Review of Hereditary and Acquired Rare Choreas

HD phenocopies

When the family history and clinical presentation points to HD but genetic testing is negative, as is reported in 1–3% of cases, clinicians should consider other autosomal dominant disorders that are phenotypically similar to HD, so-called HD phenocopies. These HD phenocopies include neurodegenerative diseases caused by repeat expansions in the C9orf72 gene, spinocerebellar ataxia (SCA) 17, Huntington disease-like 2 (HDL2), dentatorubropallidoluysian atrophy (DRPLA), neuroferritinopathy, familial prion disease (e.g. Huntington disease-like 1 [HDL1]) [7]. Recently, mutations in new genes associated with HD phenocopy syndromes have been identified, including CACNA1A, VSP13A, and VCP [89].

Non-HD phenocopies

Chorea-acanthocytosis

Chorea-acanthocytosis is one of the core neuroacanthocytosis syndromes, and is a progressive neurologic disorder characterized by prominent self-injurious orofacial dyskinesia 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 neuropsychiatric symptoms, axonal neuropathy, seizures, and a gait which is described as “rubber-person”. 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 elevated in the thousands (normal 0–200 U/I), reflecting muscle damage. Chorea-acanthocytosis 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 compound 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 clinical 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, considered 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 intellectual 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 decade of life, is a disorder of copper transport leading to copper accumulation, and is one of the few potentially treatable hereditary movement disorders [57]. The neurological manifestations vary widely. Three distinct neurological presentations 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 symptoms. Evidence of liver disease and hemolytic anemia should prompt the clinician to consider the diagnosis, which is supported by low ceruloplasmin levels, elevated 24-hour copper excretion, and Kayser-Fleischer rings on slit-lamp ophthalmological 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 midbrain. 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

Ataxia-telangiectasia is characterized by progressive neurological dysfunction associated with multisystem abnormalities and predisposition to immunological disorders and cancer. Chorea is commonly seen in ataxia-telangiectasia syndrome, with onset in childhood, prominent ataxia, peripheral neuropathy, and telangiectasias (conjunctiva and external ear). The serum concentration of alpha-fetoprotein 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. Ataxia-telangiectasia 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 frequent in AOA1 than in AOA2. AOA1 patients have hypoalbuminemia and hypercholesterolemia, in contrast with AOA2 patients who have elevated serum alpha-fetoprotein 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 heterogeneous disorders characterized by spastic gait, hyperreflexia, 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].

Xeroderma pigmentosum (XP)

XP is caused by mutations in the nucleotide excision repair pathway genes causing cutaneous, ocular and neurological manifestations. The cutaneous signs usually appear in infancy or early childhood. The neurological manifestations typically occur after the cutaneous symptoms. Movement disorders, specifically chorea, may appear in advanced stages of the disease. Patients with dermatological and oncological manifestations should be screened for XP [63].

Hereditary Epileptic-Dyskinetic Encephalopathies

The epileptic-dyskinetic encephalopathies are clinically heterogenous and are characterized by early onset drug-resistant seizures associated with hyperkinetic movement disorders. When chorea is the dominant movement disorder, mutations in FOXG1, GNAO1, GRIN1, FRRS1L and IRF2BPL genes should be considered [6465].

PDE10A mutation

Mutations in PDE10A have been reported to be inherited in both dominant and recessive manners; patients present with early-onset (5–15 years of age) chorea. Cognition and development is typically normal, however, those carrying biallelic mutations show a more severe phenotype. Brain MRI may show symmetrical T2-hyperintense bilateral striatal lesions [64].

GPR88 mutation

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

McLeod syndrome

McLeod syndrome is an X-linked recessive hereditary disorder with very similar clinical characteristics to chorea-acanthocytosis. Patients lack the red blood cell XK antigen and the expression of Kell antigens on the erythrocyte 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 presence 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 chorea-acanthocytosis, there can sometimes be tongue protrusion, feeding dystonia, and lip-biting or tongue-bitting [2566].

Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher 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 myelinating oligodendroglia.

Alcohol and other toxins

Chorea in alcohol abusers is more frequent in females and may be precipitated or exacerbated by withdrawal of alcohol. 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 organophosphates [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 “hung-up” 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 usually female and above 50 years of age, thus polycythemic chorea should be considered in the differential diagnosis of late-onset chorea, especially in women. In most cases the chorea is transient and self-limited, and responds to treatment of the polycythemia. Dopamine-blockers 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].

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 dysfunction 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 combination of corticosteroids with or without other immunosuppressive agents, dopamine blockers or dopamine depletors. The use of aspirin or anticoagulants is recommended for APS patients [85].

Autoimmune Encephalitis with Antibodies against Plasma Membrane Proteins

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 long-term morbidity. Neuro-Behcet’s disease is more common in males and neurological symptoms typically present 3 to 6 years after other systemic manifestations [9394]. Movement disorders including chorea and parkinsonism have been reported in neuro-Behcet’s disease and are believed to be related to anti-basal 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 neuropsychiatric 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 gluten-induced immune-mediated enteropathy. The inflammatory process is triggered by the ingestion of gluten present in wheat, barley, and rye in genetically predisposed individuals, and causes predominantly gastrointestinal symptoms [98]. Extra-intestinal manifestations are not uncommon; neurological symptoms are present in 10% of patients including ataxia, myalgias, or peripheral neuropathies. Chorea is rarely reported [99100]. 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 confirmatory. A strict gluten-free diet is the treatment of choice [98].

Other

Antibodies against synaptic receptors and neuronal cell surface adhesion molecules such as IgLON5, D2R, GABAaR, and Neurexin-3 alpha have been found recently to cause a wide spectrum of symptoms including encephalitis, movement disorders (including chorea), neuropsychiatric manifestations, and sleep disorders [101102103104].

Hyperthyroidism

Hyperthyroidism, in particular Grave’s disease, can also be a rare cause of acquired chorea. Young female patients (average mid-20s) 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 thyrotoxicosis are common. Chorea most commonly develops simultaneously with or after the clinical symptoms of hyperthyroidism. Signs and symptoms of hyperthyroidism, such as tachycardia and other cardiovascular symptoms, in the presence of chorea should alert the clinician to the possibility of this diagnosis. The possible underlying mechanism is related to circulating thyroid hormones [106]. Management is centered on normalization of thyroid function with antithyroid drugs. A few patients may require anti-choreic agents such as neuroleptics and tetrabenazine [107].

Hypocalcemia

Hypocalcemia as cause of chorea is more commonly seen in hypoparathyroidism, either idiopathic, postoperative, or pseudo-hypoparathyroidism [108]. Other reported causes of chorea secondary to hypocalcemia include malabsorption or bisphosphonate treatment [109110111]. 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 sometimes required.

Hyper-or Hypo-natremia

Serum sodium disturbances must be considered along with the status of the extracellular volume hypovolemia, euvolemia, 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 reported in intracranial tuberculomas [113]. A rapid correction of hyponatremia can cause central pontine and extrapontine myelinolysis which can also cause movement disorders [114115116].

Hypomagnesemia

Low magnesium blood levels may result in similar neurological 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 neurological 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 hypercalcemia. 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 ancestry, 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; however, the observation of hyperintense lesions involving the basal ganglia associated with marked surrounding edema on MRI T2-weighted 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 disorder seen in patients with advanced liver disease and portosystemic 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 middle-aged adults. Diffuse bilateral hyperintensities and cavitations in the basal ganglia on MRI and evidence of liver failure indicate 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 treatment 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 T1-weighted sequences. Supportive treatment and deep brain stimulation (DBS) may provide some improvement [124].

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 impairment, 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 abnormalities, 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.

Bacterial

Some of the reported uncommon bacterial causes of chorea include typhoid fever [136], pertussis, diphtheria, Legionnaires’ disease [137], tuberculous meningitis [138139], 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 associated 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], Epstein-Barr [146], citomegalovirus, Japanese encephalitis [147], tick-borne encephalitis [148], and HIV [149150]. In general, chorea secondary to viral infections typically develops over the course of the viral infection. 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 cytokine-mediated or cytotoxic effects of the virus is still under discussion [143]. Chorea can be unilateral or can be generalized in distribution and is usually transitory, remitting in days to weeks after the infection.

Spirochetal

Syphilis is a sexually transmitted chronic multisystemic disease which can present with a variety of systemic and neurological symptoms. Only a few patients affected with syphilis have been reported to develop movement disorders, and most are associated with HIV infection [151152]. 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 neuroborreliosis usually resolves neurological and non-neurological symptoms.

Post-pump chorea

Chorea has also been reported in children, and occasionally adults, undergoing cardiopulmonary bypass surgery [154]. This syndrome is known as “post-pump chorea” or “CHAP syndrome” (choreoathetosis, oral-facial dyskinesias, hypotonia, pseudobulbar signs). Chorea is often mild, typically develops 7–12 days after the procedure with gradual resolution of chorea after several week or months [155]. Several risk factors for post-pump chorea syndrome have been reported including patients undergoing hypothermic ischemic arrest, relative polycythemia, right ventricular outflow tract obstruction with ventricular septal defect, and very rapid cooling inducing hypothermia [155].

Mastocytosis

Mastocytosis is a rare disorder caused by excessive production 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 cognitive 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, drug-induced 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 receptor-blocking or -depleting agents are used [159].