TMEM151A variants cause paroxysmal kinesigenic dyskinesia.
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ABSTRACT:
SUBMITTER: Li HF
PROVIDER: S-EPMC8437987 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.
| S-EPMC3334308 | biostudies-literature
Project description:Paroxysmal kinesigenic dyskinesia (PKD) is characterized by sudden episodes of involuntary movements. PKD is a very rare movement disorder, and correct clinical diagnosis is often a challenge.We present the case of a 23-year-old female with PKD. The patient showed episodes of twisting movements for 3 years. The symptoms lasted for about 5-10 minutes and subsided spontaneously. She was diagnosed as having epilepsy, and depressive and anxiety disorders successively. However, her symptoms did not alleviate after taking sodium valproate and antidepressants. Though there were no mutations in her PRRT2 gene, carbamazepine was used for treatment and was effective in controlling her symptoms.The clinical features of PKD patients are not always typical; therefore, it is important to distinguish PKD from the other subtypes of paroxysmal dyskinesia and psychogenic disorders.
| S-EPMC5993030 | biostudies-other
Project description:Background:Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder, with an excellent response to carbamazepine treatment. It has been described in various populations, but not yet in an African population. Case report:In a patient who reported to clinic with side effects of carbamazepine, PRRT2 gene screening was performed based on a clinical history compatible with PKD. A common PRRT2 mutation was identified in this patient, hereby the first genetically confirmed PRRT2-associated PKD in Africa. Discussion:Reporting genetic confirmation of an unusual movement disorder from an equally unusual location shows the wide geographical distribution of PRRT2-associated disease. It also illustrates recognizability of this treatable disorder where the easiest accessible diagnostic tool is neurological history and examination.
| S-EPMC6982423 | biostudies-literature
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| S-EPMC8370144 | biostudies-literature
Project description: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.
| S-EPMC6016019 | biostudies-literature
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| S-EPMC8112851 | biostudies-literature
Project description:BackgroundAutosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by pathogenic variants in the SACS gene and is characterized by ataxia, peripheral neuropathy, pyramidal impairment and episodic conditions such as epilepsy. Paroxysmal kinesigenic dyskinesia (PKD) had not been previously described in ARSACS.MethodsWe analyzed clinical manifestations and performed whole-exome sequencing (WES) in two independent patients with ARSACS and PKD. Both patients' parents were unaffected. Genetic data were filtered for potential pathogenic variants, searching for de novo mutations suggestive of a dominant disease model or homozygous and compound heterozygous variants of a recessive model. Potential mutations that existed in both patients were generated and subjected to Sanger sequencing. The WES results of 163 PKD patients without additional symptoms from previous experiments were also reviewed.ResultsNovel compound heterozygous mutations in the SACS gene were identified in Patient 1 (p.P3007S and p.H3392fs), and a novel homozygous truncating mutation (p.W1376X) was identified in Patient 2. In both patients, each mutant allele was inherited from one of his or her unaffected parents. All 3 mutations were absent in 196 ethnic-matched control chromosomes or in data from the 1000 Genomes Project. No pathogenic variants associated with paroxysmal diseases, especially PKD and episodic ataxia, were identified. In PKD patients without additional symptoms, no homozygous or compound heterozygous variants in the SACS gene were detected.ConclusionsThis study expands the clinical phenotype of ARSACS and suggests the inclusion of SACS screening in patients with PKD plus ARSACS.
| S-EPMC6995733 | biostudies-literature
Project description:Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.
| S-EPMC7608189 | biostudies-literature
Project description:Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements. Under the condition of psychological burden, some patients' attacks may get worsened with longer duration and higher frequency. This study aimed to assess nonmotor symptoms and quality of life of patients with PKD in a large population.We performed a cross-sectional survey in 165 primary PKD patients from August 2008 to October 2016 in Rui Jin Hospital, using Symptom Check List-90-Revised (SCL-90-R), World Health Organization Quality of Life-100 (WHOQoL-100), Self-Rating Depression Scale, and Self-Rating Anxiety Scale. We evaluated the differences of SCL-90-R and WHOQOL-100 scores in patients and Chinese normative data (taken from literature) by using the unpaired Student's t-test. We applied multivariate linear regression to analyze the relationships between motor manifestations, mental health, and quality of life among PKD patients.Compared with Chinese normative data taken from literature, patients with PKD exhibited significantly higher (worse) scores across all SCL-90-R subscales (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism; P= 0.000 for all) and significantly lower (worse) scores of five domains in WHOQoL-100 (physical domain, psychological domain, independence domain, social relationship domain, and general quality of life; P= 0.000 for all). Nonremission of dyskinesia episodes (P = 0.011) and higher depression score (P = 0.000) were significantly associated with lower levels of quality of life. The rates of depression and anxiety in patients with PKD were 41.2% (68/165) and 26.7% (44/165), respectively.Depression, anxiety, and low levels of quality of life were prevalent in patients with PKD. Co-occurrence of depression and anxiety was common among these patients. Regular mental health interventions could set depression and anxiety as intervention targets. Considering that the motor episodes could be elicited by voluntary movements and sometimes also by emotional stress, and that symptoms may get worsened with longer duration and higher frequency when patients are stressed out, intervention or treatment of depression and anxiety might improve the motor symptoms and overall quality of life in PKD patients.
| S-EPMC5586178 | biostudies-literature
Project description:Background and objectivesIsolated paroxysmal kinesigenic dyskinesia (PKD) is mainly caused by PRRT2 variants and TMEM151A variants. Patients with proximal 16p11.2 microdeletion (16p11.2MD) (including PRRT2) often have neurodevelopmental phenotypes, whereas a few patients have PKD. Here, we aimed to identify 16p11.2MD in patients with PKD and describe the related phenotypes.MethodsWhole-exome sequencing and bioinformatics analysis of copy number variant (CNV) were performed in patients with PKD carrying neither PRRT2 nor TMEM151A variant. Quantitative PCR and low-coverage whole-genome sequencing verified the CNV.ResultsWe identified 9 sporadic patients with PKD and 16p11.2MD (∼535 kb), accounting for 9.6% (9/94) of our patients. Together with 9 previously reported patients with PKD and 16p11.2MD, we found that 16p11.2MD was de novo in 11 of 12 tested patients and inherited from a parent in the other patient. And 80% (12/15) of these patients had a mild language delay, 64.3% (9/14) had compromised learning ability, 42.9% (6/14) had a mild motor delay, and 50% (6/12) had abnormal neuroimaging findings. No severe autism disorders were observed.DiscussionMild developmental problems may be overlooked. A detailed inquiry of developmental history and CNV testing are necessary to distinguish patients with 16p11.2MD from isolated PKD.
| S-EPMC8855691 | biostudies-literature