Report of a family with Huntington's disease

Abstract

The aim of this article was to analyze the clinical and genetic characteristics of a patient with Huntington's disease and her family. We analyzed the clinical data of a patient with Huntington's disease and her family members in the Department of Neurology of our hospital, drew the genetic pedigree, and used gene fragment analysis to detect and analyze the genes of three people in the family according to the principle of informed consent. The genetic pedigree of the family was consistent with that of autosomal dominant diseases. A total of five people in this family developed the disease, two died, and the main clinical manifestations were dystonia, ataxia, and cognitive impairment. Three people in this family underwent genetic testing, and two exhibited normal genotypes. The cytosine–adenine–guanine trinucleotide (CAG) repeats of the proband were abnormally amplified, and the number of repeats reached 43. The main clinical features of the patient included chronic obscure onset, obvious positive family genetic history, clinical features of involuntary limb movement with cognitive impairment, rapid disease progression, poor treatment effect, and abnormal amplification of CAG repeats as shown through genetic testing. All the above features met the diagnostic criteria of Huntington's disease.

We analyzed the clinical data of a patient with Huntington's disease and her family members in the Department of Neurology of our hospital, drew the genetic pedigree, and used gene fragment analysis to detect and analyze the genes of three people in the family according to the principle of informed consent. The genetic pedigree of the family was consistent with autosomal dominant diseases, and the cytosine–adenopterin–guanine trinucleotide repeats of the proband were abnormally amplified, and the number of repeats reached 43 times.

1. CASE PRESENTATION

Huntington disease (HD), also known as Huntington chorea, is a hereditary neurodegenerative disease first reported in 1872 by George Huntington, for whom HD is named, and it was not until 1993 that its pathogenic gene (itl5 gene) was located on chromosome 4, 4p16.3‐0.05. ¹ The disease can occur in all ethnic groups and most commonly in Caucasians and can occur in different age groups, though mainly in adulthood. The average age of disease onset is 30–50 years old, and it is rare in adolescents. The major clinical symptoms are dance‐like movements, dystonia, ataxia, cognitive impairment, and mental and behavior abnormalities; HD can be diagnosed by genetic examination, but there is no effective treatment. ² Here, we report the clinical characteristics and genetic testing results of an adult HD patient diagnosed and treated in our hospital and review the clinical and genetic characteristics of HD in combination with relevant literature to improve clinicians' understanding of the disease.

The proband was female and 55 years old. She was hospitalized on July 23, 2019, because of involuntary limb movement for more than 10 years. The patient begain to develop Chorea Huntington involuntary movement of the trunk and limbs 10 years ago, and the symptoms improved when quiet, were aggravated when nervous, and disappeared when sleeping. Then, the symptoms gradually worsened, expressed as an increase in involuntary movement, and the amplitude increased, with reduced speech, slow response, and memory loss. Since the onset of the disease, the patient had no obvious dizziness, headache, limb convulsions, dysphagia, drinking water choking cough, and so forth. She was hospitalized in Foshan Central Hospital, but there was no clear diagnosis or special treatment. She took oral Chinese medicine, and her symptoms did not improve, so she went to our hospital for further diagnosis and treatment. The patient denied having previous chronic diseases, such as hypertension and diabetes; history of infectious diseases, such as hepatitis, tuberculosis, and typhoid fever; history of traumatic surgery; history of blood transfusion; history of food or drug allergy; and the history of vaccination is unknown. She usually did not smoke and drank occasionally. Her father, sister, and brother suffered from similar diseases, but her father died at the age of 50, and her sister died at the age of 48 (Figure 1). Physical examination showed that there was no abnormality in the internal medicine system. Assessment of the nervous system revealed a clear mind, indifferent expression, decreased orientation, slow responses, clear and to the point answers, memory loss, decreased executive function, analysis and induction ability, soft neck, negative meningeal irritation sign, and bilateral frontal stria symmetry. The pupils were round and equal in size, approximately 3 mm in diameter, and sensitive to light directly and indirectly. The bilateral nasolabial sulcus was symmetrical and she did not comply with the tongue extension examination; the pharyngeal reflex could not be checked, dance‐like involuntary movement could be seen in the limbs and trunk, limb muscle strength was Grade 4, limb muscle tension was weakened, and systemic tingling was weakened; the masonic movement examination could not be coordinated, the physiological reflex existed, and bilateral pathological signs were not drawn out. The Minimental State Examination score was 20 points. The auxiliary examinations were as follows: no abnormality in hematuria, routine stool results, and blood biochemistry; human immunodeficiency virus and syphilis negative; no obvious abnormalities in thyroid function and antithyroid autoantibodies; normal electroencephalogram. Magnetic resonance imaging (MRI) of the brain showed that small patchy long T2 signals were seen in the white matter area around the bilateral lateral ventricles. FLAIR showed high signals, the ventricles were enlarged, the signals were not abnormal, some brain sulci and cisterns were widened, the midbrain volume was reduced, the coracoid process was significantly thinner, and the upper edge was slightly collapsed (Figure 2). There was midbrain atrophy. HTT(ITl5) gene analysis of HD showed that the proband had 43 cytosine–adenine–guanine trinucleotide (CAG) repeats of exon 1 of the HTT gene, which is the whole mutation range and was in line with the gene mutation characteristics of HD. The genetic analysis of the proband's son showed that the CAG repeats of exon 1 of the HTT gene were repeated 18 times, which is the normal range (Figure 3). After admission, the patient was treated with itopride and haloperidol. After active treatment, the patient's symptoms improved, and he was discharged from the hospital. After the patient was admitted to the hospital, we treated the patient symptomatically with itopride and haloperidol, and the patient's symptoms improved, and she was finally discharged from the hospital.

Figure 1.

Pedigree of the patient: her father, sister, and brother suffered from similar diseases, but her father died at the age of 50, and her sister died at the age of 48. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2.

MRI of the brain showed that small patchy long T2 signals were seen in the white matter area around the bilateral lateral ventricles. FLAIR showed high signals, the ventricles were enlarged, the signals were not abnormal, some brain sulci and cisterns were widened, the midbrain volume was reduced, the coracoid process was significantly thinner, and the upper edge was slightly collapsed. MRI, magnetic resonance imaging. (A, B) T2WI axial image. (C, D) T2FLAIR axial image.

Figure 3.

HTT(ITl5) gene analysis of patient showed that the proband had 43 CAG repeats of exon 1 of the HTT gene, which is the whole mutation range and was in line with the gene mutation characteristics of Huntington's disease. CAG, cytosine–adenine–guanine trinucleotide. [Color figure can be viewed at wileyonlinelibrary.com]

2. DISCUSSION

HD is an autosomal dominant disease caused by abnormal amplification of CAG trinucleotide repeats of the IT15 gene of the 4p16.3 region of chromosome 4. Research ³ , ⁴ has shown that the number of CAG repetitions is correlated with the incidence of HD in patients; that is, when (CAG) n ≥ 40, the patients will definitely get sick; when (CAG) n is 36–39, the patients may be ill, but the penetrance rate decreases and the symptoms of patients may be mild; when (CAG) n is 27–35, they often do not get sick, but the risk of amplification of the mutation in their offspring increases; (CAG) n < 27 is the normal range. Other studies have also shown that there is a negative correlation between the number of CAG repeats and the onset time of HD patients. If the pathogenic gene of the offspring comes from the father, it has genetic anticipation, and the higher the number of trinucleotide repeats in the CAG sequence, the earlier and more serious the symptoms of patients will appear. ⁵ HD, a chronic neurodegenerative disease, is characterized by focal neuronal loss and brain atrophy, mainly in the caudate nucleus and putamen, followed by the cerebral cortex. ⁶ The morbidity of HD is 5–7/100,000, mostly in adults. The average age of onset is 40 years old, the prevalence rates in males and females are approximately equal, and if the patient is less than 20 years old, it is called juvenile HD. The main clinical manifestations include dystonia, dance‐like movement, ataxia, cognitive impairment, and psychobehavioral abnormalities. The general course of the disease is 10–20 years and gradual progression, but to date, there is no treatment measure to delay the course of HD. ⁷ At present, only butylbenzene and dibutylbenzene have been approved by the US Food and Drug Administration. The guidelines of the American Academy of Neurology recommend that if HD patients need treatment, clinicians should give Grade B treatment, such as butylbenzene (dosage can be up to 100 mg every day), amantadine (300–400 mg every day), or riluzole (200 mg every day), and they can benefit to varying degrees from treatment, but they should be carefully evaluated before taking medication; additionally, the occurrence of adverse drug events, such as depression, suicide, Parkinson's symptoms, and liver enzyme rise and patients should be closely monitored during and after taking medication. ⁸ At present, the most promising treatment method is to reduce and modify anti‐Huntington protein. With the continuous progress of clinical trials, it will not only be effective for HD but also for the treatment of other neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. ⁹ Although it is unclear how CAG repeats drive neurodegeneration, the mutated Huntington protein (mHTT) fragment is considered a toxic fragment that destroys a variety of cellular pathways. Therefore, some drug companies have tried to achieve the purpose of treatment by reducing the accumulation of mHTT toxic fragments with drugs such as rg6042, an HTT gene‐silencing drug. In Phase I and II trials, they found that it reduced the mHTT level in cerebrospinal fluid by 40%–60%, in the cerebral cortex by 55%–85%, and in the caudate nucleus region in the deep brain by 20%–50%, which indicates that a great breakthrough has been made in treatment, and RG6042 has entered phase III clinical trials‐0.02 ¹⁰ Therefore, gene‐silencing drugs are expected to prevent the progression of HD.

This patient with HD was a 55‐year‐old female with a chronic occult attack and a clear positive family history. Her main symptoms included involuntary movement of limbs, slow response, and memory loss. In addition, MRI of the brain revealed brain atrophy, and abnormal amplification of the CAG sequence was repeated 43 times as demonstrated with genetic testing, so the diagnosis of HD was clear according to her above manifestations and results. To date, the treatment of HD still focuses on comprehensive symptomatic support treatment, which aims to formulate individualized medication treatment plans for different patients, along with closely monitoring adverse drug reactions and actively providing psychological, family, and social help. However, in any case, these treatments cannot delay the progression of the disease. We urgently look forward to new breakthroughs in the research of gene silencing and modification and the emergence of drugs that can prevent disease progression as soon as possible to bring greater benefits to HD patients.

AUTHOR CONTRIBUTIONS

Wang Jian was responsible for medical data collection. Cao Piao and Luo Zhong were responsible for the first draft of the paper and further manuscript. Zhang Linhai and Hao Renfang were involved in treatment planning. Liang Tao was involved in treatment planning and guided manuscript writing. All authors contributed to the interpretation of the findings and critical revision of the manuscript, and approved the final manuscript.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ETHICS STATEMENT

The Medical Ethics Committees of the Institute of the Affiliated Hospital of Zunyi Medical University approved this case report (Lot No. KLL‐2021‐345). Written informed consent was obtained from the patient for the publication of the present case report. Written informed consent for publication of clinical details and any accompanying images was obtained from the patient herself.

Luo Z, Wang J, Cao P, Zhang L‐H, Hao R‐F, Liang T. Report of a family with Huntington's disease. ibrain. 2022;8:241‐245. 10.1002/ibra.12049

DATA AVAILABILITY STATEMENT

The materials used during the current study are available from the corresponding author on reasonable request.