Genetic testing for non-parkinsonian movement disorders: Navigating the diagnostic maze.

Genetic testing has become a valuable diagnostic tool for movement disorders due to substantial advancements in understanding their genetic basis. However, the heterogeneity of movement disorders poses a significant challenge, with many genes implicated in different subtypes. This paper aims to provide a neurologist's perspective on approaching patients with hereditary hyperkinetic disorders with a focus on select forms of dystonia, paroxysmal dyskinesia, chorea, and ataxia. Age at onset, initial symptoms, and their severity, as well as the presence of any concurrent neurological and non-neurological features, contribute to the individual clinical profiles of hereditary non-parkinsonian movement disorders, aiding in the selection of appropriate genetic testing strategies. There are also more specific diagnostic clues that may facilitate the decision-making process and may be highly specific for certain conditions, such as diurnal fluctuations and l-dopa response in dopa-responsive dystonia, and triggering factors, duration and frequency of attacks in paroxysmal dyskinesia. While the genetic and mutational spectrum across non-parkinsonian movement disorders is broad, certain groups of diseases tend to be associated with specific types of pathogenic variants, such as repeat expansions in many of the ataxias. Some of these pathogenic variants cannot be detected by standard methods, such as panel or exome sequencing, but require the investigation of intronic regions for repeat expansions, such as Friedreich's or FGF14-linked ataxia. With our advancing knowledge of the genetic underpinnings of movement disorders, the incorporation of precise and personalized diagnostic strategies can enhance patient care, prognosis, and the application and development of targeted therapeutic interventions.

[The value of re-evaluation and thorough family history taking for the diagnostic work-up of chorea]. / Het diagnostisch proces bij chorea: het belang van heroverwegen en de familieanamnese.

The differential diagnosis of chorea encompasses a broad range of disorders. In psychiatry, tardive dyskinesia may be difficult to discern from other causes, particularly when the family history is negative. A 59-year-old man with an unclear medical history had been using risperidone for over a decade when we first saw him. He presented with severe dyskinesia in all extremities. The family history for neuropsychiatric disorders was negative. We interpreted the movement disorder as tardive dyskinesia, but later he turned out to suffer from Huntington’s disease. To improve diagnostic accuracy, we should have more frequently re-evaluated the differential diagnosis and our family history should have been more thorough. We outline the diagnostic considerations in patients presenting with chorea. Finally, we highlight the value of diagnostic re-evaluation and thorough family history taking to optimize diagnostic accuracy in neuropsychiatry.

Analysis of HTT CAG repeat expansion among healthy individuals and patients with chorea in Korea.

BACKGROUND: Although the epidemiology of Huntington's disease (HD) in Korea differs notably from that in Western countries, the genetic disparities between these regions remain unclear. OBJECTIVE: To investigate the characteristics and clinical significance of cytosine-adenine-guanine (CAG) repeat size associated with HD in the Korean population. METHODS: We analyzed the CAG repeat lengths of the HTT gene in 941 healthy individuals (1,882 alleles) and 954 patients with chorea (1,908 alleles) from two referral hospitals in Korea. We presented normative CAG repeat length data for the Korean population and computed the reduced penetrance (36-39 CAG) and intermediate allele (27-35 CAG) frequencies in the two groups. Furthermore, we investigated the relationship between intermediate alleles and chorea development using logistic regression models in individuals aged ≥55 years. RESULTS: The mean (±standard deviation) CAG repeat length in healthy individuals was 17.5 ± 2.0, with a reduced penetrance allele frequency of 0.05 % (1/1882) and intermediate allele frequency of 0.69 % (13/1882). We identified 213 patients with genetically confirmed HD whose CAG repeat length ranged from 39 to 140, with a mean of 45.2 ± 7.9 in the longer allele. Compared with normal CAG repeat alleles, intermediate CAG repeat alleles were significantly related to a higher risk of developing chorea (age of onset range, 63-84 years) in individuals aged ≥55 years. CONCLUSIONS: This study provides insights into the specific characteristics of CAG repeat lengths in the HTT gene in the Korean population. The reduced penetrance and intermediate allele frequencies in the Korean general population seem to be lower than those reported in Western populations. The presence of intermediate alleles may increase the risk of chorea in the Korean elderly population, which requires further large-scale investigations.

Huntington disease-like 2: insight into neurodegeneration from an African disease.

Huntington disease (HD)-like 2 (HDL2) is a rare genetic disease caused by an expanded trinucleotide repeat in the JPH3 gene (encoding junctophilin 3) that shows remarkable clinical similarity to HD. To date, HDL2 has been reported only in patients with definite or probable African ancestry. A single haplotype background is shared by patients with HDL2 from different populations, supporting a common African origin for the expansion mutation. Nevertheless, outside South Africa, reports of patients with HDL2 in Africa are scarce, probably owing to limited clinical services across the continent. Systematic comparisons of HDL2 and HD have revealed closely overlapping motor, cognitive and psychiatric features and similar patterns of cerebral and striatal atrophy. The pathogenesis of HDL2 remains unclear but it is proposed to occur through several mechanisms, including loss of protein function and RNA and/or protein toxicity. This Review summarizes our current knowledge of this African-specific HD phenocopy and highlights key areas of overlap between HDL2 and HD. Given the aforementioned similarities in clinical phenotype and pathology, an improved understanding of HDL2 could provide novel insights into HD and other neurodegenerative and/or trinucleotide repeat expansion disorders.

[A case of a pathological variant of the PRRT2 gene in twins with paroxysmal kinesiogenic dyskinesia]. / Sluchai patologicheskogo varianta gena PRRT2 u bliznetsov s paroksizmal'noi kineziogennoi diskineziei.

Paroxysmal dyskinesia is a clinically and etiologically polymorphic group of diseases, the main clinical manifestation of which is transient attacks of extrapyramidal movements, with different conditions of occurrence. Paroxysmal kinesigenic dyskinesia belongs to the group of primary dyskinesias, which also includes paroxysmal non-kinesigenic dyskinesia and exercise-induced paroxysmal dyskinesia. The most common cause of paroxysmal kinesiogenic dyskinesia is mutations in the PRRT2 gene; in cases of non-kinesiogenic dyskinesia, a mutation in the MR1 gene is detected. The diagnosis of primary dyskinesias causes significant difficulty for clinicians due to the rarity of occurrence, as well as the large spectrum of conditions occurring with paroxysmal motor disorders in childhood. The article describes the clinical observation of 16-year-old twin brothers with transient attacks of dystonic, choreic and ballistic hyperkinesis that suddenly arose during movement. Patients were treated for tics and epilepsy for 12 years. Taking into account the clinical picture - transient attacks of hyperkinesis, their connection with movement, as well as data from video-electroencephalographic monitoring, a diagnosis of paroxysmal kinesiogenic dyskinesia was established, which in a further diagnostic search was confirmed by targeted sequencing of the pathological variant of the PRRT2 gene previously described in patients with kinesiogenic dyskinesia. The administration of carbamazepine, which is the drug of choice in the treatment of this category of patients, has achieved significant control over hyperkinesis in twins. Thus, molecular genetic diagnosis helps confirm the diagnosis of paroxysmal dyskinesias, but careful analysis of the clinical picture, considering the provoking factor, remains the basis of diagnosis.

Expanding Knowledge of the Causes of Childhood Chorea.

INHERITED AND ACQUIRED CHOREAS: Paolo Claudio M. de Gusmao, Jeff L. Waugh Seminars in Pediatric Neurology Volume 25, April 2018, Pages 42-53 Chorea is a symptom of a broad array of genetic, structural, and metabolic disorders. While chorea can result from systemic illness and damage to diverse brain structures, injury to the basal ganglia, especially the putamen or globus pallidus, appears to be a uniting features of these diverse neuropathologies. The timing of onset, rate of progression, and the associated neurological or systemic symptoms can often narrow the differential diagnosis to a few disorders. Recognizing the correct etiology for childhood chorea is critical, as numerous disorders in this category are potentially curable, or are remediable, with early treatment.

Memantine administration prevented chorea movement in Huntington's disease: a case report.

BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.

The enduring enigma of sporadic chorea: A single center case series.

Chorea can have a wide variety of causes including neurodegenerative, pharmacological, structural, metabolic, infectious, immunologic and paraneoplastic processes. We reviewed the clinical records of patients with apparently sporadic choreic movements and no relevant family history, who presented to our neurology department (Hospital Fundación Jimenez Diaz) between 1991 and 2022. We detected 38 cases of apparent sporadic chorea (ASC); Our analysis revealed 5 cases of genetic chorea (including 3 cases with Huntington's disease) while 6 cases were autoimmune/hematological; 6 drug-related chorea, 5 metabolic-vascular, 5 due to miscellaneous conditions and 4 were of mixed etiology. No clear etiology was identified in 8 cases. The differential diagnosis of ASC is extensive and challenging. Highlights: Chorea can have a wide variety of genetic and sporadic causesWe reviewed the clinical records of patients with apparently sporadic chorea (ASC), who presented to our neurology department over the last 30 yearsWe detected 38 cases of apparent ASC; Our analysis revealed a wide array of different sporadic conditions and 5 cases of genetic choreaThe differential diagnosis of ASC is extensive and challenging.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

Paroxysmal movement disorders: Paroxysmal dyskinesia and episodic ataxia.

Paroxysmal movement disorders have traditionally been classified into paroxysmal dyskinesia (PxD), which consists in attacks of involuntary movements (mainly dystonia and/or chorea) without loss of consciousness, and episodic ataxia (EA), which features spells of cerebellar dysfunction with or without interictal neurological manifestations. In this chapter, PxD will be discussed first according to the trigger-based classification, thus reviewing clinical, genetic, and molecular features of paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-induced dyskinesia. EA will be presented thereafter according to their designated gene or genetic locus. Clinicogenetic similarities among paroxysmal movement disorders have progressively emerged, which are herein highlighted along with growing evidence that their pathomechanisms overlap those of epilepsy and migraine. Advances in our comprehension of the biological pathways underlying paroxysmal movement disorders, which involve ion channels as well as proteins associated with the vesical synaptic cycle or implicated in neuronal energy metabolism, may represent the cornerstone for defining a shared pathophysiologic framework and developing target-specific therapies.

A homozygous founder variant in PDE2A causes paroxysmal dyskinesia with intellectual disability.

Intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS, OMIM#619150) is an ultra-rare childhood-onset autosomal recessive movement disorder manifesting paroxysmal dyskinesia, global developmental delay, impaired cognition, progressive psychomotor deterioration and/or drug-refractory seizures. We investigated three consanguineous Pakistani families with six affected individuals presenting overlapping phenotypes partially consistent with the reported characteristics of IDDPADS. Whole exome sequencing identified a novel missense variant in Phosphodiesterase 2A (PDE2A): NM_002599.4: c.1514T > C p.(Phe505Ser) that segregated with the disease status of individuals in these families. Retrospectively, we performed haplotype analysis that revealed a 3.16 Mb shared haplotype at 11q13.4 among three families suggesting a founder effect in this region. Moreover, we also observed abnormal mitochondrial morphology in patient fibroblasts compared to controls. Belonging to diverse age groups (13 years-60 years), patients presented paroxysmal dyskinesia, developmental delay, cognitive abnormalities, speech impairment, and drug-refractory seizures with variable onset of disease (as early as 3 months of age to 7 years). Together with the previous reports, we observed that intellectual disability, progressive psychomotor deterioration, and drug-refractory seizures are consistent outcomes of the disease. However, permanent choreodystonia showed variability. We also noticed that the later onset of paroxysmal dyskinesia manifests severe attacks in terms of duration. Being the first report from Pakistan, we add to the clinical and mutation spectrum of PDE2A-related recessive disease raising the total number of patients from six to 12 and variants from five to six. Together, with our findings, the role of PDE2A is strengthened in critical physio-neurological processes.

Diagnostic Uncertainties: Chorea.

Chorea is a hyperkinetic movement disorder with a multitude of potential etiologies, both acquired and inherited. Although the differential diagnosis for new-onset chorea is extensive, there are often clues in the history, exam, and basic testing that can help to narrow the options. Evaluation for treatable or reversible causes should take priority, as rapid diagnosis can lead to more favorable outcomes. While Huntington's disease is most common genetic cause of chorea, multiple phenocopies also exist and should be considered if Huntington gene testing is negative. The decision of what additional genetic testing to pursue should be based on both clinical and epidemiological factors. The following review provides an overview of the many possible etiologies as well as a practical approach for a patient presenting with new-onset chorea.

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

BACKGROUND: 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 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. METHODS: Phenotypic 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. RESULTS: 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 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. CONCLUSIONS: Collectively, 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.

Reduced-penetrance Huntington's disease-causing alleles with 39 CAG trinucleotide repeats could be a genetic factor of amyotrophic lateral sclerosis.

BACKGROUND: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum diseases. The aim of this study was to investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS. METHODS: We analyzed the numbers of CAG repeats in exon 1 of HTT in a cohort of 410 Taiwanese patients with ALS and 1514 control individuals by utilizing polymerase chain reaction and amplicon fragment length analysis. RESULTS: Only one of the 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had an expanded HTT CAG repeats ≥40. The patient presented with rapidly progressive bulbar-onset ALS with disease onset at the age of 64 years. He had neither chorea nor cognitive impairment. He had a family history of chorea, but no other family member manifested with ALS. None of the 1514 control individuals carried an HTT expanded allele with CAG repeats larger than 37 repeats. CONCLUSION: The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility.

Elective and Emergency Deep Brain Stimulation in Refractory Pediatric Monogenetic Movement Disorders Presenting with Dystonia: Current Practice Illustrated by Two Cases.

BACKGROUND: Dystonia is characterized by sustained or intermittent muscle contractions, leading to abnormal posturing and twisting movements. In pediatric patients, dystonia often negatively influences quality of life. Pharmacological treatment for dystonia is often inadequate and causes adverse effects. Deep brain stimulation (DBS) appears to be a valid therapeutic option for pharmacoresistant dystonia in children. METHODS: To illustrate the current clinical practice, we hereby describe two pediatric cases of monogenetic movement disorders presenting with dystonia and treated with DBS. We provide a literature review of similar previously described cases and on different clinical aspects of DBS in pediatric dystonia. RESULTS: The first patient, a 6-year-old girl with severe dystonia, chorea, and myoclonus due to an ADCY5 gene mutation, received DBS in an elective setting. The second patient, an 8-year-old boy with GNAO1-related dystonia and chorea, underwent emergency DBS due to a pharmacoresistant status dystonicus. A significant amelioration of motor symptoms (65% on the Burke-Fahn-Marsden Dystonia Rating Scale) was observed postoperatively in the first patient and her personal therapeutic goals were achieved. DBS was previously reported in five patients with ADCY5-related movement disorders, of which three showed objective improvement. Emergency DBS in our second patient resulted in the successful termination of his GNAO1-related status dystonicus, this being the eighth case reported in the literature. CONCLUSION: DBS can be effective in monogenetic pediatric dystonia and should be considered early in the disease course. To better evaluate the effects of DBS on patients' functioning, patient-centered therapeutic goals should be discussed in a multidisciplinary approach.

Detection and Characterization of a De Novo Alu Retrotransposition Event Causing NKX2-1-Related Disorder.

BACKGROUND: Heterozygous NKX2-1 loss-of-function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood-onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease-causing structural variants whose detection in routine diagnostics remains challenging. OBJECTIVE: To establish the molecular diagnosis of two first-degree relatives with clinically suspected NKX2-1-related disorder who had negative NKX2-1 Sanger (SS), whole-exome (WES), and whole-genome (WGS) sequencing. METHODS: The proband's WES was analyzed for MEIs. A candidate MEI in NKX2-1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2-1 haploinsufficiency at RNA and protein levels were performed. RESULTS: A 347-bp AluYa5 insertion with a 65-bp poly-A tail followed by a 16-bp duplication of the pre-insertion wild-type sequence in exon 3 of NKX2-1 (ENST00000354822.7:c.556_557insAlu541_556dup) segregated with the disease phenotype. CONCLUSIONS: We identified a de novo exonic AluYa5 insertion causing NKX2-1-related disorder in SS/WES/WGS-negative cases, suggesting that MEI analysis of short-read sequencing data or targeted long-read sequencing could unmask the molecular diagnosis of unsolved MD cases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Chorea and Cognitive Impairment in JAK2V617F-Positive Myeloproliferative Disorders: A Case Report and Literature Review.

Chorea is a hyperkinetic movement disorder, accompanied by dystonia, myoclonus, tics, stereotypies, and tremors. It is characterized by excessive, purposeless movements that are distressing, irregularly timed, and randomly distributed. Chorea can be present in many diseases, such as hereditary, metabolic disturbance, drug-induced, and functional disorders, and, rarely, genetic, autoimmune, and infectious diseases. Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that leads to ineffective clonal hematopoiesis, fibrous tissue deposits in the bone marrow, extramedullary hematopoiesis, and splenomegaly. In rare cases, following uncertain pathological mechanisms, it can present with chorea, particularly affecting the limbs, head, and orofaciolingual muscles. We present a case of a male patient with evolving PMF over several years who was admitted for progressive cognitive impairment and generalized involuntary movement disorder. We also present a review of all cases of myeloproliferative disorders presenting with chorea published in the last 40 years.

Chorea.

PURPOSE OF REVIEW: This article provides an overview of the diagnostic and therapeutic approach to a patient with chorea. The phenomenology of chorea is described in addition to other common hyperkinetic movements that may be mistaken for or coexist with chorea. Chorea can be acquired or hereditary. Key historical and clinical features that can aid in determining the etiology are reviewed, and pharmacologic and nonpharmacologic treatment strategies are discussed. RECENT FINDINGS: Clinical investigations are under way to target transcription and translation of the mutant huntingtin protein as a potential disease-modifying strategy in Huntington disease (HD). Additional heritable factors have been revealed through genome-wide association studies. Symptom-focused treatments for HD are are being studied, including a third vesicular monoamine transporter-2 (VMAT2) inhibitor for chorea attenuation and drugs to target irritability and cognitive impairment. Increased availability of genetic testing has led to increased awareness of HD mimics (eg, C9orf72 and IgLON5). SUMMARY: Chorea is a relatively common hyperkinetic disorder with a broad differential. The first step in the approach to a patient with chorea is accurately defining the phenomenology. Once it has been determined that the patient has chorea, the investigation into determining an etiology can begin. Factors such as age of onset, time course, family history, unique clinical features, and imaging and laboratory findings can guide the diagnosis. Treatments for most causes of chorea are purely symptomatic, although it is important to recognize causes that are reversible or have disease-modifying interventions.