Introduction to Huntington's disease

Introduction:

Huntington disease (HD)It is a dominant hereditary nervous system degenerative disease characterized by involuntary movement, mental abnormality and progressive dementia. It belongs to the category of gene dynamic mutation or polyglutamine repeat disease. Because Huntington's disease has prominent clinical symptoms, it has been named as a great chorea.Huntington's diseaseChronic progressive chorea or hereditary chorea. The disease was first described by the American physician Huntington in 1872. In 1911, Alzheimer observed the pathological changes. In 1993, the pathogenic gene was identified in the fourth pair of autosomal short arms 63. The protein, named Huntingtin. Pathological changes are characterized by the loss of nerve cells in the striatum and cerebral cortex. Recently, ubiquitin-positive neuronal inclusions and dystrophic neurites have been found in the cerebral cortex.

Cause:

(1) Causes of the disease

Huntington's disease is an autosomal dominant genetic disease affecting the striatum and cerebral cortex, showing a complete penetrance rate, with 50% of offspring of affected individuals. HD is caused by the mutation of Huntingtin gene of short arm 4p16.3 of chromosome 4, and the gene product is repeated amplification of CAG trinucleotide to produce Huntingtin protein. Normal humans have 11 to 34 CAG repeats and HD is more than 40. As long as the genetic pathogenic gene, or symptoms appear sooner or later, there is no significant difference in the clinical symptoms of homozygotes and heterozygotes, and occasionally sporadic cases. According to the age of onset, HD can be divided into young (pre-age 20) and adult.

The genetic characteristics of the disease include early detection, and there is a tendency of continuous morbidity in the offspring; the early onset tendency of paternal descent is more obvious, and both of these phenomena are related to the instability leading to HD mutation. The HD of sporadic cases (ie, no positive family history) accounted for approximately 1% of all HD patients.

The cases reported by Huntington are descendants of British immigrants from the United States. The ancestors of more than 1,000 HD patients can be traced back to 6 people immigrated from the UK in 1630. One of them can be traced back to 300 years for 12 generations. patient. Many patients in the United States are descendants of two brothers who immigrated to Long Island in the United States. Negretee (1958) found many HD patients in the small fishing village of San Luis, Venezuela, all of whom were descendants of a woman who had HD in 150 years ago. The progeny of the mutated gene affects the age of onset. The juvenile HD is more common in the paternal inheritance, and the older one is mostly maternally inherited. Another 4 pairs of single-oval twins were found to be almost the same age. The average prevalence rate of this disease is 50% per generation, and both men and women are also affected. Some members of the family are afflicted with this disease. Once the family is ill, it must be passed on from generation to generation.

(two) pathogenesis

Although the mutation point of the gene has been clarified, the pathogenesis of Huntington's disease is still unclear. The main theory of pathogenesis is that lipid peroxidation leads to abnormal energy metabolism, which further causes excitotoxicity and apoptosis of cells. Huntingin and ubiquitin appear together in the nucleus inclusions in the nucleus of the patient's striatum and cortex, as well as in dystrophic axons, but what is the relationship between Huntingin and these pathogenic factors, and by what way leads to nerve cells Apoptosis is still unclear. The possible ways are:

1. Degeneration of nerve cells at different sites by cytotoxicity of Huntingin.

2. The combination of huntin and glyceraldehyde-3-phosphate dehydrogenase leads to abnormal energy metabolism, and the activity of the caudate nucleus mitochondrial respiratory chain complex II/III is decreased, which further leads to selective neuronal apoptosis.

3. The binding of the puttin-related protein to the multi-glutamine chain of Huntingin also affects its function, further altering cellular functions, including regulation of gene translation, protein interaction, intracellular and intranuclear protein transport, and Transport of vesicles.

The pathological changes are mainly the loss of cerebral cortex and striatum cells, atrophy of the cerebral cortex, and the middle of the brain is the first to be affected by gamma-aminobutyric acid (GABA) and enkephalin and projecting to the lateral part of the globus pallidus. The caudate nucleus and the putamen are severely affected, a large number of neurons are degenerated, small ganglion cells are severely damaged, large ganglion cells are slightly invaded, glial cells are proliferated, and the ventricles are generally enlarged.

In the basal ganglia of HD patients, the inhibitory neurotransmitter GABA and its biosynthetic enzymes glutamate decarboxylase (GAD), Ach and biosynthetic enzyme choline acetyltransferase were all decreased, DA content was normal or slightly increased, resulting in muscle tone Reduce, increase the movement. Neuropeptides such as substance P, methionine, enkephalin, dynorphin, etc. in the basal gangus are reduced, and somatostatin and neuropeptide Y are increased. PET showed a reduced anatomical normal caudate nucleus glucose utilization.

Some scholars believe that in the pathogenesis of pathophysiology, it is due to damage to the basal ganglia-thalamic-cortical loop. There are two projection systems that connect the afferent and efferent structures of the basal ganglia: a single synaptic "direct" pathway between the striatum and the pallidal inner segment and the substantia nigra reticular, which is inhibitory, GABA and substance P are used as neurotransmitters; 2 through the "indirect pathway" of the globus pallidus and the subthalamic nucleus, in this pathway, between the striatum and the globus globular ganglion and the globus pallidus and hypothalamus The projections between the nucleus are both inhibitory and GABAergic, while the subthalamic nucleus-pallidal ganglia pathway is glutamatergic. Activation of the direct pathway inhibits the activity of the output nucleus, thereby de-suppressing the thalamic cortical projection neurons. Conversely, activation of the indirect pathway has a net excitatory effect on the inner segment of the globus pallidus and the substantia nigra reticular, thereby inhibiting the neurons of the thalamus cortex.

In the early stages of Huntington's chorea, the striatum to the globus pallidus (LGP) projection system selectively degenerates. The neurons that cause striatal neurons to the outer segment of the globus pallidus are selectively reduced, resulting in an increase in STN inhibitory activity by LGP neurons, resulting in a decrease in STN release impulses, ie, basal ganglia (MGP, substantia nigra SNr and SNc) excitatory impulse release is attenuated, which in turn causes enhanced feedback inhibition of the cortex by the ventrolateral nucleus (VL) of the thalamus. This can result in a partial dance or a hemiballismus.

symptom:

Huntington's disease is autosomal dominant. The incidence of children is 50%. Paternal genetic predominance is earlier in the disease, while maternal hereditary predominance is later. However, if the mother is already ill, during the pregnancy, most of the fetuses are aborted due to the interaction between the mother and the fetus. Children born by the paternal line can survive. Like other polyglutaminic repeats, the genetics of Huntington's disease is genetically early, that is, one generation is earlier than the first generation, and one generation is heavier than the first generation.

The clinical symptoms of Huntington's disease include three aspects, namely, dyskinesia, cognitive impairment, and mental disorders, all of which can appear as first symptoms.

1. The dyskinesia of progressive development of dyskinesia is characterized by sudden, rapid beating or twitching of the limbs, face and trunk. These movements are not known in advance, and can also be expressed as slow movements that cannot be controlled. Physical examination revealed involuntary movements and dystonia. Dance-like involuntary movements are the most prominent features of this disease. Most of them begin to appear as short-term uncontrollable grimace, nodding and finger flexion and extension exercises, similar to painless convulsions, but slower and non-stereotype. As the disease progresses, the involuntary movement progresses progressively, and the typical eyebrows and head flexion appear. When the object is looked at, the head rotates, and the patient walks with instability, gait, and constantly changing the posture of the hand. The action is like dancing. In the later stages of the disease, patients cannot stand and walk due to involuntary movements. Even if sitting is not stable, the body twists, suddenly stands up and suddenly sits down, after the bed, the torso and limbs are still twisting. When the disease develops, the casual movement is more and more damaged, the movement is awkward, slow, stiff, unable to maintain complex random movements, dysphagia, speech, vomiting and dysarthria. Abnormal eye movements were abnormal. In the late stage of the disease, the voluntary movement slows down, showing a stupor state in which the limbs cannot move. Most patients have reflexes and feel normal.

Dance-like dyskinesia is a typical dyskinesia of adult Huntington's disease. In the juvenile type patients (5% to 10% of Huntington's disease) who started on the age of 20, the permanent muscle rigidity was the main movement disorder. It is characterized by myotonia and myoclonus, and in the late stage, it is a kyphosis. In addition, unlike adult patients, about 50% of juvenile Huntington's patients have generalized seizures.

2. Cognitive Disorder Progressive dementia is another feature of Huntington's disease patients. Dementia is characterized by subcortical dementia in the early stage, and is characterized by cortical and subcortical mixed dementia.

Cognitive impairment can occur early in Huntington's disease. It began to show a decline in memory and computing power in daily life and work. Patients remember that new information was only slightly damaged, but the information was modified to make it difficult to store effectively, and the memory was also significantly defective. Due to the fluency of words, the function of visual space, and the ability to judge social and interpersonal relationships, patients become more confused and personality changes occur.

Changes in speech, including bad oral fluency tests, mild difficulty in finding words and dysarthria. Oral fluency damage is one of the earliest cognitive functions detected by Huntington's disease. In the mid and late stages of the disease, patients are unable to complete language tests that require organizational, continuous, and linguistic processing, nor can they complete naming tests that recall less common words. But these tests also require memory and cognitive skills that go beyond the language. There are no typical idioms and aphasia, but the vocal and rhythmic disorders are prominent features of the patient. Dance-like dyskinesia can often affect the tongue and lips, destroying the rhythm and agility of the pronunciation, hindering the volume, speed, rhythm and length of the speech, making the spoken language an outbreak. Huntington's patients can continue to communicate with people because they still retain the recognition memory of the words and the identification of the opponents and the ability to name them.

As the disease progresses, concentration and judgment are progressively impaired. The patient lacks the ability to initiate a problem-solving behavior. It is particularly difficult to work on tasks that require planning and continuous scheduling. The ability to view space is declining and it is difficult to judge the structure. In the frontal system test that requires continuous motion, it is difficult to continuously change the hand.

3. Mental disorders The first changes in mental state are changes in personality behavior, including anxiety, nervousness, irritability, or sullenness, or untidyness, and loss of interest, antisocial behavior, schizophrenia, paranoia, and hallucinations. Affective disorders are the most common psychiatric symptoms and occur more often before dyskinesias occur. Because the affective disorder occurs before the patient's dyskinesia occurs, or before understanding the characteristics of his family's disease, it is not a reactive disorder. In addition, the incidence of depressive symptoms is also high, and patients with severe depressive symptoms such as early detection and timely treatment can prevent suicide. The neurological and psychiatric disorders of Huntington's disease are progressively declining, and finally the patient is in a state of sillyness and silence.

4. Juvenile Huntington's disease begins in children and adolescents. About 10% of the onset starts before the age of 20, and about 5% of the age is less than 4 years old. The clinical manifestations are different from those of adult HD. The course of disease progresses rapidly, and dystonia is a prominent manifestation. It often replaces dance-like exercise with strong straightness. Parkinson syndrome, cerebellar ataxia, abnormal eye movement, myoclonus and seizures can be seen, and mental deterioration and behavioral abnormalities may occur. Some patients show excessive exercise. In a few cases, the motor symptoms are atypical (Westphal variant), showing progressive muscle rigidity and decreased exercise. The dance-hand and foot movements are not obvious, and are more common in children or those before the age of 20 years. Epilepsy and cerebellar ataxia are also common features of adolescents, with dementia and family history suggestive diagnosis.

The clinical diagnostic criteria for Huntington's disease are:

1. Family history of typical HD.

2. Progressive motor abnormalities caused by other factors are accompanied by dance and stiffness.

3. Mental disorders caused by other factors are accompanied by progressive dementia.

Imaging studies have found that symmetrical caudate nucleus atrophy can further support the diagnosis of Huntington's disease. In patients with symptomatic Huntington's disease, levodopa is known to increase dance-like movements. Patients with levodopa-induced dance-like movements are more likely to develop this disease than those who do not. The patient has clinical manifestations for early diagnosis. There is a certain false negative reaction in this test, and the negative result cannot completely exclude the possibility of onset. PET examination revealed a decrease in glucose metabolism in the caudate nucleus, which can also occur in patients with subclinical status and can be used as an ultra-early diagnosis. In subclinical patients, if the genetic test reveals that the Huntin gene (TT15) trinucleotide tandem repeat abnormality extends more than 40, the diagnosis can be further confirmed. Because Huntington's disease has a completely explicit autosomal dominant genetic feature, early genetic diagnosis of Huntington's disease is of great significance, providing a reliable basis for prenatal diagnosis and genetic counseling.

diagnosis:

Most patients with Huntington's disease have a family history, but some patients have been found by genetic testing, so they need to be differentiated from other types of hereditary and sporadic chorea. In familial diseases, dentate nucleus - red nucleus - globus pallidus - subthalamic nucleus atrophy, benign hereditary chorea and familial erythrocytosis have similar clinical features. Sporadic chorea mainly includes drug, pregnancy, vascular disease, hyperthyroidism, systemic lupus erythematosus, lupus anticoagulant syndrome, polycythemia, AIDS and rheumatic chorea. A detailed clinical examination and necessary auxiliary examinations for the patient contribute to the differential diagnosis of Huntington's disease.

1. Benign familial chorea An autosomal dominant, recessive and sexually linked central nervous system disease, divided into three types: early infant, childhood and early adolescent. The typical clinical symptoms are non-progressive dance performance. It differs from Huntington's disease in that both intelligence and spirit are normal, and there are no obvious abnormal changes in imaging examination. Genetic testing found that the genes of early onset are located on autosome 14p and can be treated with dopamine receptor antagonists. Recently, whether the disease is a disease An independent disease or a disease syndrome is questioned.

2. Rheumatic chorea is a kind of benign and self-limited disease. The pathological changes are mainly basal inflammatory lesions. The main onset time is 5 to 15 years old, and there are more women after 11 years old. There are many mental disorders in the onset, and then involuntary movements, mostly involving the face, may be accompanied by dysarthria and dysphagia. Involuntary movements are more abrupt, burst, beating and twitching, and dance like Huntington's disease. Different sports and non-stereotypes, some children have low muscle tone, and dementia is rare. The duration of the first onset does not exceed 6 months, but 25% of patients have recurrence after 2 years of onset. Some patients may be accompanied by rheumatic fever, myocarditis and arthritis. There was no abnormal change in imaging examination. Early treatment with penicillin and hormones can be used, but the natural course of chorea can not be shortened.

3. Neuroacupuncture A recessive hereditary disease associated with damage to the central nervous system and peripheral nerves, characterized by progressive neurodegeneration, with dance-like movements and spinous erythrocytosis. According to hereditary methods, it is divided into two types: autosomal recessive or dominant hereditary chorea, spinous polycythemia, and X-linked Mcleod syndrome. Clinical manifestations have many features in common with Huntington's disease. This disease is more than 15 to 35 years old. It begins with the dance of the limbs and trunk and the movement of the orthostatic movement. It can also show the manifestations of dystonia and Parkinson's syndrome, often combined with peripheral neuropathy. The dyskinesia continues to cause disability and deaths between the ages of 50 and 70. Patients can have serious behavioral disorders and mood changes, but dementia is not obvious. Head CT examination showed atrophy of the striatum, especially the head atrophy of the caudate nucleus. Blood smear examination revealed that the red blood cells in the peripheral blood were erythrocytes. Serum creatine phosphokinase and lactate dehydrogenase levels can be increased. Neurogenic muscle atrophy is seen in electromyography and muscle biopsy. Neuropathological examination is similar to Huntington's disease. The caudate nucleus and the putamen atrophy, small cells disappear, and large neurons are preserved, but there are no ubiquitin and huntin-positive neuronal inclusions. Clinically, the difference between neurocytic erythrocytosis and Huntington's disease is: recessive heredity, no obvious dementia, peripheral neuropathy and neuromuscular atrophy, erythrocytosis, pathological changes, no Huntingtin-positive neuronal nuclear inclusions .

4. Other types of chorea drug-induced tardive dyskinesia appear in patients with mental illness after long-term use of mental retardants, the most significant movements involving the mouth and tongue, but the hands, legs, trunk and respiratory muscles can also occur dance hand and foot Mobility, mental retardation only occurs in the late stages of some patients. The diagnosis of this disease mainly depends on the history of drugs for long-term use of psychosis drugs. Pregnancy, vascular disease, hyperthyroidism, systemic lupus erythematosus, lupus anticoagulant syndrome, polycythemia can appear chorea manifestations, these diseases have corresponding medical performance, pay attention to observe the relevant medical symptoms, the differential diagnosis is not difficult .

complication:

The literature reports that HD can be combined with other diseases, and individual patients may have epilepsy, hereditary ataxia and migraine. Becker (1953), Doll et al (1922), Pearson et al (1954), Mackey (1906), and Bruym (1970) reported that the disease was associated with progressive muscular dystrophy, polycythemia, neurofibromatosis, and deformity osteitis. (Paget disease) and distal type (hands and feet) neurogenic muscle atrophy. Schroeder (1931) and Haberlandt (1961) reported that the disease is associated with amyotrophic lateral sclerosis.

treatment:

There are currently no drugs that can change the natural course of Huntington's disease, but measures can be taken to improve clinical symptoms and reduce dance-like movements. Treatment focuses on symptomatic treatment of both psychological and neurological symptoms, with the necessary supportive care. Let the patients and those who may be sick build confidence and help each other to build an optimistic family.

In patients with Huntington's disease, gamma-aminobutyric acid (GABA) is reduced, cholinergic activity is inhibited, and dopamine is overactive, and anti-dopaminergic drugs or dopamine receptor inhibitors may be used.

1. Anti-dopaminergic drugs or dopamine receptor inhibitors Haloperidol and phenothiazines, chlorpromazine, and perphenazine are the main therapeutic drugs that block dopamine receptors. Benzoic drugs such as tiapride (tiapride) have anti-dopaminergic effects, 3 times / d, 100 mg / time.

2. Increasing the content of choline Physostigmine inhibits the activity of central cholinesterase, prevents the degradation of choline, and improves dance-like movement.

3. Increasing the γ-aminobutyric acid (GABA) content of the central nervous system Isoniazid is an inhibitor of γ-aminobutyrate transferase, which may increase the central γ-aminobutyric acid (GABA) content, making some patients light. To moderate progress. The general dose is 10-20 mg/kg, and the duration of each course of treatment is 4 months to 1 year. At the same time, the effect of vitamin B6 is better.

4. There is no good drug for the treatment of dementia symptoms. However, mental symptoms can be improved by medication. Amitriptyline and doxepin (doxepin) can be used to improve the patient's depressive symptoms. In combination with haloperidol and lithium carbonate for violent and angry outbreaks.

5. The transplantation of nerve cell transplantation or embryo striatum is still under investigation, and it is still uncertain whether it is effective or not.

6. Other treatments can be combined with the use of the nervous system to promote metabolism of drugs, vitamins and energy mixture. Anti-free radical treatment, anti-oxidation and anti-excitotoxic treatment may also have a certain effect. In addition, strengthening physical function training and psychotherapy can also achieve good results.

(two) prognosis

The disease usually lasts for 10 to 20 years and dies 15 to 16 years after the illness. Female patients have a longer course.

prevention:

There is no way to prevent or delay the development of HD, and the necessary supportive treatment can be performed on both psychological and neurological symptoms. To help patients and other potential patients in the family to build confidence and help each other to build an optimistic family. For those who have difficulties in self-care, strengthen nursing, pay attention to nutrition, and prevent complications such as pressure sores.