Somatic mutations in JAK2 are associated with chronic myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF). The most common variant, Val617Phe (JAK2 V617F), accounts for >95% of polycythemia vera and 50%–60% of essential thrombocythemia and PMF cases. 1 , 2
Chorea is a well‐described neurological complication of polycythemia vera, 3 encompassing acute‐onset occasionally reversible hemichorea and slowly progressive generalized chorea with prominent oromandibular involvement. 3 The former usually has a vascular etiology, secondary to thrombosis, hemorrhage, or hyperviscosity, whereas the latter has a poorly elucidated pathophysiology. 3
Here, we describe a case of late‐onset generalized chorea with prominent oromandibular involvement associated with JAK2 V617F‐positive essential thrombocythemia (rather than polycythemia vera) and speculate on its pathophysiology.
Case Report
A 79‐year‐old white, British woman presented with a 1‐year history of slowly progressive, persistent generalized involuntary movements most prominently affecting her face and jaw. She reported tongue and lip biting causing chewing and swallowing difficulties, which resulted in clinically significant weight loss over the past 6 months. Ten years before, the patient was diagnosed with JAK2 V617F‐positive essential thrombocythemia confirmed on bone marrow biopsy. Essential thrombocythemia had successfully been treated with hydroxyurea 500 mg OD since then, but hematological parameters had recently deteriorated. The patient was still taking hydroxyurea when choreic movements appeared. A few months before our assessment, she had undergone a bone marrow aspirate and trephine biopsy showing mild dysplastic changes in the erythroid series (that might be related to age and/or chronic treatment with hydroxyurea) but not evidence of transformation or progression to PMF. There was no history of cognitive or behavioral issues or exposure to antipsychotic drugs. Her family history was unremarkable.
Neurological examination revealed generalized chorea mainly affecting the oromandibular region and hands. Eye movements, muscle strength, sensation, and reflexes were normal. There were no parkinsonian, pyramidal, or cerebellar signs (Video S1). Her Mini Mental State Examination score was 28/30. There was no splenomegaly.
Extensive diagnostic workup for chorea was performed (Table 1). Brain magnetic resonance imaging (MRI) scan showed mild supratentorial small vessel disease and non‐specific symmetric T2 and FLAIR hyperintensities within the brainstem. Cervical spine MRI and whole‐body positron emission tomography (PET) were unremarkable. Genetic testing for Huntington disease was negative.
TABLE 1.
Laboratory and genetic findings in the patient reported
| Investigation | Result | Reference values |
| Red cell count | 2.67 × 1012/L | 3.95–5.15 × 1012/L |
| Hemoglobin | 91 g/L | 115–155 g/L |
| HCT | 0.293 L/L | 0.33–0.45 L/L |
| MCV | 109.7 fL | 80–99 fL |
| MCH | 34.1 pg | 27.0–33.5 pg |
| MCHC | 311 g/L | 320–360 g/L |
| RDW | 17.4% | 11.5–15.0% |
| Platelet count | 341 × 109/L | 150–400 × 109/L |
| MPV | 10.8 fL | 7–13 fL |
| Blood film | Anisopoikilocytosis, no acanthocytes | – |
| White cell count | 4.01 × 109/L | 3.0–10.0 × 109/L |
| Neutrophils | 2.61 × 109/L | 2.0–7.5 × 109/L |
| Lymphocytes | 0.33 × 109/L | 1.2–3.65 × 109/L |
| Monocytes | 1.0 × 109/L | 0.2–1.0 × 109/L |
| Eosinophils | 0.05 × 109/L | 0.0–0.4 × 109/L |
| Basophils | 0.02 × 109/L | 0.0–0.1 × 109/L |
| Sodium | 138 mmol/L | 135–145 mmol/L |
| Potassium | 4.5 mmol/L | 3.5–5.1 mmol/L |
| Urea | 8.2 mmol/L | 1.7–8.3 mmol/L |
| Creatinine | 145 μmol/L | 49–92 μmol/L |
| Estimated GFR | 31 | – |
| Glucose | 5.1 mmol/L | 4.0–7.0 mmol/L |
| Hb1Ac | 42 mmol/mol | 20–42 mmol/mol |
| Vitamin B12 | 419 pg/mL | 196–772 pg/mL |
| Folate | 9.8 ng/mL | 2.9–26.8 ng/mL |
| Total protein | 82 g/L | 63–83 g/L |
| Paraprotein | No paraprotein detected | – |
| Serum protein electrophoresis | Polyclonal increase in gamma globulins | – |
| Creatine kinase | 36 IU/L | 26–140 IU/L |
| Iron | 3.8 μmol/L | 6.6–26.0 μmol/L |
| Ferritin | 240 μg/L | 13–150 μg/L |
| TSH | 2.01 mIU/L | 0.27–4.20 |
| Free T4 | 15.4 pmol/L | 12.0–22.0 |
| Alpha‐fetoprotein | 3.1 kIU/L | 0–6 kIU/L |
| Beta‐2‐glycoprotein IgM and IgG | Normal | – |
| ANA screen | Negative | – |
| ENA screen | Negative | – |
| Anticardiolipin antibodies IgM and IgG | Normal | – |
| Anti‐dsDNA antibodies | Negative | – |
| Syphilis antibody testing | Negative | – |
|
Neuronal antibodies Anti‐Purkinje cell antibodies Anti‐Tr antibodies Anti‐white matter (myelin) Anti‐Hu antibodies Anti‐Yo antibodies Anti‐Ri antibodies Anti‐Ma‐1 antibodies Anti‐Ma‐2 antibodies Anti‐CV2 (CRMP‐5) antibodies Anti‐amphiphysin antibodies Anti‐Zic‐4 antibodies Anti‐Sox 1 antibodies Anti‐Tr antibodies DNER antigen Anti‐GAD |
Negative | – |
| IgLON5 antibody | Negative | – |
| HIV 1–2 antibodies | Not detected | – |
| Syphilis antibody testing | Negative | – |
| Genetic testing of HTT | Negative | – |
After excluding other etiologies, chorea was attributed to JAK2 V617F‐positive essential thrombocythemia. Tetrabenazine 12.5 mg twice daily was initiated with marked improvement. The patient was referred for hematological reassessment.
Discussion
Unlike its well‐recognized association with polycythemia vera, 3 chorea has only once previously been linked to essential thrombocythemia. 4 Venkatesan et al. reported a 55‐year‐old woman with JAK2 V617F‐positive essential thrombocythemia presenting with acute‐onset generalized chorea that reversed after hydroxyurea initiation. 4 Our case confirms JAK2‐related essential thrombocythemia as a treatable cause of late‐onset chorea and reveals that chorea may herald deterioration of hematological parameters, as in polycythemia vera. 5 Moreover, it provides further evidence of the association between chorea and JAK2 V617F.
The pathophysiology of JAK2‐associated generalized chorea is controversial. Ischemic damage to the neostriatum because of hyperviscosity and venous stasis has been hypothesized as pathomechanism in polycythemia vera‐related chorea. 3 Chorea has been reported also in secondary polycythemia and other hyperviscosity syndromes, including leukemia and sick‐cell anemia. However, most functional neuroimaging and pathological studies failed to detect different striatal characteristics in polycythemia vera patients with and without chorea. 3 Furthermore, chorea was reported in JAK2 V617F‐positive patients before or in the absence of hematological abnormalities meeting criteria for MPNs, 6 , 7 suggesting that blood hyperviscosity alone is not sufficient to explain chorea development.
Cerebrovascular congestion might alter regional concentrations of neurotransmitters. Upregulation of dopamine receptor sensitivity because of reduced levels of cerebral catecholamines and serotonin has been reported. 3 , 8 Moreover, enhanced dopamine receptor sensitivity secondary to relative estrogen deficit in postmenopause, may explain the higher frequency of polycythemia vera‐related chorea in elderly females (despite polycythemia vera being more prevalent in males). 8 Finally, excess dopamine release by platelets has been suggested in polycythemia vera‐related chorea, which can also be advocated in essential thrombocythemia. 3 , 8
Recently, Betté and Moore speculated that, because JAK2 is expressed in vivo by striatal progenitor cells, the somatic gain‐of‐function variant JAK2 V617F might cause chorea through local inflammation and impaired neurosignaling in the striatum. 7 , 9 In other words, the acquisition of JAK2 V617F by hematopoietic cells could upregulate systemic cytokines with receptors in the striatum, leading to striatal overactivation and ultimately chorea. This mechanism might also contribute to chorea in autoimmune conditions 8 but does not explain why only a small percentage of JAK2 V617F‐positive patients develop chorea. 3 Because chorea has mainly been reported in JAK2‐related MPNs, we speculate that the specific germline JAK2 haplotype that predisposes to the acquisition of JAK2 V617F in hematopoietic cells might influence the expression/regulation of (yet undetermined) genetic and/or epigenetic contributors to chorea in striatal cells. 10
Regarding laboratory findings, our patient's megaloblastic anemia could be explained by long‐term treatment with hydroxyurea. Indeed, hydroxyurea acts by causing myelosuppression, finally resulting in anemia with megaloblastosis as well as decrease in platelet and leukocyte counts. The detection of mildly elevated serum ferritin and serum polyclonal gamma globulins was consistent with an inflammatory status possibly secondary to deterioration of the hematological disease. Because the patient's neurological assessment was normal except for chorea and her brain MRI unremarkable with regard to high ferritin level, we did not pursue alternative diagnostic hypotheses. In keeping with the above‐mentioned speculation, increased ferritin levels might reflect the upregulation of systemic proinflammatory cytokines that could play a role in striatal hyperactivity and ultimately chorea.
In conclusion, late‐onset chorea may be associated with JAK2 V617F‐related essential thrombocythemia and foretell its deterioration. The pathophysiology of chorea in JAK2‐related MPNs seems multifactorial and requires further elucidation.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
S.K.K.: 1A, 2A, 2B, 3A
G.D.L.: 2A, 2B, 3A
F.M.: 2A, 2B, 3A
E.M.: 2C, 3B
A.L.: 2C, 3B
K.B.: 1A, 2C, 3B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. The authors confirm that written consent for video acquisition and publication was obtained.
Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: G.D.L. and F.M. are supported by the European Academy of Neurology (EAN) Research Fellowship 2020. K.P.B. has received grant support from Welcome/MRC, NIHR, Parkinson's UK, and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), of Marsden's Book of Movement Disorders (Oxford University Press, 2012), and of Case Studies in Movement Disorders—Common and Uncommon Presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz, and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals, and from the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society.
Supporting information
Video S1. Video of the patient showing choreiform movements in the oromandibular region, motor impersistence on tongue protrusion and mild upper and lower limb chorea in the absence of extrapyramidal or cerebellar signs.
Acknowledgments
The authors are grateful to Dr. Isacco Ferrarini (University of Verona, Italy) for his kind support in interpreting hematological findings.
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Associated Data
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Supplementary Materials
Video S1. Video of the patient showing choreiform movements in the oromandibular region, motor impersistence on tongue protrusion and mild upper and lower limb chorea in the absence of extrapyramidal or cerebellar signs.