Pediatric autosomal recessive cerebellar ataxia

Introduction to children with autosomal recessive cerebellar ataxia Among the diseases such as autosomal recessive cerebellar ataxia (autosomal recessivecerebellarataxias), Friedreich ataxia and ataxia telangiectasia are more important. The focus is on the former. Friedreichsataxia (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 accompanied by Skeletal deformity. 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. basic knowledge The proportion of illness: 0.002% Susceptible people: children Mode of infection: non-infectious Complications: optic atrophy cataract diabetes

Pediatric autosomal recessive cerebellar ataxia

(1) Causes of the disease

The disease is autosomal recessive, a few is sporadic, the disease-causing gene (FRDA) is located in 9q13, a mutant form of FRDA, a few are point mutations, and 98% are GAA trinucleotide repeat extensions, normal human GAA expansion The number of different ethnic groups varies from 7 to 22 or 5 to 10. The number of GAA extensions in FA patients can reach 200 to 900. There is no overlap with the number of repeats in normal people. The number of GAA repeats is negatively correlated with the onset age. Those who are 3 to 20 years old have a repetition rate of 800 to 900; those who start from 30 years old have a repeat number of 201 to 734, accompanied by diabetes or hypertrophic cardiomyopathy, and the number of repetitions is high. Recently, exceptions have been reported. : Some typical clinical symptoms without GAA expansion; while some GAA expand but do not have typical clinical symptoms of FA (McCabe et al, 2000).

(two) pathogenesis

Mutations lead to a decrease in the gene product, the mitochondrial protein frataxin, which is the most highly expressed tissue of frataxin; the expression of liver, skeletal muscle and pancreas is moderate; when the gene is mutated, the tissue with the highest gene expression level is the first to be involved, thus the spinal cord Denaturation and cardiomyopathy are the main manifestations of FA. The basic cause of tissue pathology is not fully understood. It is believed that frataxin directly affects mitochondrial energy metabolism and oxidative phosphorylation. It is also believed that frataxin has a regulatory function on mitochondrial iron transport. It is believed that the occurrence of this disease is related to the abnormal distribution of iron in the cells. Iron deposition in the mitochondria induces oxygen free radicals and causes cell damage. It is also believed that the occurrence of this disease is related to abnormal metabolism of inositol phospholipids and affects nerve impulses. Synaptic transmission.

The disease has a wide range of lesions. The most prominent pathology is found in the spinal cord, the posterior column of the spinal cord, the spinal cord cerebellar tract, the pyramidal tract, and the posterior root can be seen with myelin loss and axonal degeneration. The spinal cord lumbosacral involvement is the heaviest, and the cerebellar cortex is degenerated. The dentate nucleus, the lower olive nucleus, the vestibular nucleus, and the pons nucleus have different degrees of degeneration. It has been reported that there are 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.

Prevention of autosomal recessive cerebellar ataxia in children

Treatment is quite difficult. Prenatal diagnosis is the key to reducing the onset of disease. Long PCR can be used to detect the number of GAA repeats to make a genetic diagnosis, carrier diagnosis and prenatal diagnosis, and termination of pregnancy if necessary.

Pediatric autosomal recessive cerebellar ataxia complications Complications, optic atrophy, cataract, diabetes

Can occur scoliosis, arched foot or varus, limb muscle atrophy and weakness, limbs awkward, dysarthria, pyramidal tract signs or deep sensation reduction or disappearance, optic atrophy, cataract, mental retardation, psychological process Slowness and emotional instability, etc., can occur arrhythmia, heart failure, diabetes and so on.

Children with autosomal recessive cerebellar ataxia symptoms Common symptoms Gait instability, weak sensory dysfunction, nystagmus, scoliosis, paralysis, reflex, electrocardiogram, abnormal fasciculation, tremor, mental retardation, arched foot

Typical case

The onset age is 2 to 16 years old, with an average age of 11 years. Most of them start from the age of 20 years. The first symptoms are torso and lower limb ataxia, gait is unstable, running is difficult, Romberg sign is positive (both lower limbs can not stand together) ), later involved in the upper limbs, manifested as tremor, positive nasal test, rotational dysplasia, etc., a few cases with scoliosis, limb awkwardness or heart disease as the first symptom, early does not necessarily have dysarthria, pyramidal tract sign or Deep feelings are reduced or disappeared. After several years, these symptoms appear one after another. The Achilles tendon and knee tendon reflex disappear. Most patients have upper limb paralysis reflexes that disappear or weaken. Bilateral Bakr's sign is positive but muscle tension is not high. Lower limb vibratory sense and position. Decreased or disappeared, tactile sensation, pain, normal temperature, more than 2/3 patients have scoliosis, severe affecting cardiopulmonary function, common arched foot or varus in Figure 1, late visible distal muscle atrophy and weakness, The lower extremities are more obvious than the upper limbs. In the advanced stage, optic atrophy, cataract, nystagmus, a few patients have sensorineural deafness, dizziness, mental retardation in the late stage of the disease, and the mental process slows down. Xu instability are not uncommon.

Cardiomyopathy is often progressive, arrhythmia, heart failure can occur after ataxia symptoms, but also before, ECG abnormalities can be detected before neurological symptoms appear, visible T wave inversion, ST segment decline, QRS Low amplitude or arrhythmia, enlarged heart, murmur, echocardiography showing hypertrophic cardiomyopathy, late heart failure, in addition, diabetes or impaired glucose tolerance is about 10% to 20% of patients, usually 30 to 40 years old It is obvious.

Somatosensory evoked potentials were abnormal regardless of the stage or severity of the disease. EMG showed fasciculation, MRI showed spinal atrophy, and the upper neck was obvious. PET in the patients who were still able to walk showed that the local glucose metabolism rate was higher than normal. In patients who are unable to walk in the advanced stage, the local metabolic rate is reduced.

2. Atypical Friedreich ataxia

It is often seen that it may be due to different alleles or 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 reflex: Before the age of 15 years, knees, tendon reflexes, early cardiomyopathy, and high mortality.

(3) FA with vitamin E deficiency: clinical symptoms of typical FA, vitamin E deficiency.

(4) Cases without myocardial disease, 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, 1~ It is 15 years old and has a long life.

Examination of autosomal recessive cerebellar ataxia in children

1. Cerebrospinal fluid examination of children with cerebrospinal fluid examination is normal, occasionally mild protein increase and slight increase in cell number.

2. Blood sugar check blood sugar, glucose tolerance test is not normal.

3. Muscle biopsy revealed demyelination and axonal rupture of large diameter nerve fibers, as well as non-specific neuromuscular atrophy.

4.DNA detection Since 98% of the FRDA gene can detect GAA repeat expansion, long PCR can be used to detect the number of GAA repeats to make genetic diagnosis, carrier diagnosis and prenatal diagnosis, if only on one allele With GAA repeat expansion (heterozygous), it is necessary to further examine the presence or absence of point mutations in the other allele.

5. ECG examination showed prolonged QT interval or T wave inversion, arrhythmia.

6. Electromyography showed that the sensory nerve conduction velocity slowed down, the sensory nerve conduction velocity disappeared in the lower limbs, the upper limbs slowed down, and the electromyogram showed denervation abnormalities.

7. CT, MRI examination of the head CT examination of normal or mild abnormalities, MRI showed spinal cord thinning, atrophy, cerebellum and brain stem atrophy.

8. Evoked potential examination has abnormal evoked potentials. Visual evoked potentials may have prolonged latency and decreased amplitude, suggesting axonal degeneration, but clinically no visual symptoms. Auditory evoked potentials may be reduced or disappeared from mastoid recordings. Related to ganglion degeneration, there is no clinical auditory symptoms, and somatosensory evoked potentials are abnormal.

Diagnosis and diagnosis of autosomal recessive cerebellar ataxia in children

diagnosis

According to the clinical symptoms and family history, a preliminary diagnosis can be made, but because the phenotype of the disease is very different, the most accurate diagnosis depends on DNA detection. Before DNA analysis, refer to the clinical diagnostic criteria of Harding (1981). Possible diagnosis:

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.

Differential diagnosis

The disease needs to be identified with other hereditary chronic progressive ataxia in childhood.

1. Ataxia telangiectasia has telangiectasia, immunodeficiency, no bone deformity, no sensory disturbance.

2. No -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 is hyperreflexia of the knee, which may be accompanied by optic atrophy and mental retardation.

5.Marinesco-Sjorgren syndrome has congenital cataract and mental retardation.

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