Chorea in the Elderly: A Differential Diagnosis and Case Report of Late-Onset Huntington’s Disease in an Octogenarian

CASE PRESENTATION

An 89-year-old man with hypertension and hyperlipidemia presented with a 3-year-history of involuntary movements. These movements, first documented at age 86 on home videos, started subtly as low amplitude, arrhythmic, insuppressible shoulder-rolling, and progressed over years to random flowing movements of the limbs for which he sought neurological evaluation at age 89. Also at age 86, he developed depression attributed to the SARS-CoV-2 pandemic. At age 87, family noticed cognitive changes including asking questions repeatedly and visuospatial difficulty with dressing and driving. His only medications were isosorbide mononitrate and ezetimibe. He denied exposure to dopamine-blocking medications or illicit drug use. His family history is depicted in Fig. 1.

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Fig. 1

Patient Pedigree. This pedigree was obtained at the time of presentation to the authors at age 89. It has been simplified for patient privacy. The patient is indicated by the arrow in generation II. Filled in circles or squares indicate clinically affected individuals. Diagonal slashes indicate the individual is deceased. The patient’s sister in generation II was clinically affected with involuntary movements and falls in her 40 s and died in her late 50 s from suspected HD. The patient’s nephew in generation III was clinically affected with jerk-like movements and psychiatric disease in midlife and died in his early 50 s by suicide. The mother of that nephew in generation II died in her late 70 s with unknown symptoms and HD status, but she was known to be wheelchair bound. No one in the family was known to have genetic testing for their symptoms. No family members of the patient were evaluated by the authors of this paper. No further historical details regarding family history are available.

Neurological examination was remarkable for Montreal Cognitive Assessment score of 7/30 with global impairment, worsened from a mini-mental status examination score of 25/30 four months prior. He had insuppressible head movements on saccadic pursuit, increased saccadic latency, dysarthric speech, motor impersistence of tongue protrusion, mild facial and moderate four-extremity chorea, truncal dystonia, bradykinesia, paratonia, a wide-based gait with decreased left arm swing, and inability to tandem. Brain MRI was remarkable for mild microvascular ischemic changes and moderate global atrophy. Laboratory studies including complete blood count (CBC), comprehensive metabolic panel (CMP), thiamine, cobalamin, folate, thyroid function, and antinuclear antibody (ANA) were unremarkable. Given his co-morbid psychiatric and cognitive symptoms and positive family history, whole blood Huntington’s disease (HD) testing was sent to Prevention Genetics laboratory at age 89, and he was found to be heterozygous for an expanded HTT allele with 40 CAG repeats (22 repeats on the other allele), consistent with late-onset HD.

Differential diagnosis for chorea in the elderly

The predominant phenomenology of his movement disorder was generalized chorea. A differential diagnosis for chorea in the elderly is presented in Fig. 2.

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Fig. 2

Differential diagnosis of chorea in the elderly. First consider acquired etiologies systematically using the mnemonic VITAMIN. As many of these are treatable, the associated screening test is provided to include in the work-up as indicated. Next, consider inherited etiologies of chorea in the elderly of which HD is the most common, even in the absence of a family history of chorea. Thus, it is reasonable to start with HD testing. If HD testing is negative, other rare inherited HD mimics reported in patients over age 60 can be considered according to the patient’s pedigree, ancestry, and key additional clinical features. HDL = Huntington’s disease-like, DRPLA = Dentatorubral-pallidoluysian atrophy, PKAN = Pantothenate kinase-associated neurodegeneration.

Vascular etiologies include stroke, a common cause of acute-onset chorea in the elderly [1], and hyperviscosity associated with polycythemia [2]. However, our patient’s chorea was slowly progressive, and his CBC was normal, so vascular etiologies were unlikely.

Acute infectious agents listed in Fig. 2 and chronic infections such as neurosyphilis, non-inherited Creutzfeldt-Jakob disease, and human immunodeficiency virus-associated opportunistic infections have all been reported to cause chorea in the elderly [3–6]. Our patient lacked social history risk factors for the chronic infectious etiologies.

Toxic causes of chorea include exposure to carbon monoxide, heavy metals, illicit drugs, and numerous prescription drugs listed in Fig. 2 [3]. Our patient lacked these exposures.

Autoimmune causes of chorea, including systemic lupus erythematosus and antiphospholipid antibody syndrome are uncommon in the elderly [3, 7], and our patient had a negative ANA. An increasingly recognized cause of chorea in the elderly is anti-IgLON5 disease, an idiopathic autoimmune and neurodegenerative condition associated with an array of clinical presentations including sleep, cognitive, neuromuscular, and movement disorders. In a study of 22 patients with anti-IgLON5 disease, 31% had chorea which was the presenting symptom in 9% [8]. Early anti-IgLON5 disease can respond to immunotherapy so timely recognition is important [9]. Given our patient’s reported family history of chorea, we did not include anti-IgLON5 disease in his initial work-up.

The most common paraneoplastic antibody syndromes in the elderly associated with chorea are anti-ANNA1 (Hu) and anti-CRMP5 (CV2), which are both associated with small cell lung cancer. Treating the cancer can improve the chorea, and if needed, T-cell mediated immunosuppressive therapies such as steroids or cyclophosphamide can be tried [9]. Our patient’s chorea was chronic over years, rather than subacute, so paraneoplastic disease was not included in his initial work-up.

An important metabolic cause of chorea in the elderly is non-ketotic hyperglycemia. In a series of 59 patients with acute onset movement disorders from hyperglycemia, 40% presented with chorea which was bilateral in 40% of patients. The chorea is treatable with correction of the hyperglycemia in most cases [10]. Other treatable metabolic causes of chorea in the elderly include hyponatremia, hypocalcemia, and hyperthyroidism [1, 3]. Our patient had a normal CMP and thyroid studies.

The most common inherited etiology of chorea in the elderly is HD. In a prospective study of 12 patients ages 50–89 presenting with undiagnosed chorea, 50% were found to have HD, one of whom was age 87 and three of whom had no family history to suggest HD [7]. Other rare inherited causes of chorea reported in the elderly are listed in Fig. 2 [3].

DISCUSSION

HD is an autosomal dominant, neurodegenerative CAG-repeat-expansion disorder that typically presents between ages 30–50. Late-onset HD (LoHD) is defined as onset >60 constituting 4.4–11.4% of HD cases [11]. Patients with LoHD have fewer CAG repeats (40.8 on average) and 30% lack family history [11]. Our patient had a family history, but his pedigree was atypical for HD, possibly due to incomplete penetrance (36–39 repeats) in a parent who did not manifest HD in their lifetime [11]. We speculate that despite our patient’s fully penetrant 40 repeats, he did not manifest HD until his late 80 s due to genetic modifiers, particularly those outside the HTT gene involved in DNA repair, that may have been lacking in his relatives who developed clinically manifest, common-onset HD [12, 13]. For example, genome-wide association study studies have highlighted that increased expression of FANCD2-FANCI-associated nuclease 1 (FAN1), which repairs DNA interstrand cross-links, may delay HD onset [14].

Considering his subtle shoulder movements representing prodromal HD at age 86 and new diagnosis of manifest HD at age 89, he is to our knowledge the second oldest case of late-onset HD reported in the literature [7]. His case is an example of how subtle, prodromal symptoms of HD can go unnoticed in the elderly population by providers for years, and that even at 89 years of age and with reduced penetrance in the prior generation, the diagnosis of HD should be considered.

In the ENROLL-HD cohort of patients, 40 CAG repeats were associated with a 100% probability of HD diagnostic confidence level (DCL) 4 by age 86 [15]. Our patient was not found to have manifest HD (DCL of 4) until age 89. Thus, his case expands the HD phenotype and lends support to the variable age of onset, even within a family, that seeks further explanation by genetic modifiers, an active area of HD research with target implications for future disease-modifying treatments [13, 14].