Onset Of Chorea Research Articles

Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders (S42.004)

<h3>Objective:</h3> To report novel PDE10A genotype-phenotype in four affected family members <h3>Background:</h3> Phosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifested with infantile onset chorea, developmental, and cognition delay with normal brain MRI. Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development despite striatal nigral lesions. Herein, we report four cases of <i>PDE10A</i>-related chorea in a native Arab family with biallelic mutations in PDE10A. <h3>Design/Methods:</h3> Phenotypic characteristics of affected family members with PDE10A mutations were recorded, in addition to Sanger sequencing and in silico analysis to identify the mutations. <h3>Results:</h3> Four individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed an autosomal recessive GAF-B mutation (c.883G&gt;A:p. D295N; p.Asp295Asn) that was segregated from all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity without protein aggregation photocopies GAFA-mutations but is achieved through a distinct mechanism. <h3>Conclusions:</h3> Collectively, our work explains the recessive and dominant phenotypes of known variants and expands the genotype-phenotype landscape of PDE10A-associated movement disorders. <b>Disclosure:</b> Saeed Bohlega has nothing to disclose. Zainah Al- Qahtani has nothing to disclose. Francisco J. Guzmán-Vega has nothing to disclose. Dr. Ramakrishnan has nothing to disclose. Dr. Abusrair has nothing to disclose. Haya Aldosari has nothing to disclose. Amaal AlDakheel has nothing to disclose. Dr. Al Qahtani has nothing to disclose. Dorota Monies has nothing to disclose. Dr. Arold has nothing to disclose.

Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders

BackgroundPhosphodiesterase 10A (PDE10A) controls body movements by regulating cyclic adenosine monophosphate signaling in the basal ganglia. Two classes of PDE10A variants are reported with distinctive genotype-phenotype correlation. The autosomal recessive mutations in the GAF-A and catalytic domains are associated with compromised membrane localization, and manifest with infantile onset chorea, developmental, and cognition delay with normal brain MRI. Conversely, autosomal dominant mutations in the GAF-B domain cause protein aggregates which results in childhood onset chorea in the context of normal cognition and development, with striatal lesions. MethodsPhenotypic characteristics of affected individuals with PDE10A mutations belonging to a single family were recorded. In addition, Sanger sequencing and in silico analysis were used to identify the mutations. Homozygosity mapping was applied together with whole exome sequencing. ResultsFour individuals from a consanguineous family affected with PDE10A mutations were observed for up to 40 years. Although these individuals displayed a clinical phenotype attributed to the recessive GAF-A mutations, they revealed a bi-allelic GAF-B mutation (c.883G > A:p. D295 N; p.Asp295Asn) that was segregated with all affected individuals. In addition to chorea, we observed peculiar foot deformities and pronounced social phobia, with normal brain MRI. In silico structural analysis suggested that the GAF-B mutation blocked allosteric PDE10A activation. The resulting lack of PDE10A activity likely phenocopies GAF-A mutations, and this is achieved through a distinct mechanism. ConclusionsCollectively, our findings demonstrate the association of recessive and dominant phenotypes of known variants, and further expands the genotype-phenotype landscape of PDE10A-associated movement disorders.

Altered pituitary morphology as a sign of benign hereditary chorea caused by TITF1/NKX2.1 mutations

Benign hereditary chorea (BHC) is a rare genetically heterogeneous movement disorder, in which conventional neuroimaging has been reported as normal in most cases. Cystic pituitary abnormalities and features of empty sella have been described in only 7 patients with BHC to date. We present 4 patients from 2 families with a BHC phenotype, 3 of whom underwent targeted pituitary MR imaging and genetic testing. All four patients in the two families displayed a classic BHC phenotype. The targeted pituitary MR imaging demonstrated abnormal pituitary sella morphology. Genetic testing was performed in three patients, and showed mutations causing BHC in three of the patients, as well as identifying a novel nonsense mutation of the TITF1/NKX2-1 gene in one of the patients. The presence of the abnormal pituitary sella in two affected members of the same family supports the hypothesis that this sign is a distinct feature of the BHC phenotype spectrum due to mutations in the TITF1 gene. Interestingly, these abnormalities seem to develop in adult life and are progressive. They occur in at least 26% of patients affected with Brain-lung-thyroid syndrome. As a part of the management of these patients we recommend to perform follow-up MRI brain with dedicated pituitary imaging also in adult life as the abnormality can occur years after the onset of chorea.

Relationship between COVID-19 and movement disorders: A narrative review.

The scientific literature on COVID-19 is increasingly growing. In this paper, we review the literature on movement disorders in the context of the COVID-19 pandemic. First, there are a variety of transient movement disorders that may manifest in the acute phase of COVID-19, most often myoclonus, with more than 50 patients described in the literature. New onset parkinsonism, chorea, and tic-like behaviours have also been reported. Movement disorders as a side effect after COVID-19 vaccination are rare, occurring with a frequency of 0.00002-0.0002 depending on the product used, mostly manifesting with tremor. Current evidence for potential long-term manifestations, for example, long COVID parkinsonism, is separately discussed. Second, the pandemic has also had an impact on patients with pre-existing movement disorder syndromes, with negative effects on clinical status and overall well-being, and reduced access to medication and health care. In many parts, the pandemic has led to reorganization of the medical system, including the development of new digital solutions. The movement disorder-related evidence for this is reviewed and discussed. The pandemic and the associated preventive measures have had a negative impact on the clinical status, access to health care, and overall well-being of patients with pre-existing movement disorders.

A reversible lentiform nucleus T1 hyperintensity in hypoglycemic chorea

Acute to subacute onset chorea is commonly due to stroke, metabolic, post-infectious, and autoimmune disorders. Chorea in diabetes (DM) patient is mostly due to hyperglycemia, and few cases were reported due to hypoglycemia. The mechanism at the cellular level is still evolving. The MRI changes in diabetic chorea patients are variably reported. It is important to discuss our patient with hypoglycemic hemichorea because of unique features like low BMI, recently diagnosed DM on sulphonylurea with a history of hypoglycemic episodes, and acute left hemichorea that was controlled with neuroleptics, and her MRI brain showed reversible lentiform nucleus T1 hyperintensity without diffusion restriction and blooming on SWI.

Phenytoin induced Chorea: commonly used antiepileptic drug causing a rare movement disorder

Background: Phenytoin, a commonly prescribed antiepileptic drug, causes side effects like ataxia, tremor, hirsutism, gum hyperplasia, insomnia, confusion, headache and vertigo when used for longer duration. However, chorea is a rarely reported side effect of phenytoin and is completely reversible on stopping treatment. Case presentation: A twenty-one-year-old Indian male patient, who had generalized epilepsy and had been on sodium valproate for 2 years, presented with acute onset chorea four days after starting phenytoin sodium. He had normal serum phenytoin levels. A thorough evaluation was done, which suggested phenytoin as a possible cause of chorea. Phenytoin was withdrawn, resulting in a dramatic subsiding of chorea. A rechallenge with the drug resulted in reappearance of choreiform movements. These disappeared again after drug withdrawal, implicating phenytoin as the possible etiological agent for chorea. Conclusion: Phenytoin rarely induces involuntary movements as an adverse effect. During phenytoin therapy, if a patient develops involuntary movements, phenytoin toxicity should be suspected even with normal drug levels. This is important as drug withdrawal leads to complete symptomatic improvement thereby avoiding extensive workup for other secondary causes.

MOVEMENT DISORDER AS A MANIFESTATION OF DIABETIC KETOACIDOSIS

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Movement disorders are well-defined presentation of non-ketotic hyperglycemia (NKH) but are rarely associated with diabetic ketoacidosis (DKA). Here we present a rare case of movement disorder in DKA. CASE PRESENTATION: A 50-year-old female with a past medical history of HIV, migraine and hypertension presented to our tertiary care center with a chief complaint of sudden onset involuntary movement of her right upper extremity. She reported 4 days of generalized weakness as well. On physical examination, she was alert and well-oriented with choreiform movements localized to her right upper extremity. Decreased muscle strength (3/5) of her right upper extremity was also noted. No other neurological deficits were observed. Laboratory evaluation revealed serum glucose 1147 mg/dl, sodium 136 mEq/L, potassium 6.3 mEq/L, HCO3 16 mEq/L, chloride 93 mEq/L, creatinine 2.17 mg/dl, TSH 0.88 mIU/L, calcium 9.1 mg/dl and HbA1C 14%. Urinalysis revealed 1+ ketones and serum beta-hydroxybutyrate was positive. CT head was unremarkable. Patient was treated with tissue plasminogen activator (tPA) due to clinical suspicion of stroke and was started on IV fluids and insulin. MRI brain was negative for any acute ischemic process and MR angiogram of head was normal. Her serum glucose gradually normalized with insulin drip. Involuntary right upper extremity movement gradually improved as serum glucose normalized and completely resolved on 3rd day. Patient was back to her baseline with no residual weakness on 6th day of presentation. DISCUSSION: Sudden onset chorea is an uncommon presentation of DKA. Mechanism of DKA induced movement disorder remains unclear although several hypotheses have been proposed to explain the pathophysiology of movement disorder in NKH. Most patients show hemichorea-hemiballism with upper extremity involvement similar to our patient[1,3]. Characteristics MRI findings in basal ganglia were reported but imaging finding is not a prerequisite for the diagnosis of hyperglycemic movement disorder as seen in our patient[3]. Chorea is associated with a large number of hereditary and systemic diseases such as stroke, hyperthyroidism, NKH, hypocalcemia, and renal failure. It is the most common movement disorder to occur as a result of stroke. A variety of drugs have been reported to cause chorea[2]. Significant rapid improvement in symptoms after blood glucose control and anion gap closure in our case proves the role of DKA in movement disorder. CONCLUSIONS: Movement disorders are presenting symptoms for a variety of medical conditions and disorders. It can manifest as a presenting complaint in DKA. Early recognition and appreciation of these disorders will help clinicians narrow the diagnosis and avoid inadvertent use of medications. Reference #1: Jagota P, Bhidayasiri R, Lang AE. Movement disorders in patients with diabetes mellitus. Journal of the Neurological Sciences. 2012 Mar 15;314(1):5–11. Reference #2: Barton B, Zauber SE, Goetz CG. Movement Disorders Caused by Medical Disease. Semin Neurol. 2009 Apr;29(2):97–110. Reference #3: Lee S-H, Shin J-A, Kim J-H, Son J-W, Lee K-W, Ko S-H, et al. Chorea-ballism associated with nonketotic hyperglycaemia or diabetic ketoacidosis: Characteristics of 25 patients in Korea. Diabetes Research and Clinical Practice. 2011 Aug;93(2):e80–3. DISCLOSURES: No relevant relationships by Anisha Adhikari, source=Web Response No relevant relationships by Prashank Neupane, source=Web Response No relevant relationships by Bharadwaj Satyavolu, source=Web Response No relevant relationships by Zed Seedat, source=Web Response

Acute Onset Chorea in Profound Hypophosphatemia with Bilateral Basal Ganglia Lesions (2898)

Acute Onset Chorea in Profound Hypophosphatemia with Bilateral Basal Ganglia Lesions (2898)

Cerebellar cognitive-affective syndrome preceding ataxia associated with complex extrapyramidal features in a Turkish SCA48 family.

SCA48 is a novel spinocerebellar ataxia (SCA) originally and recently characterized by prominent cerebellar cognitive-affective syndrome (CCAS) and late-onset ataxia caused by mutations on the STUB1 gene. Here, we report the first SCA48 case from Turkey with novel clinical features and diffusion tensor imaging (DTI) findings, used for the first time to evaluate a SCA48 patient. A 65-year-old female patient with slowly progressive cerebellar ataxia, cognitive impairment, behavioral changes, and a vertical family history was evaluated. Following the exclusion of repeat expansion ataxias, whole exome sequencing (WES) was performed. Brain magnetic resonance imaging (MRI), including DTI, and single-photon emission computed tomography (SPECT) were used to study the primarily affected tracts and regions. WES revealed the previously reported heterozygous truncating mutation in ubiquitin ligase domain of STUB1 (ENST00000219548:c.823_824delCT, ENSP00000219548:p.L275Dfs*16) leading to a frameshift. Patient's cognitive status was compatible with CCAS. Novel clinical features different from the original report include later onset chorea, dystonia, general slowness of movements, apraxia, and palilalia, some of which have been recently reported in two families with different STUB1 mutations. CCAS is a prominent and often early feature of SCA48 which may be followed years after the onset of the disease by other complex neurological signs and symptoms. DTI may be helpful for demonstrating the cerebello-frontal tracts, involved in CCAS-associated SCA48, the differential diagnosis of which may be challenging especially in its early years.

Quick Flicks: Association of Paroxysmal Kinesigenic Dyskinesia and Tics.

BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterised by brief attacks of chorea, dystonia, or mixed forms precipitated by sudden movement.MethodsObservational study with a cohort of 14 PKD patients and genetic testing for PRRT2 mutations.ResultsIn a series of 14 PKD patients seen in our clinic at the National Hospital of Neurology, Queen Square, from 2012–2017, we noted tics in 11 patients (79%), which stand in stark contrast to the estimated lifetime prevalence of tics estimated to reach 1%.ConclusionsThe two reasons to point out this possible association are the clinical implications and the potential opportunity of a better understanding of shared pathophysiological mechanisms of neuronal hyperexcitability.

Neuropsychiatric Burden in Huntington's Disease.

Huntington’s disease is a disorder that results in motor, cognitive, and psychiatric problems. The symptoms often take different forms and the presence of disturbances of the psychic sphere reduces patients’ autonomy and quality of life, also impacting patients’ social life. It is estimated that a prevalence between 33% and 76% of the main psychiatric syndromes may arise in different phases of the disease, often in atypical form, even 20 years before the onset of chorea and dementia. We present a narrative review of the literature describing the main psychopathological patterns that may be found in Huntington’s disease, searching for a related article in the main database sources (Medline, ISI Web of Knowledge, Scopus, and Medscape). Psychiatric conditions were classified into two main categories: affective and nonaffective disorders/symptoms; and anxiety and neuropsychiatric features such as apathy and irritability. Though the literature is extensive, it is not always convergent, probably due to the high heterogeneity of methods used. We summarize main papers for pathology and sample size, in order to present a synoptic vision of the argument. Since the association between Huntington’s disease and psychiatric symptoms was demonstrated, we argue that the prevalent and more invalidating psychiatric components should be recognized as early as possible during the disease course in order to best address psychopharmacological therapy, improve quality of life, and also reduce burden on caregivers.

A diagnostic approach to pediatric early onset chorea

A diagnostic approach to pediatric early onset chorea

Hereditary chorea - what else to consider when the Huntington's disease genetics test is negative?

Chorea, cognitive, behavioural and psychiatric disturbance occur in varying combinations in Huntington's disease (HD). This is often easy to recognise particularly in the presence of an autosomal dominant history. Whilst HD may be the most common aetiology of such a presentation, several HD phenocopies should be considered if genetic testing for HD is negative. We searched PubMed and the Cochrane Database from January 1, 1946 up to January 1, 2016, combining the search terms: 'chorea', 'Huntington's disease', 'HDL' and 'phenocopies'. HD phenocopies frequently display additional movement disorders such as myoclonus, dystonia, parkinsonism and tics. Here, we discuss the phenotypes, and investigations of HD-like disorders where the combination of progressive chorea and cognitive impairment is obvious, but HD gene test result is negative. Conditions presenting with sudden onset chorea such as vascular, infectious and autoimmune causes are not the primary focus of our discussion, but we will make a passing reference to these as some of these conditions are potentially treatable. Hereditary forms of chorea are a heterogeneous group of conditions and this number is increasing. While most of these conditions are not curable, molecular genetic testing has enabled many of these disorders to be distinguished from HD. Getting a precise diagnosis may enable patients and their families to better understand the nature of their condition.

Suicidal thoughts and suicide attempts in Sydenhams chorea: a case report

Sydenham’s chorea is the most common cause of acute onset chorea in childhood; psychiatric signs and symptoms are often accompanied its clinic. After the clinical motor and cardiac symptoms, patients with Sydenham’s chorea have also been presented with the obsessive-compulsive symptoms, anxiety, depression, attention problems and emotional lability. However, in the literature, it could not be reached on a case with the suicidal thoughts or suicide attempts. In addition, although there is not enough data on how to treat the signs and symptoms that accompany psychiatric clinic, the drugs used in the treatment are known to increase the risk of psychiatric signs and symptoms. In this case, 9-year-old male patient with a diagnosis of acute Sydenham Korea whose psychiatric signs and symptoms increased with treatment, who had attempted suicide, is going to be presented and we aimed to draw attention and to discuss these issues.

ADCY5 genetic screening in benign early onset chorea (P3.036)

ADCY5 genetic screening in benign early onset chorea (P3.036)

H08 Neuropsychiatric Burden In Huntington Disease

Background The clinical manifestations of Huntington Disease include motor, cognitive and psychiatric disturbances. There is a wide spectrum of symptoms and the presence of disorders in psychiatric field worsens autonomy and quality of life of the patients. Main psychiatric syndromes may appear during progression of Huntington Disease, often in a non-typical way. Some authors have noticed even 20 years before onset of chorea or dementia symptoms of Huntington Disease. Aims We present a review of literature describing the main psychopathological pictures in Huntington Disease, whose prevalence is estimated between 33% and 76%. Results It is possible to make diagnosis of major depression in a percentage between 9% and 63%, and the suicide rate in patients is 4 to 6 times higher than normal population, with greater prevalence among patients over 50 years old. Hypomania and mania have been estimated in 4,8% to 10% of patients. Anxiety has been less studied however some studies report that it also occurs frequently (34–61%). Prevalence of irritability varies between 38% and 73%, whereas obsessive and compulsive symptoms are comprised between 5% and 52%. A picture of psychosis has prevalence estimated at 4% to 12%. Delirium, apathy and neuropsychological impairments are strictly correlated with the progression of the disease. Conclusions It is important to recognise psychiatric facets in HD, in order to tailor the psychopharmacological therapy and reduce the burden for the caregiver.

Psychiatric onset and late chorea in a patient with 41 CAG repeats in the TATA-binding protein gene

A 63 year-old woman referred to our clinic because of the recent worsening of slow, involuntary movements of the limbs, that had been present since the age of 60. Her medical history was marked by a longtime depressive disorder with psychotic features since the age of 23, for which she had undergone pharmacological treatment with tricyclic antidepressants, haloperidol and risperidone, with cessation of neuroleptics more than 10 years before examination. Family history was unremarkable for neurologic disorders: her father died of colorectal cancer, aged 83; her 92 year-old mother suffers from hypertension and chronic venous insufficiency of the lower limbs; her two siblings and two sons are in good health conditions.

Gowers' Queen Square Case Notes on Chorea (S59.004)

Objective: To analyze Gowers9 case notes on 127 patients with chorea throughout 33 years of inpatient care. Background William Richard Gowers is primarily remembered in neurological circles for his Manual of the Disease of the Nervous System. His research was based almost entirely on his own case records from which derived the definition of phenomenology and clinical features of many neurological diseases, including chorea. Design/Methods: We consulted the Gowers9 case notes available at the Queen Square Library, National Hospital for Neurology & Neurosurgery, in London, from 1878 to 1911, comprising 33 years and 42 volumes. Results: Out of 2478 cases, 127 (5.1%) received the diagnosis of chorea. Ninety-seven patients (76.3%) were female. Ages ranged from 4 to 60 years (mean 14.3). In-hospital stay and illness duration means were of 58 days and 14.7 months, respectively. Forty-three patients (33.8%) experienced recurrent attacks of chorea. Twenty-nine patients (22.8%) had a family history of chorea. Past history of rheumatic fever was observed in 46 patients (36.2%) and other illnesses occurred in 59 patients (46.4%). Thirty-four patients (26.7%) presented with chorea shortly after an emotional event or fright. Fifty-four patients (42.5%) had speech impairment; the same percentage occurring to cardiac murmur. Eleven patients (8.6%) developed swallowing difficulties whereas only 5 (3.9%) developed cognitive problems. Fifteen patients (11.8%) had weakness in the neurological examination. Generalized chorea occurred in 87.4% whereas hemichorea occurred in 11.8% of the patients. Gowers diagnosed different forms of chorea: Sydenham9s chorea was diagnosed in 89% of cases with remaining patients having Huntington9s disease, paralytic, persistent, tetanoid, functional, maniacal chorea and chorea gravidarum. Conclusions: In spite of significant advances in the knowledge of chorea in the last century, Gowers description of its phenomenology and etiology remains up-to-date. Disclosure: Dr. Cardoso has received personal compensation for activities with Roche Diagnostics Corporation, Boehringer Ingelheim Pharmaceuticals, Inc, Novartis, and Eisai, Inc. Dr. Vale has nothing to disclose. Dr. Lees has received personal compensation for activities with Genus, Novartis, Teva, Meda, Boehringer Ingelheim, GlaxoSmithKline, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira and Roche. Dr. Lees has received research support from the PSP Association and Weston Trust - The Reta Lila Howard Foundation.

Cognitive Deficits in Huntington’s Disease: Insights from Animal Models

Although Huntington’s disease (HD) is commonly recognized as a movement disorder, cognitive dysfunction is an intrinsic feature of the disease that often manifests before the onset of chorea. Neuronal loss has been demonstrated in anatomical regions known to be substrates of learning and memory, but cell loss is presaged by functional alterations. Changes in long-term synaptic plasticity, a substrate of memory processes, emerge in cognitive domains such as the hippocampus, the cortex, and the striatum. Insights from animal models provide mechanistic explanations of how long-term synaptic plasticity is altered in these regions. Glutamate and dopamine receptors play a crucial role in such changes and progress in this area of investigation has made significant strides in recent years. Based on these discoveries, novel therapies are being developed to improve clinical outcomes and ameliorate cognitive symptoms of HD.

Acute and chronic corticosteroid treatment of ten patients with paralytic form of Sydenham’s chorea

AimsTo determine efficacy and safety of corticosteroid treatment in patients with severe Sydenham’s chorea paralytic form. MethodsThis is a 4 years observational study on ten patient with severe paralytic form of Sydenham’s chorea unresponsive to neuroleptics and antiepileptics agents, treated with intravenous methylprednisolone followed by oral deflazacort therapy. Chorea paralytica patients were bedridden, unable to take independent steps, showed severe generalized hypotonia and were hospitalized for 3–4 weeks. Additional clinical evaluations were undertaken at 1, 3 and 6 months and 1, 2 and 4 years from onset of chorea. Severity chorea at the onset and during follow up was rated according to Universidade Federal de Minas Gerais (UFMG) Sydenham’s Chorea Rating Scale (USCRS). In all children video-recording was performing at onset and during clinical follow-up. ResultsWe reported a significant improvement in swallowing and chewing with partial recovery of language 2–3 days after starting intravenous methylprednisolone treatment and complete disappearance of movement disorders after 3–4 weeks of treatment. All our patients were followed for 4 years from onset and none experienced relapse of chorea, other movement disorders or psychiatric disturbances. The treatment with deflazacort was well-tolerated in all children with no significant side effects reported. ConclusionOur data showed that high dose of methylprednisolone intravenously followed by deflazacort therapy may be effective and well-tolerated in children with severe paralytic form of Sydenham’s chorea.