hereditary ataxia
Introduction
Introduction to hereditary ataxia Hereditary ataxia (hereditaryataxia) is a group of hereditary degenerative diseases characterized by chronic progressive cerebellar ataxia; the genetic background passed down from generation to generation, the ataxia manifestation and the pathological changes dominated by cerebellar damage are three major features. In addition to the involvement of the cerebellum and conductive fibers, this group of diseases often involve the posterior column of the spinal cord, pyramidal tract, pons nucleus, basal ganglia, cranial nerve nucleus, spinal ganglia and autonomic nervous system. The ataxia gait first appears and gradually worsens, eventually causing the patient to stay in bed, with complex clinical symptoms and overlapping, even if the same family can exhibit high heterogeneity. basic knowledge The proportion of illness: 0.004% Susceptible people: no special people Mode of infection: non-infectious Complications: arrhythmia respiratory infection
Cause
Causes of hereditary ataxia
Genetic inheritance (90%):
Cerebellar ataxia (CA) is an autosomal dominant inheritance. In recent years, some subtype genes have been cloned and sequenced, showing that the causal gene trinucleotide (such as CAG) repeats dynamic mutations, copy number Generation is the cause of the disease.
Autosomal dominant cerebral cerebral ataxia has genetic heterogeneity, and the most characteristic gene defect is that the amplified CAG trinucleotide repeat encodes a polyglutamine channel, which is a functionally unknown protein ( Ataxins) and P/Q-type calcium channel 1A subunits found on nerve endings; other types of mutations include CTG trinucleotide (SCA8) and ATTCT pentanucleotide (SCA10) repeat amplification, in many cases this The size of the amplified fragment is related to the severity of the disease, and the younger the age of onset, the heavier the condition.
Friedreich-type ataxia (FRDA) is caused by the abnormal amplification of the GAA trinucleotide repeat of the non-coding region of the frataxin gene of the long arm of chromosome 9 (9q13-12.1). The normal GAA repeat amplification is less than 42 times, and the patient abruptly expands. (66 to 1700 times) formation of an abnormal helical structure can inhibit gene transcription.
Pathogenesis
The pathological changes of cerebellar ataxia (ADCA) mainly include cerebellum, spinal cord and brainstem degeneration, so it is also called spinocerebellar ataxia (SCA). According to clinical features and gene mapping, it is divided into SCA1~21 subtypes.
SCAs mutations alter the properties of proteins that are not normally processed. The abnormally processed fragments bind to a ubiquitin that is involved in non-lysosomal degradation and are transported together as a protease complex. In the nucleus, it is speculated that this nuclear protein aggregation can affect the function of the nucleus. Each SCA subtype gene is located on a different chromosome, with different sizes and gene mutation sites. For example, the SCA1 gene is located on chromosome 6q22-23, and the genome span is 450Kb. The cDNA is 11Kb long and contains 9 exons. It encodes 816 amino acid residues to form the ataxia-1 protein. The protein is located in the nucleus. The CAG mutation is located in exon 8 with an amplified copy number of 40-83 and a normal human 6~. 38, SCA3 (MJD) is the most common SCA subtype in China, the gene is located in 14q24.3-32, contains at least 4 exons, encodes 960 amino acid residues to form ataxia-3 protein, distributed in the cytoplasm, CAG mutation Located in exon 4, the amplified copy number is 61-89, and the normal person is 12-41.
Although SCA has a common genetic mutation mechanism, resulting in similar clinical manifestations of different subtypes, there are still differences, such as with ophthalmoplegia, and some with retinitis pigmentosa, pathological lesions and extent are different, suggesting that in addition to polygeneration In addition to the toxic effects of glutamine, other factors may also be involved in the onset of the disease.
The common pathological changes of SCA are mainly cerebellum, brainstem and spinal cord degeneration and atrophy, but each subtype also has its characteristics. For example, SCA1 is mainly cerebellum, brainstem neurons are lost, spinal cord cerebellar tract and posterior cord are damaged, and rarely involved. Substantia nigra, basal ganglia and anterior horn cells; SCA2 below the olive nucleus, pons, cerebellar damage is heavy; SCA3 mainly damages the pons and spinal cerebellar tract; SCA7 is characterized by retinal neuronal degeneration.
The Friedreich-type ataxia (FRDA) gene product frataxin protein is present in the mitochondrial inner membrane of the spinal cord, skeletal muscle, heart and liver, leading to mitochondrial dysfunction and the onset of disease. The more repeated the expansion, the earlier the onset of the disease, the visible spinal cord changes Fine, thoracic segment; microscopically showed posterior cord, spinal cord cerebellar tract and corticospinal degeneration, loss of posterior root ganglia and Clarke column neurons, peripheral gliosis, brainstem, cerebellum and brain involvement, light heart The heart muscle is enlarged and enlarged.
Prevention
Hereditary ataxia prevention
Genetic counseling should be carried out. Preventive measures include avoidance of close relatives, genetic testing of carriers and prenatal diagnosis and selective abortion to prevent the birth of the child. The disease develops slowly, such as no serious cardiopulmonary complications, most of which do not affect life. A small number of patients are bedridden and disabled.
Complication
Hereditary ataxia complications Complications, arrhythmia, respiratory infection
Cardiopulmonary complications, such as heart enlargement, arrhythmia, respiratory infections, etc.
Symptom
Hereditary ataxia symptoms Common symptoms Limb movement incoordination Reflex disappearing Capsules Fatigue dysfunction Obstruction optic atrophy Reflex hyperthyroidism
Clinical symptoms
1, Friedreich type ataxia: Friedreich's ataxia is the most common idiopathic degenerative disease showing cerebellar ataxia, first reported by Friedreich (1863), the disease has unique clinical features, such as Childhood onset, progressive ataxia, with pyramidal tract sign, difficulty in pronunciation, deep paresthesia, scoliosis, arched foot and heart damage.
(1) usually starting from 4 to 15 years old, occasionally seeing babies and those who are sick after 50 years old, both men and women can be affected. The first symptom is progressive gait ataxia, gait squatting, shaking from side to side, easy to fall; within 2 years Bilateral upper limb ataxia occurs, showing awkward and intentional tremors; at this early stage, knee reflexes and tendon reflexes disappear, cerebellar dysarthria or fulminant language appears, both upper limb reflexes and some patients' knee reflexes can be preserved The lower extremity joint position sense and vibration sense are impaired, light touch, pain and temperature are usually not affected, and the lower limb weakness is late, which may be damage to the upper or lower motor neurons, or both.
(2) The patient usually has an extensor sacral reflex within 5 years before the onset of symptoms. The medial muscle weakness and atrophy lead to the arched foot with the claw toe. It is a common sign, or it can be an isolated manifestation of an unaffected family member. Progressive Severe posterior scoliosis can lead to functional disability and chronic restrictive lung disease. Cardiomyopathy can sometimes only be detected by echocardiography, which can lead to congestive heart failure, which is the main cause of death. Other abnormalities include optic atrophy, eyeball Tremor (mostly horizontal), paresthesia, tremor, hearing loss, dizziness, paralysis, lower extremity pain and diabetes.
(3) The physical examination showed that the knees were tested positively and closed eyes were difficult to stand up. 75% had upper thoracic spinal deformity, about 25% had optic atrophy, 50% had arched feet, and 85% had arrhythmia or heart murmur. 10% to 20% with diabetes.
(4) Auxiliary examination: 1X slice can be seen in spine and skeletal deformity; MRI can be seen to be thinned; 2 ECG common T wave inversion, arrhythmia and conduction block, echocardiogram showing ventricular hypertrophy, visual evoked potential amplitude decrease; 3DNA analysis FRDA Gene 18 intron GAA is greater than 66 repeats.
2, spinal cerebellar ataxia: Spinocerebellar ataxia (SCA) is the main type of hereditary ataxia, including SCA1 ~ 21, adulthood, autosomal dominant inheritance and ataxia, etc. It is a common feature of this disease, and it is manifested in the age of onset and the severity of the disease in several consecutive generations (genetic early onset). The symptoms of each subtype are similar, overlapping and overlapping. The phenomenon of early prevalence is a typical manifestation of SCA, and the symptoms are aggravated from generation to generation.
(1) SCA common symptoms and signs: 30 to 40 years old insidious onset, slow progress, there are also children and 70-year-old patients; lower limb ataxia is the first symptom, showing walking shaking, sudden fall and speech ambiguity, As well as clumsy hands, intentional tremor, nystagmus, dementia and distal muscle atrophy; examination can be seen dystonia, hyperreflexia, pathological signs, gait gait, tuning fork vibration sense and loss of proprioception, usually 10 ~ after onset Can't walk for 20 years.
(2) In addition to the common clinical manifestations, each subtype has its own characteristics, such as SCA1 ophthalmoplegia, upper eye can not be more obvious; SCA2 upper limb paralysis reflexes weakened or disappeared, eyeball slow saccade movement was more obvious; SCA3 muscle atrophy, facial muscle And lingual muscle fibrillation, eyelid retraction to form a convex eye; SCA8 often has difficulty in pronunciation; SCA5 disease progresses very slowly, mild symptoms; SCA6 early thigh muscle spasm, lower tremor, diplopia and positional vertigo; SCA10 pure cerebellar sign and Seizures; SCA7 loss of vision or loss, retinitis pigmentosa, heart damage is also prominent.
3, hereditary paraplegia: most of them are autosomal dominant, but also have autosomal recessive or sexual recessive inheritance, mostly in children, more common in men, mainly manifested as progressive progressive lower extremity spasm The early symptoms are stiff legs during walking, inflexibility, weak muscle strength, scissor gait due to increased tension of the extensor muscles of the lower extremities, active knee and Achilles tendon reflexes, positive pathological signs, and more unobstructed feelings, most of which have arched feet, but Not as good as Friedreich's ataxia disorder, sometimes accompanied by nystagmus and scoliosis, the disease progresses slowly, and the upper limbs are also affected. For example, when the medullary innervation muscles are involved, dysarthria may occur, dysphagia, and late sphincter function also occur. Mild obstacles.
Clinically, only according to the characteristic symptoms of each subtype, the signs are still difficult to diagnose (except SCA7), and the number of subtypes and CAG amplification can be accurately determined by PCR method for gene diagnosis.
Examine
Hereditary ataxia
Laboratory inspection
1, spinal cerebellar ataxia cerebrospinal fluid examination is normal.
2, confirmed SCA and differentiated subtypes of feasible PCR analysis, using peripheral blood leukocytes to detect the corresponding gene CAG amplification, to prove the genetic defects of SCA.
3, Friedreich type ataxia (FRDA): DNA analysis, FRDA gene 18 intron GAA greater than 66 repeats.
Film degree exam
1, spinal cord cerebellar ataxia CT or MRI shows cerebellar atrophy is very obvious, sometimes brain stem atrophy; brain stem evoked potential can be abnormal, EMG shows peripheral nerve damage.
2, Friedreich type ataxia (FRDA) X-ray can be seen in the spine and skeletal deformities; MRI can be seen in the spinal cord to be thin; ECG common T wave inversion, arrhythmia and conduction block, echocardiography showing ventricular hypertrophy, visual evoked potential amplitude decreased.
Diagnosis
Diagnosis and identification of hereditary ataxia
diagnosis
1. Friedreich type ataxia (FRDA) diagnosis: According to the onset of childhood or adolescence, progressive ataxia develops from the lower extremities to the upper extremities, and obvious deep sensory disturbances such as vibratory sensation of the limbs, disappearance of positional sense, disappearance of tendon reflexes, etc. It can usually be diagnosed, such as dysarthria, scoliosis, arched foot, cardiomyopathy, MRI showing spinal atrophy and abnormal amplification of FRDA gene GAA can be diagnosed.
2, SCA diagnosis: according to ataxia, dysarthria, pyramidal tract signs and other typical common symptoms, as well as with ophthalmoplegia, extrapyramidal symptoms and retinitis pigmentosa, combined with MRI examination found that the cerebellum, brain stem atrophy, Excluding other involvement of cerebellum and brain stem degeneration can be clinically diagnosed.
Differential diagnosis
1. Subacute combined degeneration of the spinal cord is slowly onset, and the posterior cord and pyramidal tract are involved at the same time. Deep sensory disturbance, ataxia, spastic paraplegia and sensory abnormality at the distal end of the limb, but no arched foot and posterior scoliosis Malformations, often accompanied by gastric acid deficiency and serum vitamin B12 levels and pernicious anemia.
2, multiple sclerosis lesions, there may be spinal cord, cerebellar degeneration, cerebellar ataxia and pyramidal tract signs, but the course often relieved and recurred, increased immunoglobulin in cerebrospinal fluid.
3, cerebellar tumors are more common in children, slow onset cerebellar ataxia, but prone to symptoms and signs of increased intracranial pressure, and no genetic history.
4, ring occipital deformity such as skull base depression, vertebral occipital ossification and cervical fusion, in addition to ataxia is often accompanied by posterior cranial nerve damage, short neck, segmental or conduction beam type sensory disturbance.
