Exploring the Genetic Landscape of Chorea in Infancy and Early Childhood: Implications for Diagnosis and Treatment.

Chorea is a hyperkinetic movement disorder frequently observed in the pediatric population, and, due to advancements in genetic techniques, an increasing number of genes have been associated with this disorder. In genetic conditions, chorea may be the primary feature of the disorder, or be part of a more complex phenotype characterized by epileptic encephalopathy or a multisystemic syndrome. Moreover, it can appear as a persistent disorder (chronic chorea) or have an episodic course (paroxysmal chorea). Managing chorea in childhood presents challenges due to its varied clinical presentation, often involving a spectrum of hyperkinetic movement disorders alongside neuropsychiatric and multisystemic manifestations. Furthermore, during infancy and early childhood, transient motor phenomena resembling chorea occurring due to the rapid nervous system development during this period can complicate the diagnosis. This review aims to provide an overview of the main genetic causes of pediatric chorea that may manifest during infancy and early childhood, focusing on peculiarities that can aid in differential diagnosis among different phenotypes and discussing possible treatment options.

Sydenham's chorea in a 16-year-old female from Bhutan: A case report.

Key Clinical Message: Rheumatic heart disease is a preventable disease. Patients may not present with a typical history of sore throat and polyarthritis but may present with Sydenham's chorea. We should not rely completely on clinical findings to rule out carditis. Echocardiography should be done to rule out subclinical carditis. Abstract: Sydenham's chorea is a major manifestation of rheumatic fever. It occurs primarily in children and is seen rarely after the age of 20 years. We describe a 16-year-old girl who presented with purposeless involuntary movements of her upper and lower limbs. Laboratory blood reports showed raised erythrocyte sedimentation rate and anti-streptolysin O. 2D Doppler Echocardiography confirmed subclinical carditis, thickened mitral and aortic valve with mild mitral regurgitation. She was managed as Acute Rheumatic Fever with oral Phenoxymethyl penicillin and Carbamazepine. At the latest follow-up interviewing the caregiver, the patient had no sequelae. Early diagnosis is key to preventing late consequences of acute rheumatic fever and rheumatic heart disease. Sydenham's chorea is a rare presentation of acute rheumatic fever. The absence of clinical carditis does not rule out carditis.

Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

A Case of Non-ketotic Hyperglycemic Hemichorea and Fahr Syndrome.

Non-ketotic hyperglycemic hemichorea (NHH) denotes acute hemichorea or hemiballism in patients with poorly controlled diabetes with striatal abnormalities seen on brain MRI. Here, we describe a case with diabetes mellitus and primary hypoparathyroidism who developed NHH with bilateral chorea due to the abrupt stopping of her diabetic regimen. She presented with subacute and progressive bilateral asymmetric chorea. Over the prior six months, she stopped following her diabetic regimen. Brain imaging showed features of diffuse brain calcifications suggestive of Fahr syndrome. Extensive blood investigations including genetic testing for causes of basal ganglia calcifications were unremarkable. Treatment with tetrabenazine and resumption of her diabetes medications slowly improved her chorea. This case highlights the importance of interpreting imaging findings in the context of the nature and time course of the chorea presentation. In addition, it emphasizes a systematic approach to interpreting diffuse brain calcifications with the appropriate investigations.

Steroid-Responsive Involuntary Movements as a Remote Symptom of Febrile Infection-Related Epilepsy Syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic encephalopathy that occurs in children or adolescents. To date, evidence for the management of the post-acute phase of FIRES is focused on drug-resistant epilepsy that continues from the acute phase. Information on involuntary movements, which are newly developed in the chronic phase, is limited. We report a 13-year-old boy, who had a history of FIRES at nine years of age and experienced worsening seizure control that was accompanied by unremitting involuntary　movements after two years of a fairly controlled period. The involuntary movements resulted in motor deterioration and forced him to be bedridden. Although no neuronal autoantibodies were detected, we hypothesized that the boy's neurological deterioration was triggered by an autoimmune response based on the elevation of serum anti-glutamic acid decarboxylase and serum anti-thyroid peroxidase antibodies and hypermetabolism of bilateral lenticular nuclei on 18-fluorodeoxyglucose positron emission tomography that resembled those reported in patients with other types of autoimmune encephalitis. Serial methylprednisolone pulse therapy and intravenous immunoglobulin therapy ameliorated involuntary movements and improved his activities of daily living. Late-onset involuntary movements, along with seizure exacerbation, may appear in the chronic phase of FIRES. Immunotherapy could be effective in treating these symptoms.

Crossed-reflex in antiphospholipid chorea.

Chorea is a hyperkinetic movement disorder associated with various underlyingconditions, including autoimmune diseases such as antiphospholipid syndrome (APS). APS can manifest with a wide range of neurological symptoms, including chorea. We present a case of a 77-year-old man with subacute generalized chorea secondary to primary APS. Notably, the patient exhibited a left patellar crossed-reflex, a phenomenon rarely documented in chorea cases, the pathophysiology of which has not yet been elucidated. In summary, this case challenges the traditional demographics of antiphospholipid syndrome (APS) by suggesting a potential link between APS and late-age patients. It emphasizes the importance of considering APS in late-onset chorea cases.

Preserved VPS13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?

VPS13A disease and Huntington's disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated.

Case report: Misdiagnosed orolingual dyskinesia as a consequence of seizures in a chorea-acanthocytosis patient with a novel VPS13A variation from a family with consanguineous marriage.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome with heterogeneous symptoms, which makes it a challenge for early diagnosis. The mutation of VPS13A is considered intimately related to the pathogenesis of ChAc. To date, diverse mutation patterns of VPS13A, consisting of missense, nonsense, and frameshift mutations, have been reported. In this study, we first report a clinical case that was misdiagnosed as epilepsy due to recurrent seizures accompanied by tongue bite for 9 months, which was not rectified until seizures were controlled and involuntary orolingual movements with awareness became prominent and were confirmed to be orolingual dyskinesia. The patient was eventually diagnosed as ChAc based on whole-exome sequencing revealing novel homozygous c.2061dup (frameshift mutation) and c.6796A > T dual mutations in VPS13A. The patient from a family with consanguineous marriage manifested epileptic seizures at onset, including both generalized tonic-clonic seizures and absence but normal long-term electroencephalography, and gradually developed orofacial dyskinesia, including involuntary tongue protrusion, tongue biting and ulcers, involuntary open jaws, occasionally frequent eye blinks, and head swings. The first test of the peripheral blood smear was negative, and repeated checks confirmed an elevated percentage of acanthocytes by 15-21.3%. Structural brain MRI indicated a mildly swollen left hippocampus and parahippocampal gyrus and a progressively decreased volume of the bilateral hippocampus 1 year later, along with atrophy of the head of the caudate nucleus but no progression in 1 year. We deeply analyzed the reasons for long-term misdiagnosis in an effort to achieve a more comprehensive understanding of ChAc, thus facilitating early diagnosis and treatment in future clinical practice.

Insights from European Reference Network for rare neurological disorders study surveys on diagnosis, treatment, and management of NKX2-1-related disorders.

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea. OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists. METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item. RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts. CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

Intensification of Diurnal Abnormal Movements During Sleep in Huntington's Disease.

Huntington's disease (HD) is a rare neurodegenerative disorder with a distinct phenotype, including involuntary movements, cognitive decline, and behavioral disturbances. Sleep disorder include insomnia, increased sleep onset latency, decrease in total sleep time with frequent nocturnal awakenings and excessive daytime sleepiness. Increased sleep motor activities and abnormal nocturnal agitation have been increasingly recognized as an important component affecting negatively the sleep quality. Here, we report a case of an intensification of diurnal choreic movement during the night, notably during REM-sleep in a patient with manifest HD. This case highlights the diversity of nocturnal sleep motor disorders encountered in HD.

Case Report: Chorea as a Rare Manifestation of Secondary Adrenal Insufficiency.

The word "chorea" comes from the Latin word "choreus," which means dancing movement. Chorea is defined as a hyperkinetic movement disorder characterized by uncontrolled, unintended, jerky, brief, irregular, random movements involving the limbs or facial muscles. Here, we discuss the case of a 48-year-old male with hypothyroidism for two years, which is well-controlled with medication. He presented with behavioral disturbances for the past seven months and choreiform movements affecting all four limbs, his tongue, and his face for the past six months. Investigations revealed hyponatremia and low serum osmolality. An MRI of the brain showed the empty sella sign. Further investigations revealed low levels of adrenocorticotropic hormone (ACTH), prolactin, and testosterone. Considering the diagnosis of chorea with euvolemic hyponatremia due to secondary adrenal insufficiency, the patient was started on tetrabenazine, trihexyphenidyl, oral hydrocortisone, and gradual correction of sodium level. The patient's condition improved during the hospital stay, and he continues to do well in routine follow-ups.

Atypical Presentations of Huntington Disease-like 2 in South African Individuals.

BACKGROUND: Huntington disease-like 2 (HDL2) is a neurodegenerative disorder, affecting only individuals of African ancestry. Full penetrance occurs in individuals with 40 repeats or more. OBJECTIVE: To describe the phenotypic variability of HDL2 in a group of mixed ancestry individuals from South Africa. METHODS: Eight patients were assessed with analysis of repeat size and magnetic resonance brain imaging. We applied the Unified Huntington's Disease Rating Scale (UHDRS), but in deceased patients (4), this was estimated from video material. RESULTS: Cognitive domains were more severely affected than motor; UHDRS motor scores were notable for bradykinesia, and to a slightly lesser extent, for rigidity and dystonia; a single patient had marked chorea. Repeat lengths ranged from 45 to 63 (median, 52). CONCLUSION: This South African group of mixed ancestry HDL2 individuals presented with severe cognitive and behavioral impairments, with lesser degrees or absence of chorea. This presentation is possibly related to large repeat sizes.

Movement Disorders in Patients with Subacute Sclerosing Panencephalitis: A Systematic Review.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a complication of measles, occurring after a latency of 4-10 years. It continues to occur in developing countries although resurgence is being reported from developed countries. Characteristic features include progressive neuropsychiatric issues, myoclonus, seizures, movement disorders and visual impairment. Electroencephalography (EEG) typically shows periodic generalized discharges, and elevated CSF anti-measles antibodies are diagnostic. Movement disorders are being increasingly recognized as part of the clinical spectrum, and range from hyperkinetic (chorea, dystonia, tremor, tics) to hypokinetic (parkinsonism) disorders and ataxia. OBJECTIVES: This article aims to comprehensively review the spectrum of movement disorders associated with SSPE. METHODS: A literature search was conducted in PubMed and EMBASE databases in December 2023 and articles were identified for review. RESULTS: Movement disorders reported in SSPE included hyperkinetic (chorea, dystonia, tremor and tics), hypokinetic (parkinsonism), ataxia and extraocular movement disorders. Myoclonus, a core clinical feature, was the most frequent "abnormal movement." Movement disorders were observed in all clinical stages, and could also be a presenting feature, even sans myoclonus. Hyperkinetic movement disorders were more common than hypokinetic movement disorders. An evolution of movement disorders was observed, with ataxia, chorea and dystonia occurring earlier, and parkinsonism later in the disease. Neuroradiological correlates of movement disorders remained unclear. CONCLUSION: A wide spectrum of movement disorders was observed throughout the clinical stages of SSPE. Most data were derived from case reports and small case series. Multicentric longitudinal studies are required to better delineate the spectrum and evolution of movement disorders in SSPE.

GPi/GPe borderland- a potential sweet spot for deep brain stimulation for chorea in Huntington's disease?

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington's disease (HD). OBJECTIVES: To identify stimulation-dependent effects on motor symptoms and to determine if these alterations are associated with the local impact of DBS on different pallidal parcellations. METHODS: We prospectively evaluated the effects of bilateral GPi-DBS within one year in 5 HD patients. We evaluated the effects of GPi-DBS on choreatic symptoms and UHDRS. Electrode placement in the pallidum was localized, and the local impact of DBS was estimated. RESULTS: The chorea subscore (p < 0.001) and UHDRS total motor score was significantly reduced postoperatively (p = 0.019). Pallidal DBS did not improve other motor symptoms. Activation of the lateral GPi/GPe was associated with improvement in choreatic symptoms (p = 0.048; r = 0.90). CONCLUSIONS: Our findings indicate that stimulation of the lateral GPi has a stable effect on choreatic symptoms. The modulation of the electrical field is relevant for motor outcome.

Revealing Non-ketotic Hyperglycemia as a Trigger for Hemichorea-Hemiballismus in Uncontrolled Diabetic Asthmatics: A Case Report.

Uncontrolled diabetes can trigger a movement disorder called hemichorea-hemiballismus, characterized by non-ketotic hyperglycemia-related chorea/ballism and usually reversible basal ganglia abnormalities on CT and/or MRI. The condition is diagnosed clinically and is mostly based on radiological imaging. Here, we report a case of a 68-year-old female presenting with right-sided and facial involuntary movements owing to uncontrolled hyperglycemia who was treated with antidiabetic and anticholinergic medications. The patient responded well to the treatment and showed a favorable outcome with no complications.

Chorea as the only presenting clinical feature of rheumatic fever: a case report.

Introduction and importance: Sydenham's chorea (SC), a major neurological manifestation of acute rheumatic fever (ARF), is commonly seen in young children and adolescents. It is characterized by rapid, unpredictable, involuntary, and nonpatterned contractions affecting mostly distal limbs. It can also be associated with clinical or subclinical carditis. SC has been reported as a major manifestation in only 3.87% cases of acute rheumatic fever in Nepal. Case presentation: The authors report a case of a 12-year-old boy with abnormal movement of his right hand and unsteady gait for 12 days. On examination, he had an abnormal hand grip with difficulty maintaining a tetanic contraction (Milkmaid's grip). Laboratory investigations revealed increased anti-Streptolysin O titre and erythrocyte sedimentation rate. Echocardiography revealed subclinical carditis. After thorough clinical examination and pertinent investigations, the final diagnosis of ARF with SC was made. Clinical discussion: SC is a major clinical feature of rheumatic fever according to the revised Jones criteria. It is related to a previous Group A ß-haemolytic Streptococcus pyogenes (GABHS) infection. Approximately 50-65% of the patients with rheumatic fever later develop clinically detectable carditis. Although a self-limiting condition, it might need treatment with antiepileptics, neuroleptics, and phenothiazines. Conclusion: Any child presenting with a movement disorder should also be considered for SC, necessitating additional testing, including a cardiovascular assessment. It needs to be distinguished from other causes of movement disorders as well as psychiatric conditions. Treatment is necessary for moderate to severe chorea that interfere with daily activities. Compliance with subsequent antibiotic prophylaxis is essential for avoiding future cardiac complications.