What Are the Different Types of Hereditary Ataxia?

In 1863, Friedrech first described SCA that occurred in adolescence, and further research on the disease has continued in the past. Nearly 30 SCA subtypes have been found, of which SCA3 is the most common type. SCAs account for about 10% to 15% of hereditary diseases of the nervous system. The prevalence of different subtypes varies greatly in different countries and ethnic groups. Friedreich ataxia (FRDA) is a common type of hereditary ataxia in Europe, but it is rarely reported in China; and SCAs are relatively common in China.

Ye Jing

(Chief physician)

Department of Neurology, Xuanwu Hospital, Capital Medical University

Hereditary ataxia (HA) is a group of genetic degenerative diseases of the nervous system with ataxia as the main clinical manifestation. The lesions are mainly in the spinal cord, cerebellum, and brain stem, so it is also called spinal-cerebellar-brain stem disease, also known as spinocerehenar ataxia (SCAs). More than adult onset (greater than 30 years old) manifested as balance disorders, progressive limb coordination dyskinesias, gait instability, articulation disorders, eye movement disorders, etc., and may be accompanied by complex neurological damage, such as the cone system, cone Damage to external systems, vision, hearing, spinal cord, and peripheral nerves can also be accompanied by impairment of cerebral cortical function such as cognitive dysfunction and / or mental behavior abnormalities. May also be accompanied by other system abnormalities.

Western Medicine Name: Hereditary ataxia
English name: hereditary ataxia, HA

Affiliated Department: Internal Medicine-Neurology
Contagious: Non-contagious
Whether to enter health insurance: Yes

Introduction to Hereditary Ataxia

Classification of hereditary ataxia diseases

The classification of hereditary ataxia is very confusing, and more than 60 types have been reported so far, but there is no unified and accepted classification method. Earlier, it was only divided into Friedreich type ataxia and Marie type ataxia, that is, it was divided into Friedreich type with spinal symptoms as the main manifestation, and cerebellum and brain stem mainly with spinal symptoms as Marie type Ataxia. The common classifications are as follows:

Classification of hereditary ataxia in the form of a syndrome

These classifications are named after the first individual to be discovered and reported. This is the earliest stage in the classification of hereditary ataxia. Some of these nomenclatures have continued to be used in the future, and some have been newly classified and named.

Names used: The following diseases are: Friedreich ataxia; Gerstmann-Straussler disease; Machado-Jo. seph disease

Name of the new classification: Menzel-type ataxia is now attributed to type I of OPCA (olive-pontine-cerebellar atrophy);

New name: Strflmpll-Lorrain disease is now called hereditary spastic paraplegia;

Ramsay-Humt syndrome is now called myoclonic cerebellar coordination disorder (DCM); Holmes type ataxia is now called cerebellar olive degeneration ataxia or cerebellar olive atrophy, or late-type cerebellar cortex atrophy; Bassenkornzweig syndrome is now named B-Lipoprotein Deficiency (ABL) or Achilles' Red Cell-13-Lipoprotein Deficiency; Marinenco-Sj & ouml; gren syndrome is now known as Hereditary Ataxia-Cataract-Dwarf-Intellectual Deficiency Syndrome; Roussy-Levy Syndrome The present name is Fibula atrophic ataxia; Louis-Bar syndrome is now called ataxia capillary telangiectasia; Refsum syndrome is now called hereditary ataxia polyneuritis-like disease, also known as phytane Acid storage disease; Hartnup is now called hereditary niacin deficiency; Biemond-Singh syndrome is now called posterior spinal column ataxia (PCA); Boller-Segarra syndrome is now called spinal pontine degeneration (SPD) ). ^[1]

Hereditary ataxias classified by anatomy

(1) Spinal cord type:

Friedreich ataxia.

Hereditary spastic paraplegia (Strumpell-Larrain disease).

Posterior spinal cord ataxia (Biemond syndrome).

(2) Spinal cerebellar type:

Hereditary spastic ataxia (Marie hereditary cerebellar ataxia).

-lipoprotein deficiency (Bassen-Kornzweig syndrome).

Ataxia telangiectasia (Louis-Bar syndrome).

Spinal-pontine degeneration.

(3) Cerebellar type:

Olive-pontine-cerebellar degeneration (Menzel disease).

Cerebellum-olive atrophy (Holmes disease).

Myoclonic cerebellar coordination disorder (Ramsay-Hunt syndrome).

Marinesco-Sj & ouml; gren syndrome.

Joseph disease.

Hartnup syndrome.

Vestibular cerebellar ataxia.

Hereditary ataxias classified by genetic type

Rosenberg (1982) classified the disease into the following categories.

(1) Autosomal dominant inheritance:

Olive-pontine-cerebellar atrophy type , , , (olivopontocerebellar atyophy, OPCA).

Machado-Joseph's disease (MJD).

cerebellar parenchymatous degeneration (CPD).

Spinal-pontine degeneration (SPD).

hereditary spastic paraplegia (HPG).

episodic ataxia (EA).

Posterior column ataxia (PCA).

(2) Autosomal recessive inheritance:

Olive-pontine-cerebellar atrophy type , (olivopontocerebellar atrophy, OPCA , ).

cerebellar parenchy matous degeneration type , , .

Myoclonic cerebellar ataxia, or Ramsay-Hunt syndrome.

Ataxia telangiectasia.

Friedreich ataxia.

Hereditary ataxias classified by genetic location

(1) Rosenberg classification: Rosenberg (1998) classified each cerebellar ataxia gene.

Autosomal dominant hereditary cerebellar ataxia-spinal cerebellar ataxia type I (SCA1): genetically located at 6p22 to 23, including CAG repeats, the main clinical manifestations are ataxia, cone system and cone Signs in vitro, with paralysis of extraocular muscles.

Spinal cerebellar ataxia type II (SCA2): It belongs to autosomal dominant inheritance, and its gene location is 12q23 24.1. Including CAG repeats, clinical manifestations of ataxia, mild cone and extrapyramid signs and nystagmus.

Spinal cerebellar ataxia type III (SCA3): autosomal dominant inheritance. The gene was located at 14q24.3 32 and contained CAG repeats. Clinical manifestations are ataxia, paralysis of extraocular muscles, and various cone and extrapyramid signs.

Spinal cerebellar ataxia type IV (SCA4): autosomal dominant inheritance. The gene is located at 16q21.1. Clinical manifestations are ataxia. Pyramid tract sign was positive, eye movement was normal, but with sensory axonal peripheral neuropathy.

Spinal cerebellar ataxia type V (SCA5): autosomal dominant inheritance. The gene is located in the centromere region of chromosome 11. The main clinical manifestations are ataxia, without eyeball and cone system involvement.

Dentate nucleus-Pallid bulb-Lewy body atrophy (dentatorubro-pallidolewisia atrophy, DRPLA): autosomal dominant inheritance. The gene is located at the 12p12 end and contains CAG repeats. Clinical manifestations are ataxia, dystonia (hand and foot movement), myoclonus and epilepsy, dementia, etc.

Spinal cerebellar ataxia type (SCA7): Autosomal dominant inheritance, gene mapping 3p12-21.1, rhodopsin gene, including CAG repeats. Clinical manifestations are ataxia and retinal pigment degeneration.

Paroxysmal ataxia- (EA-1): Autosomal dominant inheritance. The gene is located at 12p. Potassium channel gene- (KCNA-), the main clinical feature is episodic ataxia, shock or motion-induced, lasting several minutes each time, with fibrillation of facial and hand muscles during the attack, the application of phenytoin is effective. The disease does not progress.

Paroxysmal ataxia- (EA-2): Also known as spinal cerebellar ataxia- (SCA6) type. Autosomal dominant inheritance, gene mapping 19p. Repeated CAG, manifested as ataxia, cerebellar atrophy, point mutations with episodic ataxia or familial hemiplegia migraine. Clinical manifestations are paroxysmal ataxia, tension and fatigue can be induced, and each episode lasts for several days. A nystagmus occurs when looking down. The course of disease is progressive.

ReFriedreich ataxia: autosomal recessive inheritance, gene mapping at 9p13 21.1, including CAA repeat, clinical manifestations of ataxia in adolescents, with scoliosis, high foot arch, ankle reflex disappear, positive pathological tract signs and lower limb position sense Disappeared, accompanied by diabetes, cardiomyopathy, and mitochondrial iron transport disorders.

Friedreich Syndrome: Autosomal recessive inheritance, the gene is located at 8q13.1 13.3. It is caused by tocopherol protein deficiency.

Ataxia telangiectasia: Autosomal recessive inheritance, genetically located at 11q23, clinical features are ataxia, capillary dilatation, dysarthria, often with lymphoid malignancies and IgA, IgG deficiency. He died of secondary lung infection.

Cerebellar ataxia in infancy: autosomal recessive inheritance, the gene is located at 10q23.3 24.1. The clinical manifestations are ataxia in infants, paralysis of the ophthalmomotor, deafness, slow movements of hands and feet, sensory peripheral neuropathy and optic nerve atrophy, and female gonadal dysgenesis.

Kearns-Sayre's syndrome: Sporadic, caused by deletion or duplication of mtDNA. Clinical manifestations are ataxia, ptosis, extraocular muscle paralysis, retinal pigment degeneration, diabetes, cardiomyopathy, and elevated cerebrospinal fluid protein.

Mitochondrial encephalomyopathy.

Causes of Hereditary Ataxia

Cerebellar ataxia (CA) is an autosomal dominant inheritance. In recent years, some subtype genes have been cloned and sequenced. It shows that the trinucleotide (such as CAG) repeat mutations of pathogenic genes are dynamically mutated. Increasing generations are the cause.

Autosomal dominant inherited spinal cerebellar ataxia has genetic heterogeneity. The most characteristic genetic defect is that the amplified CAG trinucleotide repeat encodes a polyglutamine channel, which is in 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) repeats, which in many cases The size of this amplified fragment is related to the severity of the disease, and the younger the age of onset, the heavier the disease.

Friedreich type ataxia (FRDA) is caused by abnormal amplification of GAA trinucleotide repeats in the non-coding region of the frataxin gene of the long arm of chromosome 9 (9q13-12.1). Normal GAA repeats the amplification less than 42 times. Patients have abnormal amplification. (66 to 1700 times) formation of abnormal spiral structure can inhibit gene transcription.

Pathogenesis of hereditary ataxia

Hereditary ataxia triglyceride dynamic mutation

The pathological changes of cerebellar ataxia mainly show degeneration of cerebellum, spinal cord, and brainstem, so it is also called spinal cerebellar ataxia (SCA). It is divided into 1 to 21 subtypes of SCA according to clinical characteristics and gene mapping, belonging to trinucleotide. Dynamic mutation.

Dynamic triglyceride mutation: It is caused by the unstable amplification of the copy number of base repeat units in DNA. Under normal circumstances, there is a limit to the number of duplicate units, but under dynamic mutations, it is greatly increased. For example, in SCA-1, the number of duplicate unit copies is 39-91, while normal is only 6-44. Repetitive unit fragments in dynamic mutations range in size from 3 bases to 33 bases in length. Dynamic mutations have the following characteristics: the number of duplicate unit copies is inversely proportional to the age of onset, and

The severity of the disease is directly proportional, which is why dynamic mutations have the characteristic of early genetic appearance; dynamic mutations are divided into two types based on exons and exons, the former such as SCA, the latter such as FRAD, and the latter based on Whether it is in the translation area and divided into two types, the copy number of the repeat type of the former type is less than one hundred, the latter type is unlimited, reaching thousands; the repeating order is (CAG) 1'1. The CAG copy number is abnormally amplified. Because these amplified CAG short tandem repeats encode polyglutamine chains, and the number of repetitive pathogenicity is about 40 times, it can be speculated that different subtypes have similar pathogenesis. The mutation of SCAs gene changes the properties of the protein so that it cannot be processed normally. The abnormally processed fragment is combined with a defective protein ubiquitin that is involved in the degradation of non-lysosomes and is transported together as a protease complex. Into the nucleus, it is speculated that this accumulation of nuclear proteins can affect the function of the nucleus. Each SCA subtype gene is located on a different chromosome, with different sizes and mutation sites. For example, the SCA1 gene is located on chromosome 6q22-23, the genome spans 450Kb, the cDNA is 11Kb, contains 9 exons, and encodes 816 amino acid residues. The base is composed of ataxia-1 protein, which is located in the nucleus, CAG mutation is located in exon 8, the amplified copy number is 40-83, and normal people is 6-38. SCA3 (MJD) is the most common SCA subtype in China. The gene is located at 14q24.3-32, contains at least 4 exons, encodes 960 amino acid residues to form the ataxia-3 protein, and is distributed in the cytoplasm. The CAG mutation is located in 4 Exon No., the amplified copy number is 61-89, and normal people is 12-41.

Because CAG repeated amplification occurs in the coding region of the gene, this mutation allows the target protein to acquire a certain new function, causing the target protein to attract multiple components in the nucleus to form inclusion bodies. These inclusion bodies are excessively deposited, which activates a variety of cytokines and metabolic pathways, eventually leading to apoptosis and neuron degeneration. Pathological observations. Nucleic inclusions include proteolytic enzymes, molecular chaperones, and cysteine aspartase, so it is speculated that proteolytic enzyme pathways and apoptotic pathways are involved in the pathogenesis of such diseases, of which ubiquitin-I The role of protease system and cysteine aspartase in the pathogenesis of such diseases has been confirmed.

Friedreich type ataxia (FRDA) gene product frataxin protein exists in the inner mitochondrial inner membrane of spinal cord, skeletal muscle, heart and liver cells, causing mitochondrial dysfunction and pathogenesis. The more repeated amplification, the earlier the age of onset. The spinal cord becomes thinner and the thoracic segment is obvious to the naked eye. Microscopy shows degeneration of the posterior cord, spinal cerebellar tract, and cortical spinal tract. The posterior root ganglia and Clarke column neurons are lost. Peripheral glial hyperplasia occurs. light. The heart is enlarged due to myocardial hypertrophy.

DNA Hereditary ataxia DNA repair defect

Ataxia related to DNA repair include telangiectasia (AT), xeroderma pigmentosa (xP), and Cockayne syndrome. AT has a complex progressive neurological syndrome, telangiectasias, and immunodeficiency, and both humoral and cellular immunity are defective.

In the test, hypogammaglobulinemia was found, the selective IgA, IgE, and IgG in the serum were reduced or lacking, the number of peripheral blood lymphocytes was reduced and the function was abnormal, and there was atrophy of the thymus, lymph nodes, and tonsils, indicating that the disease has immune organs Of atrophy and why prone to infection. After the skin fibroblasts were cultured, the DNA repair function was confirmed to be defective by radiation irradiation, which has a diagnostic significance for AT. XP, like AT, belongs to the IAS syndrome caused by defects in DNA repair. Cockayne syndrome has physical, mental retardation, ataxia, deafness, retinal pigmentopathy, photosensitivity dermatitis, and physical signs-large nose, large ears, protruding jaws, and depressions.

Although SCA has a common genetic mutation mechanism, which leads to similar clinical manifestations of each subtype, there are still differences. Some of them are associated with ocular muscle paralysis, some with retinal pigment degeneration, and the location and degree of pathological damage are different. In addition to the toxic effects of glutamine, other factors may also be involved.

Hereditary ataxia pathology

Hereditary ataxia

The neurons selectively involved in a certain area are often symmetrical changes, and mainly involve the cerebellum, brain stem, and spinal cord, but other parts of the nervous system may be involved. These are the three characteristics of the pathological changes of IAS.

Cerebellar changes are extensive. Except for FRDA and SPG, most IAS have significant pathological changes in the cerebellum. ADCAS type I brainstem pathological changes were obvious. The pathological changes of spinal cord of FRDA and SPG were obvious. Some IASs are accompanied by pathological changes in the cerebral cortex, thalamus, brain stem motor nucleus, and optic nerve.

Hereditary ataxia seen in general

Cerebellum atrophy, weight loss, cerebellar sulcus widening; brain stem becomes smaller and atrophied; spinal cord atrophy, neck and thoracic segments are obvious.

Seen through hereditary ataxia

Nerve cell loss: Purkinje cells and granulosa cells in the cerebellar cortex, dentate nucleus nerve cells, cerebellar white matter fibers and corticospinal tract, spinal cerebellar tract, posterior cord myelin sheath degeneration, and axonal degeneration. Olive cerebellar tract, pontine cerebellar tract, axillary fibers, demyelination of the cerebellar foot and axonal degeneration. Due to axonal proliferation, axonal spheres form.

The common pathological changes in SCA are degeneration and atrophy of the cerebellum, brainstem and spinal cord, but each subtype also has its own characteristics. For example, SCA1 mainly loses neurons in the cerebellum and brainstem, and the spinal cerebellar tract and posterior cord are damaged and rarely involved. Substantia nigra, basal nucleus, and anterior horn cells of spinal cord; damage to olive nucleus, pontine, and cerebellum below SCA2 is most severe; SCA3 mainly damages pontine and spinal cerebellar tract; SCA7 is characterized by retinal neuronal degeneration.

In addition to the changes in the nervous system mentioned above, a small number of cases can be seen in endocrine, skin, bone and other changes, such as: myocardial hypertrophy, diabetes, ichthyosis and telangiectasias, scoliosis and arched feet.

Clinical manifestations of hereditary ataxia

Typical clinical manifestations of hereditary ataxia

Typical clinical manifestations of hereditary ataxia include dyskinesia, cognitive function, and mental disorders, as well as other nonspecific symptoms.

Dyskinesia

Ataxia: Abnormal gait is the most common and first symptom of hereditary ataxia. It is manifested by drunkenness or scissors gait. Walking instability is more obvious when the road is uneven. As the disease progresses, instability or inability to sit up may occur until bedridden. Dysphonia is one of the characteristics of hereditary ataxia. Patients mainly show stiff pronunciation (bursting speech), slow, monotonous and ambiguous, articulation is not clear, the volume varies, or it is intermittent. Nacha language or bard-like language; when the disease progresses to the late stage, almost all patients have dyskinesia. Dyslexia is a typical symptom of ataxia in the upper limbs. Patients often follow the symptoms of ataxia in the lower limbs as the disease progresses. It is characterized by irregular word lines and unequal spacing between words. "Critical disease", severe cases can not write. Nystagmus and nystagmus: it can manifest as horizontal, vertical, rotational, or mixed nystagmus, and some patients may have inconsistent nystagmus, periodic alternating nystagmus, or detached nystagmus; etc. It is more common in supranuclear ophthalmoplegia, or paralysis of fixation, slow eye movements, and difficulty in upward vision.

Difficulty swallowing and coughing from drinking water are caused by damage to the brain stem nerve nucleus. With the progress of the disease, clinical manifestations are gradually obvious and common.

Tremor is mainly manifested as exercise tremor, postural tremor, or intentional tremor. If accompanied by extrapyramidal damage, static tremor may also occur.

Spasticity. Caused by the damage of the pyramidal tract, manifested as increased torso and limb muscle tension, active or hypertenoid reflexes, sacroiliac ankle, and Babinski sign positive, etc., showing a significant spastic gait when walking.

Extrapyramidal symptoms. Some patients may have Parkinson's disease-like manifestations due to basal ganglia damage, or extrapyramidal manifestations such as facial and tongue muscle twitching, myoclonus, hand and foot asthma, torsion spasm, and dance-like movements.

2. Cognitive function and mental disorders

It is manifested as impaired attention, memory, and decreased task performance. Among them, depression, sleep disturbances, abnormal mental behavior, and paranoid tendencies are common mental disorders.

3. Other symptoms and signs

Optic neuropathy. Symptoms such as primary optic atrophy and retinal pigment degeneration can be seen in autosomal dominant hereditary ataxia type II, Friedreich ataxia, ataxia telangiectasia (AT), phytanic acid storage disease (and Referred to as Refsum syndrome, RD) and other subtypes, patients are often accompanied by changes in vision, visual field and pupil.

Skeletal deformity. It is a common sign, mainly manifested as scoliosis or scoliosis. A few patients can also have deformities such as claw-shaped hands or recessive spina bifida; especially in patients with Friedreich ataxia, arched feet and spinal curvature are the most common.

skin lesions. More common in the eye conjunctiva, facial and neck skin telangiectasia, skin ichthyosis, milk coffee pigmentation and other manifestations, common in ataxia telangiectasia or Refsum syndrome patients.

Hereditary ataxia spinal cerebellar ataxia

Spinocerebellar ataxia (SCA) is the main type of hereditary ataxia, including SCA1 to 21. Adult onset, autosomal dominant inheritance, and ataxia are common characteristics of the disease, and are manifested in the early onset of the disease and the state of the disease has increased in successive generations (premature inheritance). The symptoms of each subtype are similar and overlap alternately. Early genetic manifestation is a typical manifestation of SCA, and symptoms worsen from generation to generation.

(1) Common symptoms and signs of SCA: 30- to 40-year-old onset of insidious attack, slowly progressing, and also in childhood and 70-year-old onset; lower limb ataxia is the first symptom, showing walking shaking, falls, and blurred speech, and Awkward hands, intentional tremor, nystagmus, a few accompanied by dementia and distal muscle atrophy; examination showed dystonia, hypertendinosis, pathological signs, spasm gait, tuning fork vibration and proprioception. Usually cannot walk for 10 to 20 years after onset.

(2) In addition to common clinical manifestations, each subtype has its own characteristics, such as SCA1 paralysis of the eye muscles, and the upper vision cannot be more obvious; SCA2 tendon reflexes weaken or disappear, and slow saccade movement is more obvious; SCA3 muscle atrophy, facial muscles Tongue muscle fibrillation, eyelid retraction form convex eyes; SCA8 often has dysphonia; SCA5 progresses very slowly with mild symptoms; early SCA6 thigh muscle spasm, lower vision tremor, diplopia and positional vertigo; SCA10 pure cerebellum sign Seizures; SCA7 vision loss or loss, retinal pigment degeneration, and cardiac damage are also more prominent.

The first symptoms are mainly unstable walking, limb weakness, and may be accompanied by symptoms such as tremor, sweating, and ambiguity in speech. It involves the cone system and extrapyramidal system, and is characterized by cerebellar symptoms of the extrapyramidal system. Signs of multiple system damage, including the pyramidal system, extrapyramidal system, autonomic nervous system, and cranial nerve are more common. The patient presented with a wide basal gait, walking dumping, positive nasal and rotation tests, dysarthria, nystagmus, hypertenoid reflexes, and positive pathological signs. Some patients may have involuntary movements, dizziness, sweating, and bladder and rectal dysfunction. There are also some patients with advanced neurological dysfunction such as thinking, intelligence, and memory.

Friedreich Hereditary ataxia Friedreich ataxia

Friedreich's ataxia is the most common idiopathic degenerative disease manifesting cerebellar ataxia and was first reported by Friedreich (1863). The disease has unique clinical features, such as childhood onset, progressive ataxia of the limbs, with pyramidal tract signs, dysphonia, deep paresthesia, scoliosis, arched feet, and heart damage.

(1) Usually onset at the age of 4 to 15 years old, occasionally infants and those who turn on after 50 years of age, both men and women can be affected. The first symptoms are progressive gait ataxia, staggering, shaking left and right, easy to fall; ataxia of both upper limbs within 2 years, showing clumsy movements and intentional tremor; knee tendon reflexes and ankle reflexes disappear at this early stage, In the presence of cerebellar dysarthria or fulminant speech, bilateral upper limb reflexes and knee reflexes in some patients can be preserved. Both lower extremity joint position and vibration sense are impaired, light feeling, pain and temperature are usually not affected. The weakness of the lower limbs occurs later, which can be damage to the upper or lower motor neurons, or both.

(2) Patients usually have extensor diaphragmatic reflexes within 5 years before the onset of symptoms. The weakness and atrophy of the medial foot muscles cause arched feet with claw-shaped toes, which are common signs and can also be isolated manifestations of unaffected family members. Progressive severe scoliosis can lead to functional disability and chronic restrictive pulmonary disease. Myocardial disease can sometimes only be detected by echocardiography, which can lead to congestive heart failure and is the main cause of death. Other abnormalities include optic nerve atrophy, nystagmus (mostly horizontal), paresthesia, tremor, hearing loss, dizziness, cramps, pain in the lower limbs, and diabetes.

(3) Physical examination showed positive heel and tibia test and closed eyes difficulty sign, 75% had upper thoracic spinal deformity, about 25% of patients had optic atrophy, 50% with arched feet, 85% with arrhythmia or heart murmur 10% to 20% are accompanied by diabetes.

(4) Auxiliary examination: X-ray shows spinal and skeletal deformities; MRI shows spinal cord thinning; Common T-wave inversion, arrhythmia and conduction block in ECG, echocardiography shows ventricular hypertrophy, and visual evoked potential amplitude decreases; DNA analysis FRDA The intron GAA of gene number 18 is greater than 66 repeats.

Hereditary ataxia hereditary spastic paraplegia

Most are autosomal dominant, but there are also autosomal recessive or sexually recessive. Mostly onset in children, more common in men, mainly manifested as progressive spastic paralysis of the lower limbs. Early symptoms are stiff legs, inflexibility, and weakened muscles when walking. Scissors gait due to increased tension of lower limb extensors. Knee and Achilles tendon reflexes were positive and pathological signs were positive. Feeling more accessible. Most have arched feet, but not as pronounced as Friedreich's ataxia. Sometimes accompanied by nystagmus and scoliosis. The disease progressed slowly, and later both upper limbs were also affected. If medulla oblongata muscles are involved, dysarthria can occur and swallowing is difficult. Mild disturbances of advanced sphincter function also occur.

Laboratory inspection

1. Spinal cerebellar ataxia cerebrospinal fluid examination is normal.

2. The diagnosis of SCA and subtype differentiation is feasible by PCR analysis, and the peripheral blood leukocytes are used to detect the CAG amplification of the corresponding gene, which proves the genetic defect of SCA.

3. Friedreich type ataxia (FRDA) DNA analysis, GAA intron 18 of FRDA gene has more than 66 repeats.

Film degree exam

1. Spinal cerebellar ataxia CT or MRI shows that cerebellar atrophy is obvious, sometimes brain stem atrophy can be seen; brain stem evoked potentials can appear abnormal, and electromyography shows peripheral nerve damage.

2. Friedreich type ataxia (FRDA) X-rays show spinal and skeletal deformities; MRI shows spinal cord thinning; T-wave inversion, arrhythmia, and conduction block are common on electrocardiograms; echocardiography shows ventricular hypertrophy, and the amplitude of visual evoked potentials decreases. ^[2]

Diagnosis and differential diagnosis of hereditary ataxia

Basic diagnostic strategies for hereditary ataxia

The clinical diagnosis of hereditary ataxia is mainly based on two common characteristics, one is the slow occurrence (a few are acute or intermittent) and the progress of symmetrical ataxia, and the other is a family genetic history. The general sequence for diagnosing hereditary ataxia: first, confirm that the patient's main clinical feature is ataxia, and collect family history data; second, exclude non-hereditary causes, and detect whether there are specific biochemical indicators abnormal, and finally perform genetics Detection.

Specific diagnostic methods for hereditary ataxia

(1) Identify ataxia syndrome and determine its genetic characteristics. Nystagmus, bard-like language, poor discrimination, tremor, and gait ataxia are the main signs of the cerebellum, and they can be accompanied by dementia, pyramidal signs, and signs of spinal cord and peripheral nerve damage. Family history should be collected in detail after the diagnosis of progressive ataxia according to clinical manifestations, and the genetic type should be determined according to the genetic characteristics of the family.

(2) CT or MRI shows that cerebellar atrophy is obvious, and sometimes brain stem atrophy can be seen;

(3) Exclude non-hereditary causes. Many neurologically acquired diseases can also cause progressive balance disorders, but no family history can be identified. For patients whose family history cannot be determined, non-hereditary causes must be ruled out one by one. Common causes are multiple sclerosis, multiple cerebral infarction, alcoholic or toxic cerebellar degeneration, cerebellar tumors, tumors or inflammation infiltrating the basal meninges, paraneoplastic syndromes, and hypothyroidism.

The course of some diseases is similar to that of hereditary ataxia. It progresses slowly and has cerebellar atrophy, but it is not inherited. It is called "sporadic ataxia". Gene mutations have been identified in some patients. Some with extrapyramidal and autonomic dysfunction are atrophic in multiple systems and often develop after the age of 55, while primary late-onset cerebellar ataxia develops between the ages of 40 and 55. Alcoholism is the most common cause of toxicities, and its typical symptoms are lower limb signs than upper limbs. Glutein ataxia is related to circulating anti-gluten antibodies. Progressive cerebellar ataxia can occur after gluten intake in susceptible individuals. The clinical characteristics are characterized by slow onset gait ataxia. About half of the patients have sensory Motor axonal neuropathy can occur in patients without small intestinal glutenin-sensitive bowel disease (presented as celiac disease). Human leukocyte antigen DQ2 (HLADQ2) protein is highly expressed in patients. Paraneoplastic cerebellar degeneration is often subacute. It is most common in patients with small cell lung cancer, breast cancer, ovarian cancer, and lymphoma. Cerebellar degeneration can occur before the tumor is found. Imaging examination shows progressive cerebellar atrophy, blood and Anti-neuro (Yo), anti-self (Hu), anti-ribonuclease inhibitor (Ri) and other corresponding antibodies can be detected in cerebrospinal fluid, which is helpful for diagnosis.

(4) Determining special biochemical index abnormalities: Some hereditary ataxias with specific biochemical index abnormalities. If blood compound testing is easier than genetic mutation analysis or treatment tests are feasible, blood compound testing should be preferred. Ataxia with myoclonus or myoclonic epilepsy, including mitochondrial encephalomyopathy, ceroid lipofuscinosis, sialidosis, etc. Hepatolenticular degeneration (HLD). Some patients with hepatolenticular degeneration have significant signs of cerebellum. Serum aeruginin testing is helpful for diagnosis. -lipoprotein deficiency is related to vitamin E malabsorption, but its symptoms may gradually weaken with age. Spinal erythrocytes can often be found under a light microscope, and beta lipoproteins cannot be detected in serum. Cerebral tendon xanthomatosis, which is prevalent in young people, is mainly manifested by spasm, ataxia syndrome, atherosclerosis, and cataract. The presence of tendon xanthomas and high serum cholesterol levels help to diagnose possible xanthomas in the skull. Chenodeoxycholic acid and pravastatin are effective for patients.

(5) Determining specific gene types: There are many laboratory tests for patients with hereditary ataxia without special abnormalities. Only by providing clues provided by detailed clinical data, the selection of genetic mutations and linkage analysis methods are the only means of diagnosis . The main basis for selecting a genetic testing program is the family history, clinical phenotype, and type of disease in the population. In view of the lack of corresponding clinical and genetic analysis epidemiological data in China, genetic testing is mainly based on family history and characteristic phenotypes.

As can be seen from the above, SCA has a wide range of clinical aspects, and there is a large overlap in clinical phenotypes between types. Clinical typing is very difficult. Therefore, the final diagnosis of SCA must rely on genetic testing. Pay attention to the following points:

First: Clear clinical diagnosis is the key, otherwise genetic diagnosis cannot proceed.

Second: Determine the hereditary mode, determine whether it is familial or sporadic according to the family history, and determine whether it is autosomal dominant or recessive according to the genetic method.

Third: Infer the most likely SCA subtypes based on clinical characteristics, determine the sequence of genetic testing, and save resources and time. Although the clinical manifestations of each subtype overlap, according to clinical practice and literature reports, there are still some differences between the subtypes, and even some subtypes have obvious characteristics, such as SCA7 combined with macular atrophy and retinal pigment degeneration; SCA3 has exophthalmos , Tendon reflex, facial muscle twitch, muscle spasm, gaze disorder, peripheral neuropathy; SCA4 has prominent multiple peripheral neuropathy; SCA5 manifests as simple cerebellar syndrome; SCAl2 has early distal distal tremor and gradually develops into the head Tremors, ataxia gait, hypertendinous reflexes, reduced movement, abnormal eye movements, and dementia later on.

Fourth: Complete genetic diagnosis. Genetic diagnosis was performed according to the sequence determined above, and further sequencing confirmed if necessary.

Because the clinical diagnosis only determines the approximate range of HA, the specific subtypes cannot be determined according to clinical symptoms and signs, and the genetic diagnosis can only be finalized through DNA testing. This has accurate genetic counseling, prenatal diagnosis and even preimplantation diagnosis. Important guiding significance. In the process of genetic testing, it is necessary to combine clinical characteristics and follow certain diagnostic strategies and procedures in order to detect different subtypes faster and more accurately.

For patients with typical clinical manifestations of cerebellar ataxia, the genetic type can be determined based on family genetic history after excluding secondary causes. For patients with spinal cerebellar ataxia, the clinical manifestations and frequency of genetic mutations determine their molecular detection order. Since SCA3 is the most common clinically, the screening order is SCA3, SCA2 and SCA1, SCA6 and SCA7, and finally Detect SCA12, SCA17, dentate nucleus, and pale bulbous Lewy body atrophy. Among them, patients with Parkinson's-like manifestations should first be screened for SCA2 and SCA3; those with peripheral neuropathy should be screened for SCA3 and SCA4 ; For those with simple cerebellar ataxia and later onset age, first screen for SCA6; For those with retinal degeneration, first screen for SCA7; For patients with dementia or microchorea, first screen for dentate nucleus, red nucleus, pale ball Lewy body atrophy and SCA17 Types; those with myoclonus manifestations first screen for dentate nucleus pale globule Lewy body atrophy; epilepsy authors first screen for SCA10 type and dentate nucleus pale globule Lewy body atrophy; tremor first Screen for SCA2SCA8 and SCA12; those with mental retardation are first screened for SCA17 and dentate nucleus red nuclear pale bulb Lewy body atrophy. Of the autosomal recessive ataxias, Friedreich ataxia has the highest incidence. Therefore, Friedreich ataxia should be screened first, followed by ataxia and capillary telangiectasia, followed by detection of ataxia with eye movement. Types I and II, phytanic acid storage disease, ataxia with selective vitamin E deficiency and beta lipoprotein deficiency, etc. Among them, patients with ataxia and peroneal muscular atrophy are first screened for peroneal muscular atrophy Ataxia (also known as RoussyLévy syndrome); patients with telangiectasia and recurrent lung infections are first tested for ataxia telangiectasia; patients with eye movement disorders and peripheral neuropathy are first tested for comorbidities with eye movement Patients with peripheral neuropathy and decreased serum vitamin E levels, first screen for ataxia with selective vitamin E deficiency; patients with corneal KF ring, cirrhosis, and decreased serum ceruloplasmin levels are primarily screened for liver Lenticular degeneration, negative results should consider other subtypes of autosomal recessive ataxia, may also be autosomal Hereditary ataxia, need to be screened for autosomal dominant hereditary ataxia genes. For patients with sporadic spinal cerebellar ataxia, first detect SCA3 and Friedreich ataxia, and then screen for SCA6, SCA2, SCA1, dentate nucleus, red nucleus, pale ball Lewy body atrophy, etc. Adrenal white matter dystrophy should be detected first in patients with X-linked ataxia that develops during childhood; those with middle-to-late age disease should first detect X-linked ataxia. ^[3-4]

Treatment of Hereditary Ataxia

Principles of Hereditary Ataxia Treatment

At present, there is no treatment that can completely prevent the progression of hereditary ataxia. The clinical treatment of hereditary ataxia is still mainly based on empirical symptomatic treatment. The main goal is to reduce symptoms, ease the progression of the disease, and maintain the ability to take care of daily life.

Treatment of hereditary ataxia dyskinesia

(1) Symptoms of ataxia: the 5HT1A (5HT1A) receptor agonist buspirone can partially improve the symptoms of mild cerebellar ataxia [26], and Tandospirone for SCA3 type effective. Levo-5hydroxytryptamine (5HT precursor) is used to treat cerebellar ataxia. The effect is not clear. Dcycloserine (NMDA receptor allosteric activator) can be used to treat ataxia, which can partially improve somatic ataxia and dysarthria, but has no obvious effect on ataxia of limbs and eye movement disorders. Branched-chain amino acids such as leucine and isoleucine can significantly improve the cerebellar symptoms in patients with spinal cerebellar ataxia, especially for patients with SCA6 type, and the medium dose is more effective, but the specific mechanism has not yet been elucidated. Histone deacetylase inhibitors also have a certain therapeutic effect. In addition, non-drug treatment is also an adjuvant treatment method. For example: gait instability can be improved by continuous neuromuscular exercise; ataxia with skeletal deformity can be elective orthopedic surgery. In addition, try to perform cerebellar vascular bypass surgery to improve the cerebellar blood supply to reduce the symptoms of ataxia in patients, but the effect is not very obvious; transcranial magnetic stimulation (TMS) can significantly improve the symptoms of ataxia in the trunk of the patient and increase cerebellar blood flow; Chronic thalamic stimulation can partially improve clinical tremor symptoms in patients with SCA2.

(2) Extrapyramidal and spasm symptoms: Levodopa can enter the central nervous system through the blood-spleen cerebrospinal fluid barrier, and is converted to dopamine by dopa decarboxylase to improve symptoms such as myotonia and reduced movement; Trihexyphenidyl) has a blocking effect on the central nervous system choline receptors, which can improve symptoms such as muscle rigidity and decreased exercise; Physostigmine has anticholin esterase action; the center of some hereditary ataxia patients The nervous system can improve the synthesis of acetylcholine in the brain by supplementing pyruvate dehydrogenase. Ethylphenidone (Myonal) can inhibit the transmission of multiple synapses and single synapses in the spinal cord and inhibit the spontaneous spinal cord motor neurons Sexual impulses have the effect of relaxing muscle tone. Patients with ataxia and myoclonus may choose clonazepam. Those with muscle spasm should be treated with chloramphenicol, which mainly acts on -aminoaminobutyric acid type B receptors. The new antiepileptic drug Gabapentin can improve the cerebellar symptoms of patients, and it also has a good effect on the pain effect after muscle spasm and nerve injury. Patients with dystonia can be treated with botulinum toxin injections.

(3) Other symptoms: The antiepileptic drug carbamazepine can better control the seizure symptoms of patients. At present, there is no effective symptomatic treatment for the symptoms of dysarthria associated with patients, which can be improved through speech correction training. Non-drug interventions include: improving the living environment, strengthening communication with patients, daily care, and behavior training for patients' self-protection.

Cognitive function of hereditary ataxia and treatment of mental disorders

(1) Cognitive dysfunction: There is currently no effective drug treatment. Early psychological treatment strategies for patients, including cognitive-behavioral interventions, can help to respond positively after symptoms appear. Psychotherapy mainly adopts cognitive therapy to change patients 'irrational beliefs, improve cognitive distortions and negative thinking, arouse patients' positive emotions, and enable them to exert their own initiative. In addition, emotional care should also be strengthened. When patients are not interested in things and their self-evaluation is too low, they should be given positive care to help them rebuild confidence. Try to get patients out of the monotonous lifestyle and actively communicate with patients. At the same time, group treatment methods can be adopted, and regular patient exchange meetings are held to allow patients to communicate and encourage each other. (2) Depression: Patients with depression may choose selective serum reuptake inhibitors (SSRI), including paroxetine, sertraline, citalopram, etc. Mirtazapine also has a certain effect; quetiapine is often used in Concurrent illusion. Patients with mania can choose mood-stabilizing drugs such as sodium valproate and lithium carbonate; patients with obsessive-compulsive symptoms and irritable patients should provide emotional support, accompanied by selective serum reuptake inhibitor antidepressants drug.

Hereditary ataxia nutrition protection treatment

(1) Dilation of blood vessels and improvement of circulation: Nicotinic acid has a strong peripheral vasodilation effect, and the niacin that enters the body can be converted into nicotinamide, which is a component of coenzyme and coenzyme and participates in Biological oxidation processes in the body. Vitamin E Nicotinate (Vit E, nicotinate) can directly affect the blood vessel wall to relax the surrounding blood vessels and promote blood circulation in the brain tissue. Cyclandelate has the effect of directly expanding vascular smooth muscle, expanding blood vessels and increasing local cerebral blood flow. Pentoxifylline can dilate peripheral blood vessels and improve blood circulation.

(2) Neuronal activating drugs: These drugs all have the effect of increasing neuronal activity and delaying the progress of hereditary ataxia. Citicoline is a nucleoside derivative that can improve brain tissue metabolism and promote nerve function recovery. Pyritinol is a vitamin B6 derivative, which can promote glucose and amino acid metabolism in brain tissue and improve cerebral blood flow. Piracetam (Piracetam) is a -aminoaminobutyric acid derivative, which can directly act on brain tissue, and has the function of protecting and repairing neurons. Duxil has the effects of resisting hypoxia, improving brain metabolism and microcirculation, thereby enhancing neuron function. Coenzyme Q10 (Ubidecarenone) can promote neuronal metabolism and respiratory function, promote oxidative phosphorylation, and has the effects of anti-oxidation and protecting the structural integrity of biological membranes.

(3) Vitamins: It has a certain effect on maintaining the normal metabolic process of neurons and improving function. Although most patients with hereditary ataxia may not be deficient in vitamins, vitamins have a protective effect on neurons and are beneficial for improving the patient's condition. Vitamin B1 (Vit B1) is involved in the oxidative decarboxylation of pyruvate and -ketoglutarate during glucose metabolism in the body. In the absence of redox reaction, the oxidation-reduction reaction is blocked, forming keto acids and accumulating lactic acid, thereby affecting energy metabolism. Nicotinamide is a component of coenzymes and , and is a coenzyme of many dehydrogenases. When it is lacking, it can affect the respiratory metabolism of cells. Vitamin B6 (Vit B6) can be transformed into pyridoxal phosphate and pyridoxamine phosphate, which are physiologically active co-enzymes of aminotransferases and decarboxylase of some amino acids, which are involved in various metabolisms in the body. process. Vitamin B12 (Vit B12), as a coenzyme, participates in the metabolism of many substances in the body, such as methyl transfer in the process of forming methionine by homocysteine, tetrahydrofolate metabolism in thymidine synthesis, and Carboxylic acid cycle metabolism and thiolase metabolism, etc., have neuron protection. Vitamin C (Vit C), involved in amino acid metabolism and neurotransmitter synthesis, dopamine, norepinephrine and serotonin all need hydroxylase hydroxylation during metabolism in the body, and hydroxylation requires Vitamin C supplement. Vitamin E (Vit E), which can enhance the antioxidant effect of cells, participate in the metabolism of deoxyribonuclease, ribonuclease, arylsulfatase, etc., and have a protective effect on thiolase. It is beneficial for vitamin E supplementation for patients with selective vitamin E deficiency ataxia and beta lipoprotein deficiency.

Precautions before treating hereditary ataxia

Genetic counselling should be performed. Preventive measures include avoiding marriages between close relatives, genetic testing of carriers, prenatal diagnosis and selective abortion, etc. to prevent the birth of children. The disease develops slowly. Most of them do not affect lifespan without serious cardiopulmonary complications. A few patients are bedridden and disabled.