Huntington's disease
Introduction
Introduction to Huntington's disease Huntington's disease (HD) is a dominant hereditary nervous system degenerative disease characterized by involuntary movement, mental disorders and progressive dementia. It belongs to the category of gene dynamic mutation or polyglutamine repeat disease. Because of the prominent clinical symptoms of Huntington's disease, the disease was named as big chorea, Huntington's disease, chronic progressive chorea or hereditary chorea. Most of the onset age is 25 to 40 years old, and the average age of onset is 40 years old. The disease lasts for 5 to 30 years, with an average of 14 years. 5% to 10% of patients have an onset age of 10 to 20 years, 1% of patients have an onset age in childhood, and the age of onset of individual patients is after 80 years of age. basic knowledge The proportion of illness: 0.001% Susceptible people: no specific population Mode of infection: non-infectious Complications: epilepsy hereditary ataxia migraine progressive muscular dystrophy neurofibromatosis malformation osteitis amyotrophic lateral sclerosis
Cause
Cause of Huntington's disease
Autosomal dominant genetic disease (30%):
It has a complete penetrance rate, 50% of the offspring of the affected individuals, and HD is caused by the Huntingtin gene mutation of the short arm of chromosome 4, 4p16.3. The gene product is a repeating amplification of CAG trinucleotide to produce Huntingtin protein. Normal humans are 11 to 34. The CAG repeat sequence, 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, clinical sporadic cases, according to the age of onset, HD can 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; paternal descent has a more pronounced premature tendency, both of which are related to the instability leading to HD mutation, sporadic cases ( That is, HD without a positive family history accounted for about 1% of the entire HD patient.
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 immigrating to Long Island, United States. Negretee (1958) found many HD patients in the small fishing village of San Luis, Venezuela. All patients were descended from a woman who had HD in 150 years ago. The parentality of the mutated gene affects the age of onset. The juvenile HD is more common in the paternal inheritance. The older morbidity is mostly maternal inheritance. In addition, 4 pairs of single-oval twins are almost the same age, and the average prevalence of each disease is 50%. Men and women are also affected. Some members of the family are guilty of this disease. Once the family is ill, it must be passed on from generation to generation.
Gene mutation (35%):
However, 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 patients with striatum. In the nucleus inclusions of the somatic and cortical nerve cells, and in the dystrophic axons, but what is the relationship between Huntingin and these pathogenic factors, and by what way to cause neuronal apoptosis, it is not clear, the possible way is :
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 huntingtin-related protein to the multi-glutamine chain of Huntingin also affects its function, further altering cell function, including regulation of gene translation, protein interaction, intracellular and nuclear protein transport, and Transport of vesicles.
Pathological changes:
Mainly the cerebral cortex and striatum cells are lost, the cerebral cortex is atrophied, and the spine neurons containing gamma-aminobutyric acid (GABA) and enkephalin in the posterior region of the brain and projecting to the lateral part of the globus pallidus are the first to be affected. The nucleus and 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 proliferate, and the ventricles are generally enlarged.
The inhibitory neurotransmitter GABA and its biosynthetic enzyme glutamate decarboxylase (GAD), Ach and biosynthetic enzyme choline acetyltransferase were all decreased in the basal ganglia of HD patients, and the DA content was normal or slightly increased, resulting in muscle tone. Decreased, increased movement, neuropeptides such as substance P, methionine, enkephalin, dynorphin, etc. in the basal ganglia decreased, somatostatin and neuropeptide Y increased, and PET showed a normal anatomical decrease in glucose utilization in the caudate nucleus .
Some scholars believe that in the pathogenesis of pathophysiology, due to the damage of the basal ganglia-thalamic-cortical loop, there are two projection systems connecting the afferent and efferent structures of the basal ganglia:
1 a single synaptic "direct" pathway between the striatum and the inner segment of the globus pallidus and the substantia nigra reticular, this pathway is inhibitory, with GABA and substance P as neurotransmitters;
2 through the "indirect pathway" of the globus pallidus and the subthalamic nucleus, in this pathway, the projection between the striatum and the globus pallidus and between the globus pallidus and the subthalamic nucleus are inhibitory. And GABAergic, and the subthalamic nucleus-the globus pallidus pathway is glutamatergic. Activation of the direct pathway inhibits the activity of the exporting nucleus, thereby de-suppressing the thalamic cortical projection neurons, and vice versa, activating the indirect pathway to pale The inner segment of the bulb and the substantia nigra have a net excitatory effect, 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, causing the neurons of the striatum to the ectopic outer segment to selectively decrease, resulting in LGP neuronal pairs. The STN inhibitory activity is enhanced, resulting in a decrease in STN release impulses, ie, a decrease in excitatory impulse release to the basal ganglia (MGP, substantia nigra SNr and SNc), which in turn causes an enhancement of cortical feedback inhibition by the ventrolateral nucleus (VL) of the thalamus This can cause a partial dance or a partial throw (hemiballismus).
Prevention
Huntington disease prevention
There is no way to prevent or delay the development of HD. It can provide necessary supportive treatment for both psychological and neurological symptoms. It is necessary to help patients and other potential patients in the family to build confidence and help each other to build an optimistic family. Self-care for people with difficulties in life, strengthen nursing, pay attention to nutrition, and prevent complications such as pressure sores.
Complication
Huntington's disease complications Complications epilepsy hereditary ataxia migraine progressive muscular dystrophy neurofibromatosis malformation osteitis amyotrophic lateral sclerosis
The literature reports that HD can be combined with other diseases, individual patients can have epilepsy, hereditary ataxia and migraine, etc., Becker (1953), Doll et al (1922), Pearson et al (1954), Mackey (1906), Bruym (1970) Reported this disease with progressive muscular dystrophy, polycythemia, neurofibromatosis, deformity osteitis (Paget disease) and distal type (hand and foot) neurogenic muscle atrophy, Schroeder (1931) and Haberlandt (1961) ) reported that the disease combined with amyotrophic lateral sclerosis.
Symptom
Huntington's disease symptoms common symptoms convulsions anxiety mental disorders dysphagia depression illusion dementia dysarthria subcortical dementia
Huntington's disease is autosomal dominant, the incidence of children is 50%, the paternal inheritance is earlier, and the maternal genetic predominance is later, but if the mother is already ill, during pregnancy, due to maternal and Fetal interactions, most fetuses are aborted, and children born by paternal lines can survive. Like other polyglutamate duplications, the genetics of Huntington's disease is genetically early, that is, one generation is earlier than the first generation, and one generation is better than the first generation. The symptoms are heavy.
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.
Dyskinesia
Progressive dyskinesia manifests as sudden, rapid beating or twitching of the extremities, face, and trunk. These movements are not known in advance, and can also be expressed as uncontrollable slow movements. Physical examination reveals dance-like involuntary movements and dystonia. Dance-involuntary movement is the most prominent feature 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, with the development of the disease, Involuntary movement is progressively aggravated, and typical eyebrows and head flexion appear. When the object is looked at, the head rotates, the patient walks with instability, and the gait increases, and the posture of the hand is constantly changed. The whole body moves like a dance. In the late stage of the disease, the patient can't stand and walk because of involuntary movement. Even if he is sitting, he is not stable, his body is twisted, he suddenly stands up and suddenly sits down. After bed, his trunk 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 Throughput spit and dysarthria, abnormal eye movements appear abnormal, involuntary movement in the late disease slowed, showing a state of stupor limbs can not activities, and most patients feel normal tendon reflexes.
Dance-like dyskinesia is a typical dyskinesia of adult-type Huntington's disease. In juvenile patients (5% to 10% of Huntington's disease) who started on the age of 20, permanent muscle rigidity is the main dyskinesia. Muscle rigidity, myoclonus, and angulation in the late stage, in addition to adult patients, about 50% of juvenile Huntington's disease have systemic seizures.
2. Cognitive impairment
Progressive dementia is another characteristic of patients with Huntington's disease. Dementia is characterized by subcortical dementia in the early stage, and later manifested as cortical and subcortical mixed dementia.
Cognitive impairment can occur early in Huntington's disease, beginning with a decline in memory and computational power in daily life and work. Patients remember that new information is only slightly damaged, but the information is modified to make it difficult to store effectively. There are also significant flaws. Due to the fluency of words, the ability to visualize space and the ability to judge social and interpersonal relationships decline, patients become more chaotic and personality changes occur.
Speech changes, including poor oral fluency test, mild difficulty in finding words and dysarthria, oral fluency damage is one of the earliest detectable cognitive dysfunction in Huntington's disease, in the middle and late stages of the disease, patients Language tests that require organizational, continuous, and linguistic processing are not completed, nor can naming tests that recall infrequently used words be completed, but these tests also require memory and cognitive abilities beyond the language range, without typical idioms and aphasia. However, the vocal and rhythmic disorders are prominent features of the patient. The dance-like dyskinesia often affects the tongue and the lips, destroying the rhythm and agility of the pronunciation, hindering the amount, speed, rhythm and length of the speech. Spoken language presents an outbreaking nature, and patients with Huntington's disease can continue to communicate with others because the patient still retains the recognition memory of the word and the identification of the opponent and the ability to name the object.
With the development of the disease, the concentration and judgment are progressively impaired, and the patient lacks the behavior to initiate problem solving. It is particularly difficult to work on the need to plan and continuously arrange information. It is difficult to judge the structure when the space capacity is reduced. In the frontal system test of continuously arranging movements, it is difficult to continuously change the movement of the hand.
3. Mental disorders
The first changes in mental state are changes in personality behavior, including anxiety, nervousness, excitement, irritability, or unhappiness, or untidyness and loss of interest, antisocial behavior, schizophrenia, paranoia, and hallucinations. Emotional disorders are the most common. Psychiatric symptoms, and more often before the occurrence of dyskinesia, because the affective disorder occurs before the patient's dyskinesia occurs, or before understanding the characteristics of the family's disease, so it is not a reactive disorder, and the incidence of depressive symptoms is also high, for patients The symptoms of severe depressive symptoms, such as early detection and timely treatment, can prevent suicide, and the neurological and mental disorders of Huntington's disease patients are progressively declining. Finally, the patient is in a state of silly and silent.
4. Juvenile Huntington chorea
In the onset of childhood and adolescence, about 10% of the onset is about 20 years old, and about 5% of the onset 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 can occur, and 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.
Examine
Huntington's disease check
Cerebrospinal fluid can be found to have decreased levels of gamma-aminobutyric acid.
Genetic testing
It is an important means of diagnosis. The PCR method detects the copy number of CAG in the IT5 gene. The normal person does not have more than 38 copies, and the number of patients is more than 39. No overlap has been found so far. The positive rate is high. It is only necessary to test the patient himself. Pre-symptomatic diagnosis and prenatal diagnosis.
2. EEG
There may be diffuse abnormalities, no specificity, mainly low-wave amplitude fast waves, especially frontal lobe, abnormal rate accounted for 88.9%, activity decreased or absent, amplitude decreased, visual evoked potential amplitude decreased, but the first wave part of the incubation period was normal, Patient P100 is not normal, and detection of P300 may be an objective indicator of early intellectual impairment in this disease.
3. Imaging examination
Head CT or MRI has important clinical value for the diagnosis of Huntington's disease. The typical imaging features are atrophy of the bilateral caudate nucleus, which causes the lateral anterior horn of the lateral ventricle to face outward. SPECT examination reveals the caudate nucleus and the nucleus nucleus. The flow decreased significantly, and the blood flow in the frontal and parietal lobe also decreased. It was related to the pathological changes in these parts of the patient. PET showed a significant decrease in glucose metabolism in the caudate nucleus, and the metabolic activity in the caudate nucleus decreased before the caudate nucleus was atrophied. .
Diagnosis
Huntington's disease diagnosis and identification
Diagnostic criteria
God's decline and abnormal behavior, some patients showed excessive exercise, a few cases of atypical motor symptoms (Westphal variant), showing progressive muscle rigidity and decreased exercise, dance - hand and foot movement symptoms are not obvious, more common in childhood or 20 years old Previously, 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, and levodopa can cause dance-like movements. Does not cause the dance-like actor to be more likely to develop this disease, can induce clinical manifestations of patients in the subclinical state, for early diagnosis, there is a certain false negative reaction, the negative results can not completely exclude the possibility of onset, PET examination It is found that the glucose metabolism in the caudate nucleus is reduced, and it can also be seen in patients with subclinical status. It can be used as an ultra-early diagnosis. In subclinical patients, if the genetic test finds the Huntin gene (TT15) trinucleotide tandem repeat abnormality An extension of more than 40 can further confirm the diagnosis. 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.
Differential 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, the 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 resistance Coagulation syndrome, polycythemia, AIDS and rheumatic chorea, detailed clinical examination of patients and necessary auxiliary examinations contribute to the differential diagnosis of Huntington's disease.
Benign familial chorea
An autosomal dominant, recessive, and sexually linked central nervous system disorder, classified into three types: early infant, childhood, and early adolescent. The typical clinical symptoms are non-progressive dance performance, which differs from Huntington's disease in that The intelligence and spirit are normal, and there is no obvious abnormal change in imaging examination. The gene examination found that the early onset gene is located on the autosome 14p and can be treated with dopamine receptor antagonist. Whether the disease is an independent disease or a disease comprehensive recently. The sign is questioned.
2. Rheumatic chorea
A kind of benign self-limited disease, the pathological changes mainly manifested as basal inflammatory lesions, the main onset time is 5 to 15 years old, more women after 11 years of age, more onset of mental disorders, and then involuntary involuntary Exercise, mostly involving the face, may be associated with dysarthria and dysphagia, involuntary movements are more abrupt, outbreaks, beating and twitching, and dance-like movements of Huntington's disease, unlike non-stereotypes, some children have low muscle tone Dementia is rare. The duration of the first episode is less than 6 months, but 25% of patients have recurrence after 2 years of onset. Some patients may have rheumatic fever, myocarditis and arthritis. There is no abnormal change in imaging examination. Early Penicillin and hormone therapy 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, classified as autosomal recessive or dominant inheritance according to genetic pattern There are two types of choroidal disease - spinous polycythemia and X-linked Mcleod syndrome. The clinical manifestations have many characteristics in common with Huntington's disease. The disease is more than 15 to 35 years old, with limb and trunk dance and oral movement. The disorder begins to develop, and the symptoms of dystonia and Parkinson's syndrome can also occur. Often combined with peripheral neuropathy, dyskinesia continues to cause disability, and death occurs in 50 to 70 years old. Patients can have serious behavioral disorders and emotional changes, but Dementia is not obvious, CT scan of the head shows striatum atrophy, especially the head atrophy of the caudate nucleus is the most obvious, blood smear examination found that the peripheral blood red blood cells are erythrocytes, serum creatine phosphokinase and lactate dehydrogenase content can be increased Electromyography and muscle biopsy have neurogenic muscle atrophy, neuropathological examination is similar to Huntington's disease, caudate nucleus and putamen atrophy, small The cells disappeared and the large neurons were preserved, but there was no ubiquitin and huntin-positive nerve cell inclusions. Clinically, the difference between neurocytosis and Huntington's disease is: recessive inheritance, no obvious dementia, peripheral neuropathy And neurotrophic muscle atrophy, erythrocytosis, pathological changes without Huntingtin-positive neuronal nuclear inclusions.
4. Other types of chorea
Drug-induced tardive dyskinesia occurs in patients with mental illness after long-term use of psychosis drugs, the most significant movements involving the mouth and tongue, but the hands, legs, trunk and respiratory muscles can also occur dance hand and foot acrodynamics, intelligent obstacles only appear In the late stage of some patients, the diagnosis of this disease mainly depends on the history of long-term use of psychosis drugs, pregnancy, vascular disease, hyperthyroidism, systemic lupus erythematosus, lupus anticoagulant syndrome, polycythemia can occur chorea Performance, these diseases have corresponding medical performance, pay attention to observe the relevant medical symptoms, its differential diagnosis is not difficult.
