletal muscle and pancreas is moderate. In the case of gene mutation, the tissue with the highest gene expression level is the first to be involved, so spinal cord degeneration and cardiomyopathy are the most important manifestations of FA. The basic reasons for tissue lesions are not fully understood. It is believed that frataxin directly affects the energy metabolism and oxidative phosphorylation of mitochondria. It is also believed that frataxin has a regulatory function on the transport of mitochondrial iron. It is believed that the occurrence of this disease is related to the abnormal distribution of intracellular iron, and iron deposits in the mitochondria induce Oxygen free radicals cause cell damage. It is also believed that the occurrence of this disease is related to abnormal metabolism of inositol phospholipids, affecting the synaptic transmission of nerve impulses.
The disease has a wide range of lesions. The most prominent pathology is found in the spinal cord. Myelin degeneration and axonal degeneration were seen in the posterior column of the spinal cord, the cerebellar tract of the spinal cord, the pyramidal tract, and the posterior root. The lumbosacral spine is the most affected. The cerebellar cortex is degenerated. The dentate nucleus, the lower olive nucleus, the vestibular nucleus, and the pons nucleus also have varying degrees of degeneration. There have been reports of slight neuronal changes in the cerebral cortex motor area. Cardiomyopathy is one of the characteristics of this disease, often progressive cardiac hypertrophy, chronic interstitial fibrosis and inflammatory infiltration.
symptom
1. The typical age of onset is 2 to 16 years old, with an average age of 11 years. Most people start to get sick before the age of 20. The first symptom is ataxia and lower limb ataxia, gait is unstable, running is difficult, Romberg sign is positive (both lower limbs can not stand together). Later, the upper limbs were involved, which showed tremor, positive finger and nose test, and poor rotation. A few cases have scoliosis, limb clumsi or heart disease as the first symptom. Early signs of dysarthria, pyramidal tract signs, or deep sensations are reduced or disappeared, and these symptoms appear several years later. Achilles tendon and knee reflexes disappeared, and most patients with upper limb paralysis also disappeared or weakened. Bilateral Bakr's sign is positive but muscle tone is not high. The vibration and position of the lower limbs weaken or disappear, and the sense of touch decreases. Pain and warmth are normal. More than 2/3 patients have scoliosis, and severe cases affect cardiopulmonary function. In the late stage, the distal muscles of the limbs were atrophied and weak, and the lower limbs were more obvious than the upper limbs. In the advanced stage, optic atrophy, cataract, and nystagmus can also be seen. A small number of patients have sensorineural deafness and dizziness. Late mental retardation, slow mental processes and emotional instability are not uncommon.
Cardiomyopathy is often progressive. Arrhythmia and heart failure can occur after the symptoms of ataxia, or they can appear before. An abnormal ECG can be detected before the onset of neurological symptoms. It can be seen that the T wave is inverted, the ST segment is decreased, and the QRS amplitude is low or arrhythmia. The heart is enlarged, there is noise, echocardiography shows hypertrophic cardiomyopathy, and late heart failure. In addition, abnormalities in diabetes or impaired glucose tolerance are seen in 10% to 20% of patients, usually at 30 to 40 years of age.
Somatosensory evoked potentials are abnormal regardless of the stage or severity of the disease. Electromyography shows fasciculation. MRI showed spinal atrophy and obvious upper neck. In patients with PET walking, the local glucose metabolism rate is higher than normal, while in patients who are unable to walk in the late stage, the local metabolic rate is reduced.
2. Atypical Friedreich ataxia is often seen, probably due to different alleles, and may be other diseases, and genetic diagnosis is often required for diagnosis.
(1) Late-type Friedreich: Onset at about 30 years of age, the progress is slower and the symptoms are milder.
(2) FA preserved by sputum reflexes: onset before the age of 15 years, knee and tendon reflexes exist, early cardiomyopathy, and high mortality.
(3) FA with vitamin E deficiency: clinical symptoms of typical FA, vitamin E deficiency.
(4) Cases without cardiomyopathy, skeletal abnormalities, and muscle atrophy.
(5) MRI showed cases of mild degeneration of the spinal cord and severe degeneration of the cerebellum.
(6) Ataxia with eye movement apraxia: autosomal recessive inheritance, progressive cerebellar ataxia, loss of tendon reflex, peripheral neuropathy, ocular apraxia, scoliosis, varus. It is ill from 1 to 15 years old and has a long life.
diagnosis
Based on clinical symptoms and family history, a preliminary diagnosis can be made, but because the phenotype of the disease varies widely, the most accurate diagnosis depends on DNA testing. Prior to DNA analysis, refer to Harding's (1981) clinical diagnostic criteria to make possible diagnoses:
1. The child is sick.
2. Recessive inheritance.
3. Progressive torso and lower limb ataxia.
4. The lower extremity tendon reflex disappears.
5. Gradual dysarthria, pyramidal tract signs, deep sensory disturbances, and limb weakness.
6. Cardiomyopathy.
7.10% with diabetes, or impaired glucose tolerance.
8. About 2/3 have scoliosis and arched feet.
9. A small number of distal muscle atrophy, optic atrophy, cataract, nystagmus.
Identification
The disease needs to be identified with other hereditary chronic progressive ataxia in childhood.
1. Ataxia telangiectasia There are telangiectasia, immunodeficiency, no bone deformity, no sensory disturbance.
2. No β-lipoproteinemia has erythrocytosis, steatorrhea, and decreased blood lipids.
3. Refsum disease has night blindness, retinitis pigmentosa, ichthyosis, and increased serum phytanic acid.
4. Hereditary spastic paraplegia Knee paralysis is hyperthyroidism, which may be accompanied by optic atrophy and mental retardation.
5.Marinesco-Sjorgren syndrome has congenital cataract and mental retardation.
complication
Scoliosis, arched foot or varus foot, muscle atrophy and weakness of the distal limbs, awkward limbs, dysarthria, pyramidal tract sign or deep sensation reduction or disappearance, optic atrophy, cataract, mental retardation, psychological process Slow down and emotional instability. Arrhythmia, heart failure, diabetes, etc. can occur.
treatment
Western medicine treatment
There is no special treatment for this disease. It can be treated symptomatically. Surgical treatment of scoliosis should be cautious. If the patient is able to walk with a side bend of more than 40°, surgery should be considered. Cardiopulmonary function should be monitored before surgery. Severe cardiomyopathy treats heart loss. Those with diabetes can try it outinsulinBut more than invalid. In the early stages of the disease, try to do balance training and exercise muscle strength and do physical therapy. The authors have proposed trials of anti-oxidants, iron chelators, free radical scavengers and other drugs, and there is no empirical summary.
prevention
Treatment is quite difficult, and prenatal diagnosis is the key to reducing the incidence. Gene diagnosis, carrier diagnosis, and prenatal diagnosis can be performed using long PCR techniques to detect the number of GAA repeats. The pregnancy should be terminated if necessary.
Prognosis
The disease progresses slowly and cannot walk independently after 6 to 27 years of onset. The sooner you start, the sooner you can't walk. Cardiomyopathy and diabetes are indicators of poor prognosis and are the cause of death in most patients.
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