Generalized Chorea and JAK2V617F Mutation‐Positive Myeloproliferative Disorders

https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312935-sup-v001.htm

Polycythemia vera (PV) is often attributed to the JAK2V617F mutation and is well known to be associated with chorea. We present an elderly patient who developed generalized chorea and was found to have the JAK2V617F mutation without PV. We also review the literature on this disorder and discuss possible mechanisms of the associated chorea.

Case Report

An 86‐year‐old right‐handed man presented with 1 month of involuntary movements. He had involuntary facial grimacing, tongue chewing, grunting, slurred speech, shoulder shrugging, and leg movements. He was not able to suppress the movements, felt no urge to move, no restlessness, and did not have the abnormal movements in sleep. The patient also had gait difficulty related to weakness after cervical spinal fusion, but his gait worsened after onset of the involuntary movements. He did not have exposure to neuroleptics or antiemetics. He had a 17‐pound unintentional weight loss over the past 1 month. The patient had no family history of involuntary movements. Relevant medical history includes left amaurosis fugax 18 months preceding onset of involuntary movements, left acoustic neuroma treated with gamma knife radiation, and C2 to C7 spinal fusion complicated by left hemiparesis.

General exam was notable for facial plethora and diffuse ecchymoses. Neurological exam was notable for mild generalized chorea with oro‐buccal‐lingual predominance and mild left hemiparesis. Brain MRI was unremarkable apart from left internal auditory canal enhancement. Cervical spine MRI showed multilevel postoperative changes without myelomalacia. On routine laboratory testing 3 months before developing involuntary movements, the patient was noted to have an elevated white blood cell (WBC) count of 11.8 with normal differential, low hemoglobin (Hgb) of 11.4 (chronic), and normal platelets at 202. Erythropoietin level was 4 (low), and flow cytometry was normal. Further testing revealed a positive JAK2V617F mutation. Six months later, the patient had a further elevated WBC of 16.4 with normal differential, normal Hgb of 14.4, and normal platelets at 209. His elevated WBC count was ascribed to a Janus kinase 2 (JAK2) mutation‐positive myeloproliferative disorder. Workup for other causes of chorea, including Huntington's disease, was unrevealing. We concluded that his chorea is associated with the JAK2V617F mutation. The history of amaurosis fugax and the presence of facial plethora and ecchymoses suggest relative erythrocytosis and platelet dysfunction, although he never met criteria for diagnosis of PV.

The patient was prescribed hydroxyurea, tetrabenazine, and continued on aspirin. Therapeutic phlebotomy was not attempted because of his history of long‐standing anemia. His blood counts normalized and chorea improved 2 months after initiation of hydroxyurea, with peak improvement at 4 months.

Discussion

PV is a myeloproliferative neoplasm characterized by erythrocytosis. Major diagnostic criteria include Hgb >16.5 g/dL or hematocrit >49% (>16.0 g/dL or 48% in women) or increased red cell mass, bone marrow biopsy showing hypercellularity, and presence of the JAK2 mutation. Minor criteria include subnormal serum erythropoietin level. A patient needs three major or two major criteria and one minor criterion for diagnosis.1 PV is associated with the JAK2V617F gene mutation, a somatic heterozygous gain‐of‐function mutation. There are additional myeloproliferative disorders caused by this gene mutation, including essential thrombocythemia, primary myelofibrosis, leukemia, and others.2

Chorea associated with PV is well described in the literature. However, generalized chorea with isolated leukocytosis and JAK2V617F gene mutation has not been previously described, and there are few case reports on this mutation in the absence of PV. As suggested by Lew et al.,3 this may be a type of forme fruste of the full manifestation of the myeloproliferative disorder. Our case demonstrates the importance of checking a complete blood count as part of the workup for late‐onset chorea.

Hyperviscosity in the basal ganglia is the oft‐proposed mechanism for the generation of chorea, although few patients develop chorea despite having symptoms of hyperviscosity in other organs, and patients with chorea need not have particularly high hematocrit.4 Another possible mechanism, proposed for the first time in our article, is directly by the JAK2 mutation. Whereas Janus kinase/signal transducer and activator of transcription signaling pathways are essential for development, homeostasis, and immunity,2 it appears that they also play a role in the inflammatory response to neurotoxicity. JAK2 is expressed in vivo by central nervous system striatal progenitor cells and is subject to activation by typical cytokine pathways.5 In mice with quinolinic acid striatal lesions, inhibition of JAK2 resulted in reduced apoptosis and reduced astrogliosis, suggesting that JAK2 inhibition is neuroprotective.6 Expression of JAK2 in the striatum, with activation leading to astrogliosis and inflammation, provides the possibility of a direct mechanism of chorea through the JAK2V617F‐activating mutation. Theoretically, the resulting proinflammatory state in the striatum would result in dysfunctional neuronal signaling, generating chorea. This link remains conjecture at this time and merits further exploration, as do the factors that determine why only a small percentage of patients with the JAK2V617F mutation develop chorea.

Author Roles

(1) Case Report: A. Conception, B. Execution; (2) Literature Review: A. Conception, B. Execution; (3) Manuscript: A. Writing of First Draft, B. Review and Critique.

S.B.: 1B, 2A, 2B, 3A

H.M.: 1A, 2A, 3B

Disclosures

Ethical Compliance Statement

Good Clinical Practice guidelines were followed in the patient assessment and manuscript development. This study was under exemption by The University of Miami Miller School of Medicine Human Subject Research Office that oversees IRBs. Written informed consent for use of medical information and video was obtained from the patient, using approved forms from the University of Miami Miller School of Medicine. 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.

Funding Sources and Conflicts of Interest

The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months

The authors declare that there are no disclosures to report.

Supporting information

Video 1. Segment 1: demonstration of ecchymoses, generalized chorea, and facial plethora. Segment 2: detailed demonstration of oro‐buccal‐lingual chorea.