Huntington's disease (HD) is a rare autosomal dominant genetic disease.The patients usually get sick in middle age and have sports, cognitive and mental symptoms.The clinical symptoms of Huntington's chorea are complex and changeable, and the patients' condition worsens gradually, and they usually die 15 to 20 years after onset.The onset of the disease is concealed and the progress is slow. The main characteristics of the disease are dance like movements with progressive cognition, mental dysfunction and dementia.The cause is the wrong expression of polynucleotide repeat sequence on Huntington gene, which affects different molecular pathways and ultimately leads to neurological dysfunction and degeneration.
On May 11, 2018, the National Health Commission and other five departments jointly formulated the First Batch of Rare Diseases Catalogue, which included Huntington's chorea.[1]
Misexpression of polynucleotide repeat sequences in Huntington gene
common symptom
The main characteristics of the disease are dance like movements with progressive cognition, mental dysfunction and dementia
infectivity
nothing
pathogeny
Announce
edit
Huntington's disease is an autosomal dominant genetic disease with complete penetrance.After confirming the gene locus, we found its pathogenic gene Htt (Huntingtin) after years of research.This gene encodes the Htt protein, and its first exon contains a duplicate CAG triplet codon.In HD, the number of repetitions of this triplet codon will increase abnormally.Individuals with 36 CAG repeat triplets experience illness.However, if the number of repetitions is 36~39, the total penetrance is low.The number of triplet repeats is unstable and may change when it is inherited to the next generation.The variant Htt protein expressed in the brain leads to neural function degradation through different molecular mechanisms.The mutant protein not only increases the abnormal function of the protein but also leads to the loss of normal function.The normal Htt protein itself has a variety of cell functions, and the variation of Htt protein causes these dysfunction.Protein variation is often first expressed as abnormal expression of related genes. Previous studies have shown that abnormal expression of genes related to nerve conduction occurs in the striatum of HD.In addition, the abnormal repetition of CAG can affect the interaction between molecules on a large scale, leading to the disorder of intracellular protein transport.The variation of Htt protein not only disrupts the gene regulation of mitochondrial function related proteins, but also reacts with the proteins on the surface of mitochondrial membrane, impairs the function of respiratory chain, hinders the fixation of mitochondria to microtubules, affects the dynamic fusion and division of mitochondria, and increases calcium transport.Mutant proteins can also inhibit autophagy, promote apoptosis, and change neurotrophic energy supply and intracellular biological and signal synthesis.
The prevalence rate of HD varies greatly among different populations. The prevalence rate of the western population is 4-8 cases in 100000 people.Recent studies show that the prevalence rate of HD in China/Japan is 0.40, while that in Europe/North America and Oceania is 5.7.There were only a few case reports in the Chinese literature before, but with the recognition of this disease, case reports will gradually increase.
clinical manifestation
Announce
edit
The main clinical symptoms of Huntington's disease (HD) are generally divided into three categories, including motor symptoms, cognitive dysfunction and mental disorders.In addition, HD will also affect other systems, and other system symptoms can be primary or secondary complications.The onset of HD is generally around 40 years old, but there are also cases of very young or very old onset. These patients usually have atypical clinical symptoms, such as children with severe growth retardation or Westphal variant, while elderly patients may have very mild symptoms.
The typical symptom of HD is chorea.Chorea itself is similar to the movement disorder caused by levodopa.It is characterized by temporary uncontrollable grimaces, nods, and finger jumps. With the aggravation of the disease, the involuntary movement becomes increasingly progressive, and typical dance like involuntary movement, dysphagia, and dysarthria occur.
Cognitive symptoms of HD sometimes appear many years earlier than chorea.Some studies have found that 40% of HD gene carriers have mild cognitive impairment, and the closer to the onset, the more obvious their cognitive impairment.These early changes seriously affect patient function.The type of cognitive dysfunction in HD patients is different from that of other neurodegenerative diseases, such as Parkinson's disease or Alzheimer's disease.In the early stage of HD disease, cognitive impairment is mainly limited to a single brain functional domain and does not affect the whole brain.In the early stage of the disease, patients will not only have memory affected, but also have obvious executive dysfunction, and may also have defects in emotional cognition, especially aversion cognition.This may seriously hinder their social interaction ability.Executive dysfunction is also a major problem in HD.HD patients often fail to recognize the severity of symptoms.With the development of the disease, the dementia symptoms of patients often worsen, but even in severe cases, some cognitive functions may still be preserved.
The mental symptoms of HD are often complex and changeable, which is related to brain function damage in the course of disease.Long before the onset of exercise symptoms, HD patients may have anxiety due to knowing their family history and disease risk, and may have depressive symptoms.Later, the patient may also have slight changes in personality, aggressive behavior and disinhibition behavior.
Affected by the disease, HD patients will have sleep disorders, such as prolonged sleep latency, decreased sleep efficiency, increased nocturnal awakenings and decreased deep and slow wave sleep.The changes of sleep status are closely related to other clinical symptoms and the severity of brain morphological changes.
inspect
Announce
edit
The disease mainly involves the basal ganglia and cerebral cortex. The caudate nucleus and putamen atrophy are the most obvious, with neuron loss and glial cell proliferation.The cerebral cortex (especially the frontal lobe) atrophy, especially the loss of pyramidal nerve cells and small neurons in layers III, V and VI, and no proliferation of glial cells.The loss of nerve cells can also affect the ventrolateral nucleus of thalamus, hypothalamus, reticular formation of substantia nigra, olivary body, nucleus of gracile tract and cuneate tract, white matter and diencephalic nucleus.
Most of the early imaging examinations had no special manifestations.With the development of the disease, the typical manifestation is symmetrical caudate nucleus atrophy, and the caudate nucleus area of the anterior foot of the lateral ventricle is bulging outward in a spherical shape, which is butterfly shaped.Further development of the disease can lead to varying degrees of cortical and subcortical atrophy.
diagnosis
Announce
edit
The diagnosis was made according to the positive family history, typical dance like movements, mental disorders and progressive dementia, as well as the positive results of gene testing.
treatment
Announce
edit
Several existing HD therapies can be classified as symptomatic treatment or cause specific treatment.The symptomatic treatment is based on the objective diagnosis of doctors and the subjective feedback information of patients, directly targeting patients' symptoms.Symptomatic treatment can be further classified.It can be divided into HD specific and HD non-specific symptomatic treatment according to the treatment of different main symptoms in sports, spirit and cognition.
Cause specific therapy includes direct gene therapy and indirect molecular therapy.The former regards the mutant gene and its transcript as the only cause of disease and treats it from the root;The latter is to achieve therapeutic effect by correcting complex molecules and nerve related pathways that lead to disease.Although the treatment of etiology cannot be realized at present, a lot of research is being carried out on the above different molecular pathways in order to slow down the disease.In addition, we must also pay attention to the care of HD patients.It is very important to treat symptoms according to the needs of patients, and it is best to implement it through multidisciplinary cooperation.Before onset and at the first stage of onset, this multidisciplinary team can include neurologists, psychiatrists and genetic consultants. With the change of patients' conditions, physical therapists, language and occupational therapists, nurses and other professional medical personnel are required to join.And hospice care and terminal treatment are also increasingly valued.The main purpose of treatment is to improve the quality of life of patients.According to the needs of the patient, if there are symptoms including sense of shame, body damage, unstable gait, difficulty in working and restless sleep, it means that they need to start taking drugs to treat chorea.Psychotropic drugs are the first choice for patients with psychosis or aggressive behavior.Bufenquizine is one of the drugs approved by the US Food and Drug Administration (FDA) to treat HD dance movements.The main mechanism of bufenquizine is to inhibit monoamine vesicular transport.The dance symptoms can be significantly alleviated when the drug dosage is large, but if the drug is stopped, the dance symptoms will be aggravated.Attention should be paid to the side effects of such drugs, including bradykinesia and tremor.Attention should also be paid to depression.Psychotropic drugs also include olanzapine, risperidone, or terpiride.Pay attention to the need to adjust the dosage according to the patient's reaction when taking medicine.For some specific patients, it is sometimes necessary to try several different psychotropic drugs to find the most suitable one.Baclofen and benzodiazepine are effective in the treatment of motor disorders at the end of the disease.Chemical nerve blockers such as botulinum toxin can treat local spasms, such as bruxism or focal spastic hyperreflexia.At the same time, physical therapy is also very important.Recent studies have shown that focusing on posture and gait training is very helpful for HD patients.
As there are few studies on drug therapy for cognitive impairment in HD, there is still no effective drug.
For the symptoms of compulsion, irritability and irritability, it can be suggested to take the stepped treatment.In patients with mild cognitive impairment, serotonin reuptake inhibitors can be used first, and behavior therapy can be combined at the same time.If depression, anxiety and obsessive-compulsive behavior occur at the same time, serotonin reuptake inhibitors can also be used as first-line drugs.After the medication is adjusted to the optimal dosage, it should be combined with medication, or behavioral therapy can be used.
Dysphagia usually occurs in the later stage of the disease. At present, there are guidelines for swallowing food (guidance should be started before cognitive impairment affects learning ability), including correct food preparation and providing food under the monitoring environment.It is very important to increase the energy intake of patients with appropriate methods.There is no specific and effective treatment for Huntington's chorea at present.Some drugs can relieve symptoms but cannot stop the disease from progressing.Etiological treatment is carried out at the gene level or cell level, but both are in the research stage.
Deep brain stimulation has begun to be applied to patients with relatively rapid progress of motor symptoms due to its unique advantages.The target of electrical stimulation is mainly located in the medial part of bilateral globus pallidus, and some studies have found that electrical stimulation can not only improve the motor symptoms of HD patients, but also improve their mood, physical strength and daily living ability.Therefore, the improvement of motor function can significantly improve the quality of life and prolong the time of independent life for patients with less involvement of higher cortical function.
As a new therapeutic method, gene therapy.In particular, RNAi, neurotrophic factor gene transfer and other methods have shown certain efficacy in Huntington disease animal model experiments.However, there is still a long way to go from animal experiments to human experiments.
HD patients and their relatives will also face many social and medical problems, which need to be reasonably solved by trained professionals.
prevention
Announce
edit
At present, there are many symptomatic treatments available for HD, and the comprehensive care plan also benefits patients and their families.Clinical research and nursing projects have been in place, and a large network of clinics, researchers and medical organizations has been established worldwide.With the cooperation of researchers, medical workers, patients and social environment, it is believed that HD patients can get early diagnosis and optimal treatment.
