Review of Hereditary and Acquired Rare Choreas

Background: Movement disorders are often a prominent part of the phenotype of many neurologic rare diseases. In order to promote awareness and diagnosis of these rare diseases, the International Parkinson’s and Movement Disorders Society Rare Movement Disorders Study Group provides updates on rare movement disorders. Methods: In this narrative review, we discuss the differential diagnosis of the rare disorders that can cause chorea. Results: Although the most common causes of chorea are hereditary, it is critical to identify acquired or symptomatic choreas since these are potentially treatable conditions. Disorders of metabolism and mitochondrial cytopathies can also be associated with chorea. Discussion: The present review discusses clues to the diagnosis of chorea of various etiologies. Authors propose algorithms to help the clinician in the diagnosis of these rare disorders.


Introduction
Accurate diagnosis of rare movement disorders (RMD) is often challenging. Although different strategies for appro aching RMD have been suggested, including identification of red flags, syndromic patterns, or genetic findings, none are highly reliable. One of the main objectives of the Rare Movement Disorders Study Group of the International Par kinson and Movement Disorders Society is to educate and help clinicians better diagnose RMD. Because of the large number of RMD, many of which have overlapping pheno types, we proposed an initial approach according to the predominant movement disorder in the clinical evaluation. The present review provides an update on the differential diagnosis of rare disorders that can cause choreas. We have included disorders where chorea is predominant in the clin ical picture. We also propose algorithms to guide clinicians in the diagnosis of these rare disorders (Figures 1 and 2).  systematically evaluated; the absence of a family history does not exclude a hereditary cause. Disorders of metabol ism and mitochondrial cytopathies are also cause of heredit ary choreas. The diagnosis of chorea can be challenging and even with an extensive workup, some patients remaining undiagnosed. Next generation sequencing technologies have helped increase the candidate gene list associated with choreas and other movement disorders, facilitating the sub sequent diagnosis and understanding the disease process [5,6]. However, this field is in constant evolution with new genes being discovered each year as cause of chorea. It is, of course, critical to identify acquired causes of chorea since these are potentially treatable conditions. The main causes of acquired choreas include infectious/postinfectious, autoimmune, metabolic, vascular, and druginduced causes.
Other less common causes of acquired choreas include posttraumatic, paraneoplastic, or demyelinating conditions. The present review includes possible etiologies of rare dis orders where chorea is a predominant symptom in the clin ical picture.
The following sections are organized by possible etiolo gies followed by a brief discussion of diagnostic clues for the different diseases. We also provide algorithms to offer the clinician a guide to organize their diagnostic thinking about chorea. Readers need to be aware that this algorithmic method cannot account all possible scenarios and should be interpreted within the clinical context.

Hereditary Choreas
Hereditary choreas are inherited in autosomal dominant, autosomal recessive, and Xlinked hereditary modes. The hereditary choreas are described in Table 1. The paroxysmal kinesigenic dyskinesias are beyond the scope of this review.

C9orf72 expansions
C9orf72 expansions are a rare cause of chorea, but appear to be the most common cause of HD phenocopies in Caucasian populations [10]. The expanded hexanucleotide repeat in C9orf72 gene is responsible for diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia [11].
Patients typically present around 40-50 years of age, and although a variety of movement disorders and neuropsy chiatric symptoms may develop, the clinical features may be quite similar to those of HD [12]. Upper motor neuron abnormalities and frontal lobe signs may suggest the diagnosis.
Spinocerebellar ataxia 17 (SCA17) SCA17 has been reported in Caucasian and Asian popu lations [13]. A family originally described with what was termed "Huntington's diseaselike 4" was subsequently diagnosed with this disorder. Patients with SCA17 are characterized by a clinical picture dominated by ataxia, in addition to other movement disorders such as chorea, dystonia, tremors, or parkinsonism. Patients may also develop pyramidal signs, cognitive impairment, seizures, or psychiatric symptoms. Age of onset is variable, but usu ally presents in early to midlife (between 20s-40s) [14]. SCA17 is caused by a trinucleotide CAG repeat expansion of chromosome 6q27 of the TATA box-binding protein (TBP) gene. Brain MRI typically shows caudate nucleus or cere bellar atrophy while putaminal rim hyperintensities have rarely been reported [15].
Huntington disease-like 2 (HDL2) HDL2 has only been reported in people of African ancestry, and has been documented primarily in South Africa, in addi tion to North, Central and South America, the Caribbean, and Europe [16,17]. HDL2 is the most commonly reported HD phenocopy in this population. Fewer than 100 cases have been reported in the literature worldwide. HDL2 strongly resembles HD clinically, radiologically, and neuropatholo gically [18]. HDL2 is caused by a CAG repeat expansion of the junctophilin-3 (JPH3) gene on chromosome 16q24.2 [17,19]. As with HD, the age of onset is inversely related to the size of CAG repeat expansion.

Dentatorubropallidoluysian atrophy (DRPLA)
DRPLA is characterized by a striking variety of symptoms including seizures, ataxia, chorea, myoclonus, dementia, and psychiatric symptoms that vary with age of presenta tion. Some patients can present with a clinical phenotype very similar to that of HD, with chorea as the predomin ant manifestation. DRPLA is highly prevalent among the Japanese population, but has occasionally been reported elsewhere [20]. The age of presentation depends upon the size of the CAG repeat expansion in atrophin-1 (ATN1) on chromosome 12p13-31 [21]. Brain MRI typically shows white matter lesions and cerebellar and brainstem atrophy.

Neuroferritinopathy
Neuroferritinopathy is a "neurodegeneration with iron accu mulation (NBIA)" disorder, characterized by a variety of movement disorders including chorea, dystonia, and parkin sonism. A clinical hallmark is the presence of prominent oro mandibular chorea. Patients can develop other neurological  [22]. Brain MRI shows iron accumulation or cystic changes in cortical regions or in the basal ganglia with pal lidal necrosis and edema in later stages of the disease [23]. Muscle biopsy may show abnormalities in the mitochondrial respiratory chain. Neuroferritinopathy is exceedingly rare, and has been reported predominantly in the Cumbrian region of England. It is caused by a mutation on chromo some 19q13 of the light chain of ferritin (FTL) gene.

Prion diseases
The majority of the cases of prion disease are either sporadic or acquired in nature [24]. Around 15% of all prion disease are caused by muta tions in the prion protein gene, which are inherited in an autosomal dominant fashion. Huntington diseaselike 1 (HDL1) is a rare familial prion disease with which can rarely present with similar clinical manifestations to HD, in addition to seizures and ataxia [25]. Prominent psychiatric symptoms and myoclonus can suggest this diagnosis. More typically, it causes cognitive problems, neuropsychiatric symptoms, or ataxia; chorea is rare. Age of presentation is   similar to that of HD in early adulthood, between the 20s and 40s. Symptoms lead to death within months or years. Neuropathology typically shows basal ganglia and fronto temporal and cerebellar atrophy with multicentric plaques that stain with antiprion antibodies. HDL1 is caused by a mutation on chromosome 20p12 of the prion protein (PRNP) gene [26]. Of the acquired/sporadic prion disorders, a new variant CreutzfeldtJakob disease (associated with Bovine Spongiform Encephalopathy) has been reported to cause chorea [27].

Spinocerebellar ataxias
Other spinocerebellar ataxias, such as SCA1, SCA2, SCA3, SCA7, SCA8, SCA12, and SCA48 should be considered in the differential diagnosis of autosomal dominant hereditary choreas with an ataxic phenotype [28]. Trinucleotide repeat expansion disorders, as in these SCAs, display the anticipa tion phenomenon. Many of the SCAs are caused by mutation of their respective ataxin (ATXN) genes. SCA1 has a mean age of onset in the 30s. Fifteen percent of the patients will develop chorea. In addition to ataxia, patients may develop pyramidal symptoms, dystonia, or oculomotor abnormalit ies. Brain MRI shows pontine and cerebellar atrophy [29]. SCA2 is a common reported cause of HD phenocopies in European populations, Cuban and Indian ethnicities. The average age of onset is similarly in the 30s. Chorea may be present, however, additional typical findings in SCA2 are impaired slow saccades, myoclonus, faciolingual fascicula tions, cognitive impairment, and parkinsonism. Brain MRI also shows pontine and cerebellar atrophy [30]. SCA3, also known as MachadoJoseph disease, is the most common autosomal dominant ataxia worldwide. It has a wide range of onset ages and a variety of clinical manifestations. Brain MRI also shows pontine and cerebellar atrophy [31]. SCA7 presents typically with ataxia, visual loss, ophthalmoplegia, and rarely chorea. Brain MRI shows cerebellar and brainstem atrophy [28,32]. SCA8 is highly prevalent in Finland and its clinical presentation is highly variable, however, reports describe several symptoms that seem to be share between cases, including ataxia, pyramidal symptoms, sensory symp toms, cognitive impairment, myoclonus, and migraine head aches. MRI shows cerebellar atrophy [33]. Chorea can be an atypical clinical characteristic of SCA8 [34]. SCA12 is charac terized by slowly progressive ataxia, neuropsychiatric symp toms, and rarely with cognitive decline. Additional features are parkinsonism and hyperreflexia. Recently, a case was reported to present as HDlike, expanding the phenotypic spectrum of SCA12. Brain MRI shows cerebral cortex atrophy [35]. SCA48 has recently been described as an adultonset ataxia associated with a cognitivepsychiatric disorder and other variable symptoms including chorea, parkinsonism, dystonia, epilepsy, and urinary problems. MRI shows cere bellar atrophy and T2 hyperintensities in the dentate nuclei extending to middle cerebellar peduncles [36].

Non-HD phenocopies Primary Familial Brain Calcification
Primary familial brain calcification (PFBC) is a neurode generative disorder characterized by calcium deposits in a variety of brain areas observed on neuroimaging. Brain CTs show calcification in caudate nuclei, cerebellum, white mat ter, thalami, cortex, vermis, midbrain, pons, and medulla. PFBC is predominantly caused by mutations in SLC20A2 gene, although a number of other genes have recently been implicated, such as PDGFB, PDGFRB, and XPR1 genes [37]. The pattern of inheritance is an autosomal dominant pattern in most cases. The clinical symptoms are variable, and can include cognitive impairment, psychiatric symp toms, and movement disorders. The age of onset is usually in the 30s and 40s. The most common movement disorder reported is an akinetic syndrome with or without tremor, although chorea and dystonia can also be seen [38].

ADCY5-Related Dyskinesia
Mutations in ADCY5 were first reported in families described as having "Familial Dyskinesia with Facial Myokimia" [39].
The clinical phenotype has expanded since then; core fea tures include infantile or early childhoodonset of facial myoclonus, axial hypotonia, and exacerbations of dyskinetic movements in an episodic manner in relation to drowsi ness and sleep [40]. The dyskinetic movements have been variably described as chorea, athetosis, dystonia, or myoclo nus, typically more prominent in the upper limbs [40]. It is important to note that while ADCY5 mutations are typ ically transmitted in autosomal dominant fashion, it also can occur de novo [41]. Delayed milestones and signs of spasticity may also be part of the clinical spectrum. ADCY5 mutations have also been found in patients carrying the dia gnosis of "benign hereditary chorea" [42].

Benign Hereditary Chorea
Mutations in TITF1/NKX2-1 are the most common cause of benign hereditary chorea (BHC) [43]. BHC typically presents in childhood, preceded by hypotonia, and is characterized by chorea with mild clinical progression [44]. It is argued that this is not necessarily a "benign" condition, as it is associated mainly with pulmonary and thyroid disorders in the most severe expression of the TITF1/NKX21related disorders. This triad is also called "brainlungthyroid disease" [45].
Commonly reported pulmonary disorders include neonatal respiratory distress syndrome, recurrent pulmonary infec tions, obstructive airway disease, and chronic interstitial lung disease. Thyroid disorders reported may include con genital hypothyroidism or thyroid agenesis [46]. Mutations in SLC16A2 gene have also been described as a cause of BHC or "brainlungthyroid disease" [47]. Carriers of mutations in TITF1/NKX2-1 can have increased risk of malignancy, specifically lung cancer, and should undergo appropriate screening [43].

Tuberous sclerosis
Tuberous sclerosis is a genetic disorder characterized by numerous benign tumors in many parts of the body, skin abnormalities, developmental problems, behavioral symp toms, and seizures. Although rare, chorea may be a mani festation of this complex disorder, likely related to nodules located in the basal ganglia [48,49].

Chorea-acanthocytosis
Choreaacanthocytosis is one of the core neuroacanthocyt osis syndromes, and is a progressive neurologic disorder characterized by prominent selfinjurious orofacial dysk inesia and generalized chorea. Patients typically develop speech and swallowing problems, hypersalivation, or vocal tics such as grunts, snorts, echolalia, and other utterances. Feeding dystonia, in which the tongue pushes food out of the mouth during eating, is characteristic. Head drops can often be seen. Other neurological characteristics are neuro psychiatric symptoms, axonal neuropathy, seizures, and a gait which is described as "rubberperson". The age of onset is usually in the third or fourth decades of life. Brain MRI shows caudate atrophy. Acanthocytes are seen on peripheral blood smear, although this is a variable finding. More useful for diagnosis is the observation that creatine kinase is elev ated in the thousands (normal 0-200 U/I), reflecting muscle damage. Choreaacanthocytosis is caused by mutations of the VPS13A gene on chromosome 9q21 [50].

Friedreich's ataxia
Friedreich's ataxia is characterized by progressive ataxia and peripheral neuropathy in patients under 25 years of age [51]. The disease is mainly caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene; a shorter repeat expansion length correlates with older age at onset and milder disease [52]. Around 2% of the patients are com pound heterozygotes who have repeat expansions in one allele with a point mutation in the other allele [53]. Patients with heterozygous repeat expansion may have atypical clin ical features, such as chorea. However, chorea has also been reported in patients homozygous for the expansion [54].

Aceruloplasminemia
Aceruloplasminemia is a disorder of iron metabolism, con sidered as one of the NBIA disorders, that shares clinical characteristics with HD. Patients tend to develop anemia and diabetes in their 20s and may present with ataxia, chorea, parkinsonism, cognitive decline, and psychiatric symptoms.
Retinal degeneration is a characteristic feature. Brain MRI displays symmetrical deposition of iron in the basal ganglia, thalamus, red nuclei, and dentate nuclei. Aceruloplasminemia is caused by mutations in the CP gene [55].

Huntington disease-like 3 (HDL3)
Only one Saudi Arabian family consisting of 5 affected individuals was reported to have a disease termed "HDL3". The age of onset was in childhood (3-4 years of age) with a variety of clinical manifestations such as chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intel lectual impairment. Brain MRI shows frontal and caudate atrophy. The causative gene is still unknown; the disease locus mapped to chromosome 4p15.3 [56], although this has been questioned.

Wilson's disease
Wilson's disease typically presents in the second or third dec ade of life, is a disorder of copper transport leading to cop per accumulation, and is one of the few potentially treatable hereditary movement disorders [57]. The neurological mani festations vary widely. Three distinct neurological presenta tions are suggested; a dystonic/choreic syndrome, an ataxic syndrome, and a parkinsonian syndrome. Chorea is reported in 9% of Wilson patients and should therefore be considered in the differential diagnosis of HDL disorders. Patients also develop cognitive impairment and neuropsychiatric symp toms. Evidence of liver disease and hemolytic anemia should prompt the clinician to consider the diagnosis, which is sup ported by low ceruloplasmin levels, elevated 24hour copper excretion, and KayserFleischer rings on slitlamp ophthal mological examination. Abnormal signals in the putamen, caudate nucleus, globus pallidus, thalamus are frequently seen on brain MRI in addition to brainstem changes [58].
Although not uniformly present across patients, brain MRI shows a characteristic "face of the giant panda" in the mid brain. Wilson's disease is caused by mutations in ATP7B gene [59]. The goal of therapy is to establish a net negative copper balance. This can be achieved by increasing copper excretion with chelating agents, and by reducing copper absorption with zinc and reducing dietary intake [57].

Ataxia-telangiectasia
Ataxiatelangiectasia is characterized by progressive neuro logical dysfunction associated with multisystem abnormal ities and predisposition to immunological disorders and cancer. Chorea is commonly seen in ataxiatelangiectasia syndrome, with onset in childhood, prominent ataxia, peri pheral neuropathy, and telangiectasias (conjunctiva and external ear). The serum concentration of alphafetoprotein is elevated. In addition, patients develop immunoglobulin deficiency resulting in repetitive upper respiratory tract infections, and have increased sensitivity to radiation with high risk of developing cancers. Ataxiatelangiectasia is caused by mutations in ATM gene [60].
Ataxia with oculomotor apraxia 1 and 2 Ataxia with oculomotor apraxia 1 (AOA1) typically presents with ataxia, axonal sensorimotor neuropathy, oculomotor apraxia, and movement disorders including chorea and/or dystonia. Ataxia with oculomotor apraxia 2 (AOA2) presents similarly to AOA1 [61]. Cognitive impairment is more fre quent in AOA1 than in AOA2. AOA1 patients have hypo albuminemia and hypercholesterolemia, in contrast with AOA2 patients who have elevated serum alphafetoprotein levels. The age of onset is usually earlier in AOA1 compared to AOA2, which presents during childhood and adolescence. Brain MRI in both AOAs usually shows cerebellar atrophy. AOA1 is caused by mutations in APTX gene and AOA2 is caused by mutations in SETX gene.
Spastic ataxia type 2/Spastic paraplegia type 58 The hereditary spastic paraplegias (HSPs) are a group of het erogeneous disorders characterized by spastic gait, hyper reflexia, and spasticity. Complex HSPs are associated with additional neurologic manifestations including ataxia and other movement disorders. Chorea has been reported in spastic paraplegia type 58, also known as spastic ataxia type 2, caused by a mutation in KIF1C gene. The age of onset ranges from infancy to adulthood [62].

GPR88 mutation
Mutations in GPR88 has been reported in three children of one consanguineous Palestinian family. Affected individu als with GPR88 mutation typically present with early onset slowly progressive chorea, mental retardation, and develop mental delay [64].

McLeod syndrome
McLeod syndrome is an Xlinked recessive hereditary disorder with very similar clinical characteristics to choreaacanthocytosis. Patients lack the red blood cell XK antigen and the expression of Kell antigens on the eryth rocyte membrane surface is reduced. Chorea is a common symptom in addition to areflexia due to a sensorimotor axonopathy. Distinguishing features are male gender, the age of onset, which tends to be in the 40s-60s, and the pres ence of cardiomyopathy and arrhythmias. Liver enzymes and creatine kinase are elevated. Patients also develop seizures, significant myopathy, and peripheral neuropathy. While less common than in choreaacanthocytosis, there can some times be tongue protrusion, feeding dystonia, and lipbiting or tonguebitting [25,66].

Pelizaeus-Merzbacher disease
PelizaeusMerzbacher disease (PMD) is a clinically and genetically heterogeneous leukodystrophy characterized by central hypomyelination with neurologic dysfunction and progressive deterioration [67]. PMD usually presents within the first years of life with pendular nystagmus, head tremor, generalized hypotonia, mental retardation, choreoathetosis, cerebellar ataxia, and pyramidal signs. Brain MRI shows hypomyelination of the corona radiata, optical radiations, and internal capsule. PMD is caused by mutations in the PLP1 gene which encodes the proteolipid protein of myelin ating oligodendroglia.

Inborn Errors of Metabolism
Inborn errors of metabolism are common causes of hyper kinetic and hypokinetic movement disorders in children. A single error of metabolism can cause multiple movement disorders. Diagnosis of these disorders requires screening for specific metabolites in urine, serum or cerebrospinal fluid, the results of which can direct further biochemical or genetic analyses. Movement disorders in these children can cause lifelong disability. Chorea is not an uncommon symtptom of inborn errors of metabolism ( Table 2), and is a predominant characteristic of glutaric aciduria type 1, gluc ose transporter type 1 (GLUT1) deficiency, and LeschNyhan disease. A recent report described that Niemann Pick type C in the adultonset can mimic HD phenocopies and should be considered in the diagnostic approach of patients with a choreic phenotype [68].
In general these disorders present in infancy or early childhood with a variety of neurological symptoms includ ing encephalopathy, developmental delay, central or peri pheral hypotonia, autonomic dysfunction, seizures and/or movement disorders [69]. Identification and management of potentially treatable inherited metabolic disorders is dis cussed elsewhere [70][71][72].

Mitochondrial Cytopathies
Mitochondrial disorders are a clinically and genetically het erogeneous group of diseases due to dysfunction of the mitochondrial respiratory chain, usually in the oxidative phosphorylation system and pyruvate dehydrogenase com plex ( Table 2) [73]. These disorders may present at any age with a highly variable clinical course and with a wide spec trum of clinical manifestations. Neurologic mitochondrial symptoms often include seizures, encephalopathy, stroke like episodes, migraine, dementia, spasticity, and peripheral neuropathy. A multisystem clinical presentation involving several organs, including peripheral and central nervous systems should prompt the clinician to consider a possible mitochondrial disorder. A clue to the diagnosis is the pres ence of other family members with myopathic disorders or ophthalmoplegia [7]. Movement disorders are common in mitochondrial diseases. Patients with mutations in POLG, MTTG, MTND4, HSD10, MICU1, COX20 have been reported to have choreic movements [74]. However, chorea is a pre dominant symptom in Leigh syndrome, pyruvate carboxylase deficiency, and pyruvate dehydrogenase complex deficiency [75]. The disorders of metabolism and mitochondrial cyto pathies where chorea predominates are describe in Table 2.

Acquired Choreas
In the following sections, we will discuss the rare acquired choreas ( Table 3). We will not discuss some of the acquired choreas that are relatively common such as those induced by medications (levodopainduced or tardive chorea), vascu lar choreas, Sydenham's chorea, chorea secondary to non ketotic hyperglycemia, neoplasms, causes of brain hypoxia, and cerebral palsy. Since a variety of genetic and metabolic conditions may mimic cerebral palsy, we recommend that the diagnosis of cerebral palsy be reconsidered when there is absence of risk factors in the birth/neonatal history or neuroimaging findings consistent with brain injury or con genital abnormalities [76].

Alcohol and other toxins
Chorea in alcohol abusers is more frequent in females and may be precipitated or exacerbated by withdrawal of alco hol. Movements are typically localized to the upper part of the body [77]. It is suggested that vitamin B1 deficiency contributes to the underlying cause [78]. Symptoms usually resolve within several weeks. Other toxins that may produce chorea include mercury, thallium, lead, and organophos phates [79].

Polycythemia vera
Polycythemia vera (PCV) is a neoplastic bone marrow stem cell disorder characterized by an elevated red blood cell mass due to uncontrolled production of erythrocytes. Although a rare manifestation, gradual onset of generalized or asymmetric chorea can be a presenting symptom of PCV. Hypotonia and pendular or "hungup" knee jerks have been reported. The underlying mechanism for the generation of chorea is uncertain, however hyperviscosity may lead to decreased blood flow in the basal ganglia. Patients are usu ally female and above 50 years of age, thus polycythemic chorea should be considered in the differential diagnosis of lateonset chorea, especially in women. In most cases the chorea is transient and selflimited, and responds to treat ment of the polycythemia. Dopamineblockers or depleting agents are sometimes required [80].

Essential thrombocythemia
Essential thrombocythemia (ET) is a clonal myeloproliferative disease characterized predominantly by a markedly elevated platelet count without known cause, with predisposition to vascular occlusive events and hemorrhages. Generalized chorea has been reported recently as an initial presentation of ET [81].

Autoimmune
Factors that will guide the clinician to consider an autoim mune etiology of chorea are a subacute onset of the sympto matology, a fluctuating course with spontaneous remissions, frequent coexistence of neurological disorders atypical for HD, and absence of oculomotor abnormalities [82]. Sydenham's chorea will not be discussed in the present review.
Systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS) The neurological system is involved in 20 to 65% of SLE cases. Patients may develop seizures, cranial nerve lesions, sensory abnormalities, neuropsychiatric symptoms, and neuropathies [83]. Chorea has been reported in about 4% of SLE patients, and in approximately 1/4 of these cases, chorea is the initial manifestation. Most cases are reported in young adult patients. The underlying mechanism associated with basal ganglia dysfunction remains to be determined, but potential pathophysiologies include vascular dysfunc tion as well as circulating antiphospholipid antibodies [84]. Some SLE patients are predisposed to develop APS. In most cases of SLE or APS, chorea is transitory. Cerebrospinal fluid analysis and brain MRI are usually normal. The treatment of chorea associated with SLE and APS relies on the combina tion of corticosteroids with or without other immunosup pressive agents, dopamine blockers or dopamine depletors. The use of aspirin or anticoagulants is recommended for APS patients [85].

Membrane Proteins
Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis AntiNMDAR antibodies have recently emerged as an important cause of autoimmune encephalitis, which can result in a fatal outcome if not recognized and treated early [86,87]. This disorder affects young individuals (mean age at onset 21 years), predominantly female (4:1). Neuropsy chiatric symptoms typically develop suddenly with an early presentation of movement disorders including chorea, ste reotypies, and dystonia. Perioral movements are common. Cognitive disorders, autonomic symptoms, waxy flexibility, sleep problems, and seizures are also part of this complex disorder [88]. A significant number of cases are associated with underlying ovarian teratomas, with less frequent asso ciation of teratomas in men and children. Diagnostic criteria have been established [89]. Brain MRI is usually unremark able and detection of CSF antibodies against the GluN1 subunit of the NMDAR confirms the diagnosis. Treatment includes immunosuppressive measures, corticosteroids, intravenous immunoglobulin (IVIg), plasma exchange, and in unresponsive cases, rituximab, cyclophosphamide, mycophenolate or other immunosuppressors are used [90]. The hyperkinetic disorders associated with antiNMDAR encephalitis usually respond to dopamine depleting drugs, such as tetrabenazine, deutetrabenazine and valbenazine [84]. AntiNMDAR encephalitis association with ovarian teratoma is common, especially in women of reproductive age. If present, surgical excision of teratoma is necessary to improve patient prognosis [91].

Behcet's disease
Behcet's syndrome is a multisystemic inflammatory disease characterized by ocular lesions (uveitis), genital and oral aphthosis, and skin lesions [92]. Neurological involvement is a rare manifestation but an important cause of longterm morbidity. NeuroBehcet's disease is more common in males and neurological symptoms typically present 3 to 6 years after other systemic manifestations [93,94]. Movement disorders including chorea and parkinsonism have been reported in neuroBehcet's disease and are believed to be related to antibasal ganglia antibodies [95]. Treatment recommendations are for steroid administration in case of an acute attack, which should be continued for at least 6 months. Other immunosuppressive agents should also be administered to young patients or those who develop neurological manifestations after a short latency to prevent recurrence and progression [93].

Sjögren syndrome (SS)
Choreic movements are rare extraglandular symptoms of SS. Current data suggest that chorea associated with SS can be isolated or present in combination with neuropsy chiatric symptoms and radiological findings [96]. Evidence shows that the presence of neurologic disease in SS is a strong indicator of disease activity and damage. In these cases, early initiation of treatment has contributed to good recovery [97].

Celiac disease
Celiac disease is a gluteninduced immunemediated entero pathy. The inflammatory process is triggered by the inges tion of gluten present in wheat, barley, and rye in genetically predisposed individuals, and causes predominantly gastro intestinal symptoms [98]. Extraintestinal manifestations are not uncommon; neurological symptoms are present in 10% of patients including ataxia, myalgias, or peripheral neuro pathies. Chorea is rarely reported [99,100]. In patients in whom celiac disease is suspected, measurement of serum IgA antibodies to tissue transglutaminase is considered the first screening test. IgA antiendomysial antibody test is confirm atory. A strict glutenfree diet is the treatment of choice [98].

Other
Antibodies against synaptic receptors and neuronal cell sur face adhesion molecules such as IgLON5, D2R, GABAaR, and Neurexin3 alpha have been found recently to cause a wide spectrum of symptoms including encephalitis, movement disorders (including chorea), neuropsychiatric manifesta tions, and sleep disorders [101][102][103][104].

Endocrine and Metabolic
Hyperthyroidism Hyperthyroidism, in particular Grave's disease, can also be a rare cause of acquired chorea. Young female patients (average mid20s) are more commonly affected [105]. Chorea in hyperthyroidism has a varied presentation in terms of onset, distribution, and severity. Additional neurological and psychiatric signs associated with thyro toxicosis are common. Chorea most commonly develops simultaneously with or after the clinical symptoms of hyperthyroidism. Signs and symptoms of hyperthyroid ism, such as tachycardia and other cardiovascular symp toms, in the presence of chorea should alert the clinician to the possibility of this diagnosis. The possible under lying mechanism is related to circulating thyroid hor mones [106]. Management is centered on normalization of thyroid function with antithyroid drugs. A few patients may require antichoreic agents such as neuroleptics and tetrabenazine [107].

Hypocalcemia
Hypocalcemia as cause of chorea is more commonly seen in hypoparathyroidism, either idiopathic, postoperative, or pseudohypoparathyroidism [108]. Other reported causes of chorea secondary to hypocalcemia include malabsorption or bisphosphonate treatment [109][110][111]. Chorea is usually generalized and patients may show other manifestations of hypocalcemia. Normalization of blood calcium levels is the main treatment. Dopamine modulating agents are some times required.

Hyper-or Hypo-natremia
Serum sodium disturbances must be considered along with the status of the extracellular volume hypovolemia, euvole mia, and hypervolemia. Neurological symptoms include confusion, neuromuscular excitability, hyperreflexia, seizures, or coma. Chorea may appear during the hyper or hyponatremic phase or after correction of the electrolyte disturbance [112]. Chorea in association with hyponatremia has been repor ted in intracranial tuberculomas [113]. A rapid correction of hyponatremia can cause central pontine and extrapontine myelinolysis which can also cause movement disorders [114][115][116].

Hypomagnesemia
Low magnesium blood levels may result in similar neuro logical symptoms to hypocalcemia such as increased deep tendon reflexes and presence of Chvostek's sign [1]. Chorea is not rare, and usually occurs in the setting of other neuro logical features. The main causes of low magnesium blood levels are a deficient oral intake (e.g. parenteral nutrition), diarrhea, renal disease, diuresis, acute pancreatitis, or hyper calcemia. Treatment is focused on correcting the deficiency of magnesium.

Uremia
Chorea has been reported in patients with uremia [117], and is more commonly seen among people of East Asian ances try, for reasons which are unknown. It can be difficult to differentiate whether the chorea is secondary to nonketotic hyperglycemia, which is usually present, or uremia; how ever, the observation of hyperintense lesions involving the basal ganglia associated with marked surrounding edema on MRI T2weighted sequences, and the relatively younger age of the patient can facilitate the diagnosis. Chorea may improve after correction of uremia however, the movement has been reported to persist after resolution of the metabolic derangement [118].

Non-wilsonian hepatolenticuar degeneration
Acquired hepatocerebral degeneration is a progressive dis order seen in patients with advanced liver disease and por tosystemic shunts [119]. Features of hepatic disease usually precede neurological symptoms. Neurological symptoms include cognitive impairment, speech problems, movement disorders, paratonia, ataxia. Tremor, myoclonus, chorea, and athetosis can be seen [120]. Chorea is present in about 20% of patients. Patients can also develop pyramidal signs and paraparesis. This disorder usually presents in middleaged adults. Diffuse bilateral hyperintensities and cavitations in the basal ganglia on MRI and evidence of liver failure indic ate the diagnosis [121].

Kernicterus
Kernicterus describes a chronic encephalopathic syndrome in neonates as a result of excessively elevated bilirubin leading to movement disorders, auditory dysfunction, oculomotor abnormalities, dental enamel hypoplasia, and gastrointestinal abnormalities [122]. The aggressive treat ment of perinatal hyperbilirubinemia has led to a decline in the incidence kernicterus [123]. Dystonia and athetosis are more commonly reported than chorea. Brain MRI may show hyperintense lesions in the globus pallidus in T1weighted sequences. Supportive treatment and deep brain stimula tion (DBS) may provide some improvement [124].

Nutritional
Vitamin B12 and B1 deficiency Movement disorders related to vitamin deficiencies are rare. Chorea is not a typically recognized characteristic of vitamin B12 deficiency. When present, it be unilateral or generalized in distribution, and is more commonly seen in male patients [125]. However, the most prevalent symptoms of vitamin B12 deficiency include vibratory and proprioceptive impair ment, cognitive impairment, dizziness, muscle cramps, ataxia, erectile dysfunction, fatigue, psychiatric symptoms, and macrocytic anemia [126]. The mechanism of chorea induced by vitamin B12 deficiency is not well understood [127]. Thiamine deficiency is also a rare cause of nutritional chorea (likely due to a similar mechanism as that seen with disorders of thiamine metabolism). Patients usually present with altered mental status, ataxia, and oculomotor abnor malities, in addition the movement disorder. Brain MRI may show hyperintensities in both thalami on FLAIR sequence [128]. Chorea usually resolves after correction of nutritional deficiency.

Multiple Sclerosis (MS) and other demyelinating diseases
Chorea has been rarely reported during the course of established MS [129]. Patients are typically young and female with brain MRI findings may show demyelinating lesions in the region of the basal ganglia, especially in the contralateral striatum [130]. In most cases the chorea improves or disappears after the MS relapse. If the move ment persists, dopamine receptor blockers or depletors or low doses of carbamazepine can be used [131]. Chorea has also been rarely reported in other demyelinating disorders including acute disseminated encephalomyelitis, central pontine myelinolysis and extrapontine myelinolysis, and hypomyelination with atrophy of the basal ganglia and cerebellum. The impact of treatment in the chorea of these other demyelinating disorders is still not well under stood [131].

Paraneoplastic
Chorea should be suspected as being due to a paraneoplastic origin when symptoms develop in a subacute manner, in adult patients above 50 years of age, male gender, and in the presence of other neurological and systemic symp toms such as peripheral neuropathy and weight loss [132]. Paraneoplastic chorea is associated with antibodies directed against intracellular antigens including antiHu, antiMa, antiCRMP5/CV2, and antiP/Q and Ntype voltagegated calcium channels, and with antibodies directed against cell surface antigens including antiNMDAR, antiLGI1, and anti Caspr2 [133,134]. The most common associated cancer is small cell lung cancer and the most frequently associated antibody is CRMP5 [82]. The treatment and prognosis are highly related to the treatment of the underlying malig nancy. Patients typically have a short survival [84,135].

Infectious
Bacterial Some of the reported uncommon bacterial causes of chorea include typhoid fever [136], pertussis, diphtheria, Legion naires' disease [137], tuberculous meningitis [138,139], and mycoplasma [140]. The mechanism is suggested to be related to a cytotoxic effect of bacteria [137]. Bacterial chorea develops during the course of the infection, is asso ciated with systemic symptoms, and typically affects young patients.

Viral
Viral infections causing chorea include measles [141], rubella, varicella [142], mumps, influenza A [143], ECHO virus 25 [144], herpesvirus [145], EpsteinBarr [146], citomegalovirus, Japanese encephalitis [147], tickborne encephalitis [148], and HIV [149,150]. In general, chorea secondary to viral infections typically develops over the course of the viral infec tion. Clinicians should suspect a viral etiology if the chorea presents in an acute or subacute fashion, and if associated with encephalopathy or other systemic signs and symptoms of the viral infection. Whether the mechanism is cytokineme diated or cytotoxic effects of the virus is still under discussion [143]. Chorea can be unilateral or can be generalized in dis tribution and is usually transitory, remitting in days to weeks after the infection.

Spirochetal
Syphilis is a sexually transmitted chronic multisystemic dis ease which can present with a variety of systemic and neuro logical symptoms. Only a few patients affected with syphilis have been reported to develop movement disorders, and most are associated with HIV infection [151,152]. Chorea is rare and resolves with treatment of the disease. Similar to the previously mentioned spirochete, Lyme disease can cause a variety of neurological symptoms, but movement disorders, specifically chorea, are rare [153]. Treatment of neurobor reliosis usually resolves neurological and nonneurological symptoms.

Post-pump chorea
Chorea has also been reported in children, and occasion ally adults, undergoing cardiopulmonary bypass surgery [154]. This syndrome is known as "postpump chorea" or "CHAP syndrome" (choreoathetosis, oralfacial dyskinesias, hypotonia, pseudobulbar signs). Chorea is often mild, typ ically develops 7-12 days after the procedure with gradual resolution of chorea after several week or months [155]. Several risk factors for postpump chorea syndrome have been reported including patients undergoing hypothermic ischemic arrest, relative polycythemia, right ventricular out flow tract obstruction with ventricular septal defect, and very rapid cooling inducing hypothermia [155].

Mastocytosis
Mastocytosis is a rare disorder caused by excessive produc tion and accumulation of defective mast cells and CD34+ mast cell precursors [156]. It manifests in a variety of forms with an increased risk of anaphylaxis. Systemic mastocytosis is commonly seen in adults. Neurological manifestations commonly include headache, seizures, dizziness, and cognit ive impairment. Chorea is an extremely rare manifestation. It usually affects the upper body and remits after treatment of the underlying condition [157].

Chorea gravidarum
Chorea gravidarum is a neuropsychiatric disorder occurring in approximately 1 per 2,000 to 3,000 pregnancies [158]. Chorea may be mild to severe with symptoms beginning in the first or early second trimester. In most cases, chorea usually resolves by the third trimester or halts within hours of delivery. Psychiatric symptoms may include personality changes, depression, tourettism, hallucinations, delirium, or cognitive impairment. Collagen vascular disorders and a history of Sydenham's chorea are frequently associated with the disorder. Other commonly associated disorders are SLE, APS, thyrotoxicosis, druginduced chorea, Wilson's disease, or HD. Chorea gravidarum may recur in later pregnancies. Chorea, likely due to a similar mechanism, can be seen with the use of oral contraceptives or topical estrogen. If needed, symptomatic therapy for chorea with dopamine recept orblocking or depleting agents are used [159].

Conclusions
The diagnosis of chorea can be challenging. In order to pro mote awareness of rare disorders that can cause chorea, we provide clues to the diagnosis, clinical and radiological char acteristics of rare causes of chorea. Consideration of the age of onset and, if possible, whether the disorder is hereditary or acquired, will guide the diagnostic evaluation. The most common causes of rare disorders resulting in chorea are genetic, and these are often neurodegenerative. The field of genetic causes of choreas or other movement disorders is in constant evolution, however, it is critical to identify the acquired choreas since these are treatable conditions.

Funding Information
Authors report no funding sources related to the present review.
Daniel MartinezRamirez: No financial disclosures related to the present manuscript. DMR has received honoraria from Abbott and consulting fees from UCB and Abbvie.
Ruth H Walker: No financial disclosures related to the present manuscript. RHW has received honoraria from Neurocrine Biosciences, Inc. and the International Parkinson and Movement Disorder Society, and consulting fees from Advance Medical Opinion.
MRV and EMG have no disclosures.