A Challenging Diagnosis of Huntington’s Disease With Mild Clinical Features: Case Report

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disease characterized by neuropsychiatric symptoms including chorea, dementia, and depression. It is inherited in an autosomal dominant fashion and exhibits anticipation leading to earlier and more severe symptoms in the affected offspring of a patient. With a much lower prevalence in Asia than in Europe and other parts of the world, its diagnosis can be missed easily in the early stages due to mildness of the symptoms and significant overlap between its symptoms and those of other diseases. We present the case of a 38-year-old male of Pashtun ethnicity presenting with mild cognitive impairment and clumsiness who was eventually diagnosed with HD, but his mild clinical features, no documented history of HD in his parents, and his relatively young age coupled with the relatively low prevalence of HD in his geographical location presented a significant challenge in our diagnosis of his condition. This case underscores the importance of keeping a high clinical suspicion for HD in patients with chorea despite a negative parental history, especially in resource-limited areas where the parents may have gone undiagnosed and highlights the need for further research on HD’s prevalence in different parts of the world as well as the barriers to its diagnosis.

Introduction

Huntington’s disease (HD), one of the most common hereditary diseases of the brain, is an autosomal dominant neurodegenerative disease, caused by mutations (CAG tri-nucleotide repeat expansion) in the Huntingtin gene (HTT) on Chromosome 4. It is characterized by neurological and psychiatric symptoms including movement disorders (most commonly chorea), dementia, depression, and other cognitive disturbances. ¹ The mean age at onset varies from 30 to 50 years with the median age being 45 years. ² Diagnosis is dependent on genetic testing which usually reveals >40 copies of the CAG tri-nucleotide in the affected gene. Characteristic features may also be seen on magnetic resonance imaging (MRI). ¹ There is no curative treatment available for HD and management relies upon symptomatic and supportive measures. Its prevalence in Asia has been reported to be significantly lower than in the Western world by multiple studies.^3-5 An explanation suggested for this lower prevalence is the under-diagnosis of HD due to religious and cultural beliefs, social stigma, lack of genetic and neurological testing resources and a refusal to undergo genetic testing. ⁵

We present the case of a 38-year-old Pashtun male with chorea eventually diagnosed as HD, who posed a diagnostic challenge due to his mild clinical features, no documented history of HD in his parents, young age, geographic location, and features suggestive of Wilson’s disease. This case highlights the importance of keeping a high clinical suspicion for HD in its initial stages, paying special attention to family history, and taking a multidisciplinary approach to the diagnosis of HD, especially in resource-limited areas, and further reinforces the hypothesis that missed diagnosis might be the reason for HD’s lower prevalence in some parts of the world.

Case

This case has been reported in line with the CARE guidelines. ⁶

A 38-year-old Pashtun male with no previous comorbidities presented to the hospital with mild cognitive impairment and clumsiness for the last 1 year. He also complained of generalized body weakness and bilateral lower limb pain for the last few days. His memory and attention were slightly impaired, but he was otherwise doing well. He had no significant past medical or surgical history. He gave a history of symptoms similar to his current symptoms in his 7-year-old son. Rest of his family history was unremarkable. According to the patient, both parents had died a natural death. The patient had no history of drug use or abuse and was from a poor socioeconomic background.

On examination, he was found to have a blood pressure of 110/80 mm Hg, SpO₂ of 92%, and a pulse of 91 bpm. Neurological examination revealed chorea of the upper face and head. There was head bobbing and random irregular blinking of the eyes along with enlarged palpebral fissures, elevation of the eyebrows, and marked contraction of the frontalis muscle. He was unable to perform the tandem gait and had reduced arm swing while walking. There was no chorea in the extremities. The rest of his organ systems were normal on examination.

Laboratory investigations revealed normal Hb (14.3 mg/dL), ferritin, folate/B12 levels, and erythrocyte sedimentation rate (ESR). His mean corpuscular volume (MCV), however, was low (63 fL). His thyroid function tests were normal, and treponema pallidum hemagglutinin (TPHA) test results were negative. Based on his findings, the primary team suspected Wilson’s disease and ordered serum ceruloplasmin testing, which was also found to be normal (23.9 mg/dL). He was referred to the Ophthalmology Department to look for Kayser-Fleischer Rings, which were not found on slit lamp examination. By this time, the patient had already been admitted for 5 days. The only treatment he had received during this period was intravenous multivitamins.

An MRI of the brain showed dilatation of the frontal horns secondary to atrophy of the caudate nuclei (Images 1 and 2). On the basis of these findings, he was advised genetic testing for CAG repeat which revealed 18 CAG repeats in 1 allele and >40 CAG tri-nucleotide repeats in the other allele of the HTT gene on chromosome 4, thus confirming the diagnosis of Huntington’s disease.

Image 1.

MRI brain coronal view. Left: MRI of the patient showing dilation of the lateral ventricles (red arrows). Right: MRI with normal ventricles for comparison.

Image 2.

MRI brain horizontal view. Left: MRI of the patient showing dilation of the frontal horns of the lateral ventricles (red arrows). Right: MRI with normal ventricles for comparison.

The patient was counseled prior to genetic testing, as the confirmation of this diagnosis can sometimes worsen the psychiatric symptoms in patients and can even lead to suicide. There is no curative treatment for this condition, and based on the patient’s mild symptoms accompanied by the fact that they did not cause any distress to the patient, he was discharged without any medication in order to avoid causing side effects of medications but was scheduled for regular follow-up visits to re-evaluate his symptoms and the need for symptomatic treatment.

Discussion

The earliest clinical features of HD usually are cognitive and psychiatric disturbances, followed later by the development of movement disorders such as chorea. However, HD usually goes undiagnosed till the development of chorea, which is its most characteristic feature. Other movement abnormalities include motor impersistence (the inability to maintain voluntary muscle contraction at a steady level), tics, myoclonus, gait and postural instabilities, and oculomotor abnormalities. Neuropsychiatric symptoms include depression and anxiety with a high frequency of suicidal ideation. The reported lifetime prevalence of suicide attempts among these patients is 5% to 10%. ¹ Hallucinations and delusions may occur, but frank psychosis is uncommon. In our case, the patient had very few of these symptoms, and they were very mild. He did not seem to follow the usual timeline of symptoms as he developed chorea and cognitive disturbances almost simultaneously.

An important feature of HD reported in the literature is anticipation, the phenomenon in which an inherited disease develops earlier or in a more severe form in the offspring than in the parent. We suspect this in our case with the patient’s son developing symptoms at 7 years of age; however, the literature and clinical experience suggests that symptoms would not have developed this early; therefore, we are not sure of this at the moment. A limitation of our report is that the patient’s son was not present and could not be examined or genetically tested, thus leaving us unable to verify our suspicion. However, this served as an important diagnostic clue in our case. Anticipation usually occurs in a paternal inheritance pattern because genomic instability is more pronounced in spermatogenesis than oogenesis. ¹ The reason why the patient did not give a history of HD in his parents could be due to multiple reasons including early death of the affected parent or loss of contact with the parent due to the neuropsychiatric features of the disease. De novo mutations are also a less likely possibility. A limitation of our case report is that his parents were not present and thus could not be examined or genetically tested, and we had to rely on the patient’s judgment that no one in his family had had similar symptoms before him. The absence of a family history of diagnosed HD cases should not serve to rule out HD in resource-limited areas where patients often go undiagnosed.

The pathogenesis of HD involves the HTT gene located on the short arm of chromosome 4. The normal HTT gene is involved in intracellular signaling, trafficking and metabolism. The normal form of the gene contains a short CAG tri-nucleotide repeat. ⁷ Normal CAG repeat lengths of 26 or less number of repeats are not associated with disease; between 27 and 35 CAG repeats indicate an intermediate allele, which is seen in healthy people, while 36 or more repeats are pathogenic. The CAG repeats of 40 or more convey full penetrance, which was the case with our patient. ¹ The expansion of CAG repeats leads to neurodegeneration through mechanisms that remain unclear. The disease is inherited in an autosomal dominant fashion; thus, a person with 1 affected allele will develop the disease, and each offspring of an affected person carries a 50% risk of having the disease. This is why it is important to diagnose the condition early in order to advise prenatal testing for HD.

Diagnosis of the disease depends on genetic testing as well as MRI findings. Presence of >40 CAG repeats on the HTT gene confirms the diagnosis on genetic testing, whereas MRI findings include atrophy of the caudate nucleus and ex vacuo ventriculomegaly. These tests are unavailable in resource-limited areas and costly when available, thus posing a significant challenge to diagnosing this condition. The MRI and genetic testing were delayed in our case because the patient had a poor socioeconomic background. In addition, the diagnosis of HD can lead to many adverse outcomes because the disease is not curable. This includes worsening of the psychiatric symptoms, sometimes leading to suicide. Therefore, genetic counseling by a trained professional is extremely important before prescribing genetic testing. The average age of survival after onset of symptoms is 15 to 20 years. There is no causal therapy, and the symptomatic treatments available include tetrabenazine, olanzapine, and amantadine for chorea, escitalopram and sertraline for depression and anxiety, and other medications as required. However, there is limited evidence regarding the relative efficacy of these drugs. The treatment decision is based on clinical experience rather than experimental evidence and is often limited by side effects. ¹ In our case, a joint decision between the attending neurologist and the patient was reached to refrain from prescribing any medications at the present moment, as the patient’s symptoms were mild and did not cause him distress. However, the patient was scheduled for follow-up in order to re-assess his condition and the need for symptomatic treatment.

Studies report the prevalence of HD in Europe to be around 5 to 10 in 100 000, whereas in Asia, it is reported to be as low as 1 in 100 000. ² Some studies have suggested that this might be due to missed diagnosis of HD in resource-limited areas due to factors such as social stigma, religious and cultural beliefs, lack of genetic and neurological testing resources, and a refusal to undergo genetic testing. ⁵ Our case reinforces this hypothesis as we could have easily missed the diagnosis if genetic testing had not been performed. However, studies on HD’s prevalence in Asia are very few. Further research on the prevalence of HD and trends in diagnostic strategies is required in order to test this hypothesis.

Conclusion

The HD can be a challenging diagnosis and can easily be missed if the threshold for suspicion is not kept low. Symptoms may be very mild in the initial stages, and MRI along with genetic testing should be advised to diagnose the condition early. Although one of the parents usually has HD diagnosed in their lifetime, it may also have been missed in some cases, and the absence of an HD diagnosis in the parents should not be used to rule out HD. Further studies are required in order to find out the true prevalence of HD in Asia and to investigate the factors that may be influencing its prevalence or delaying diagnosis.