Paroxysmal Nonkinesigenic Dyskinesia Research Articles

BK Channelopathies and KCNMA1-Linked Disease Models.

Novel KCNMA1 variants, encoding the BK K+ channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation.

Mitochondrial HIGD1A inhibits hepatitis B virus transcription and replication through the cellular PNKD-NF-κB-NR2F1 nexus.

Hepatitis B Virus (HBV) replication has been reported to be restricted by the intrahepatic host restriction factors and antiviral signaling pathways. The intracellular mechanisms underlying the significant viremia difference among different phases of the natural history chronic HBV infection remain elusive. We herein report that the hypoxia-induced gene domain protein-1a (HIGD1A) was highly expressed in the liver of inactive HBV carriers with low viremia. Ectopic expression of HIGD1A in hepatocyte-derived cells significantly inhibited HBV transcription and replication in a dose-dependent manner, while silence of HIGD1A promoted HBV gene expression and replication. Similar results were also observed in both de novo HBV-infected cell culture model and HBV persistence mouse model. Mechanistically, HIGD1A is located on the mitochondrial inner membrane and activates nuclear factor kappa B (NF-κB) signaling pathway through binding to paroxysmal nonkinesigenic dyskinesia (PNKD), which further enhances the expression of a transcription factor NR2F1 to inhibit HBV transcription and replication. Consistently, knockdown of PNKD or NR2F1 and blockage of NF-κB signaling pathway abrogated the inhibitory effect of HIGD1A on HBV replication. Mitochondrial HIGD1A exploits the PNKD-NF-κB-NR2F1 nexus to act as a host restriction factor of HBV infection. Our study thus shed new lights on the regulation of HBV by hypoxia-related genes and related antiviral strategies.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Genetic Links to Episodic Movement Disorders: Current Insights.

Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1-9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5-related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.

BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models.

KCNMA1 forms the pore of BK K+ channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of KCNMA1 mutations and the basis for clinical heterogeneity in PNKD3 has not been established. Here, we evaluate the relative severity of three KCNMA1 patient variants in BK channels, neurons, and mice. In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF) properties, whereas BKH444Q channels showed loss-of-function (LOF) properties. The relative degree of channel activity was BKN999S > BKD434G>WT > BKH444Q. BK currents and action potential firing were increased, and seizure thresholds decreased, in Kcnma1N999S/WT and Kcnma1D434G/WT transgenic mice but not Kcnma1H444Q/WT mice. In a novel behavioral test for paroxysmal dyskinesia, the more severely affected Kcnma1N999S/WT mice became immobile after stress. This was abrogated by acute dextroamphetamine treatment, consistent with PNKD3-affected individuals. Homozygous Kcnma1D434G/D434G mice showed similar immobility, but in contrast, homozygous Kcnma1H444Q/H444Q mice displayed hyperkinetic behavior. These data establish the relative pathogenic potential of patient alleles as N999S>D434G>H444Q and validate Kcnma1N999S/WT mice as a model for PNKD3 with increased seizure propensity.

Screening of the TMEM151A Gene in Patients With Paroxysmal Kinesigenic Dyskinesia and Other Movement Disorders.

BackgroundParoxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent involuntary movements usually triggered by sudden movements. Mutations in the TMEM151A gene were found to be the causative factor of PKD in recent studies. It has also been revealed that loss-of-function is the mechanism by which TMEM151A mutations cause PKD.MethodsTo investigate the genetic basis of PKD and broaden the clinical spectrum of the TMEM151A mutations, we recruited 181 patients of Chinese origin with movement disorders (MDs), including 39 PRRT2-negative PKD, 3 paroxysmal exercise-induced dyskinesia (PED), 2 paroxysmal non-kinesigenic dyskinesia (PNKD), 127 isolated dystonia, 8 choreas, and 2 myoclonus-dystonia syndromes. Whole-exome sequencing was applied to identify their possible disease-causing mutations. Then, Sanger sequencing was performed for validation and co-segregation analysis. Genetic analysis was also performed on additional family members of patients with TMEM151A mutations. Clinical manifestations of all PKD cases with mutations in TMEM151A reported, so far, were reviewed.ResultsTwo novel variants of the TMEM151A gene (NM_153266.4, NP_694998.1), c.627_643dup (p.A215Gfs*53) and c.627delG (p.L210Wfs*52), were identified in 2 patients with PKD by whole-exome sequencing and further Sanger sequencing. Both variants were inherited by the patients from their respective mothers. No mutation of the TMEM151A gene was found in the other type of movement disorders. In reviewing the clinical presentation of TMEM151A-related PKD, no statistically significant difference in the age of onset, family history, duration of attacks, laterality, and phenotype was found between genders. More male patients received treatment and had a good response. A higher proportion of female patients did not receive any treatment, possibly because they had a milder condition of the disease.ConclusionsThis study further validated the role of TMEM151A in PKD. Future studies on protein function will be needed to ascertain the pathogenesis of TMEM151A in PKD.

Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report

BackgroundMutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype–phenotype correlation of PIGN.Case presentationDuring the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2–5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient’s granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1–2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age).ConclusionThis is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype–phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.

Striatal Indirect Pathway Dysfunction Underlies Motor Deficits in a Mouse Model of Paroxysmal Dyskinesia.

Abnormal involuntary movements, or dyskinesias, are seen in many neurologic diseases, including disorders where the brain appears grossly normal. This observation suggests that alterations in neural activity or connectivity may underlie dyskinesias. One influential model proposes that involuntary movements are driven by an imbalance in the activity of striatal direct and indirect pathway neurons (dMSNs and iMSNs, respectively). Indeed, in some animal models, there is evidence that dMSN hyperactivity contributes to dyskinesia. Given the many diseases associated with dyskinesia, it is unclear whether these findings generalize to all forms. Here, we used male and female mice in a mouse model of paroxysmal nonkinesigenic dyskinesia (PNKD) to assess whether involuntary movements are related to aberrant activity in the striatal direct and indirect pathways. In this model, as in the human disorder PNKD, animals experience dyskinetic attacks in response to caffeine or alcohol. Using optically identified striatal single-unit recordings in freely moving PNKD mice, we found a loss of iMSN firing during dyskinesia bouts. Further, chemogenetic inhibition of iMSNs triggered dyskinetic episodes in PNKD mice. Finally, we found that these decreases in iMSN firing are likely because of aberrant endocannabinoid-mediated suppression of glutamatergic inputs. These data show that striatal iMSN dysfunction contributes to the etiology of dyskinesia in PNKD, and suggest that indirect pathway hypoactivity may be a key mechanism for the generation of involuntary movements in other disorders.SIGNIFICANCE STATEMENT Involuntary movements, or dyskinesias, are part of many inherited and acquired neurologic syndromes. There are few effective treatments, most of which have significant side effects. Better understanding of which cells and patterns of activity cause dyskinetic movements might inform the development of new neuromodulatory treatments. In this study, we used a mouse model of an inherited human form of paroxysmal dyskinesia in combination with cell type-specific tools to monitor and manipulate striatal activity. We were able to narrow in on a specific group of neurons that causes dyskinesia in this model, and found alterations in a well-known form of plasticity in this cell type, endocannabinoid-dependent synaptic LTD. These findings point to new areas for therapeutic development.

The case of paroxysmal kinesigenic dyskinesia: a long way from a symptom to the diagnosis

Paroxysmal kinesigenic dyskinesia belongs to the group of primary dyskinesias, which also includes paroxysmal non-kinesigenic dyskinesia and exercise-induced paroxysmal dyskinesia. Due to the rarity of this disease group, as well as to the existence of a wide spectrum of disorders associated with transient movement abnormalities, the diagnosis is often difficult. A thorough analysis of clinical presentation, objective registration of paroxysmal events (video-electroencephalography monitoring) is helpful in the diagnosis. The most common causes of paroxysmal kinesigenic dyskinesia are mutations in the PRRT2 gene, while paroxysmal non-kinesigenic dyskinesia is caused by the MR1 gene mutations.The paper describes a clinical case of a 13 year old patient with acute, movement-associated, shortterm dystonic, choreic and ballistic hyperkinesis attacks. The patient had been treated with the diagnosis of epilepsy, tics, and dystonia for a long time without any effect. During diagnostic workup, a mutation in the PRRT2 gene intron was identified by a new generation sequencing of gene panel. Despite of this mutation has not been previously described, taking into account the type of Informed consent statement hyperkinesis attacks, association of their onset to movements, as well as the data of instrumental assessments, the diagnosis of paroxysmal kinesi-genic dyskinesia was made. Treatment with carbamazepine was successful with complete control over hyperkinesis.The diagnosis of paroxysmal dyskinesias remains based on the analysis of clinical picture and the trigger type. Molecular genetic diagnostics, with consideration of the most frequent causal mutations related to these conditions, can minimize both time and financial costs.

Paroxysmal Genetic Movement Disorders and Epilepsy.

Paroxysmal movement disorders include paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and episodic ataxias. In recent years, there has been renewed interest and recognition of these disorders and their intersection with epilepsy, at the molecular and pathophysiological levels. In this review, we discuss how these distinct phenotypes were constructed from a historical perspective and discuss how they are currently coalescing into established genetic etiologies with extensive pleiotropy, emphasizing clinical phenotyping important for diagnosis and for interpreting results from genetic testing. We discuss insights on the pathophysiology of select disorders and describe shared mechanisms that overlap treatment principles in some of these disorders. In the near future, it is likely that a growing number of genes will be described associating movement disorders and epilepsy, in parallel with improved understanding of disease mechanisms leading to more effective treatments.

Hemiplegic Migraine in Glut1 Deficiency Syndrome and Paroxysmal Dyskinesia at Ketogenic Diet Induction: Case Report and Literature Review.

A rare symptom of Glut1 deficiency syndrome (Glut1 DS) is hemiplegic migraine (HM). We report a patient with Glut1 DS with a mild phenotype. His leading symptom was HM. As an unusual complication of the initiation of a ketogenic diet (KD), our patient developed paroxysmal nonkinesigenic dyskinesia. Paroxysmal dyskinesia occurred first and exclusively at the initiation of KD. There are a few case reports for HM in Glut1 DS. All patients had additional neurological symptoms. Regarding central nervous system symptoms such as paroxysmal dyskinesia triggered by KD, we found only 1 other case report. HM is part of the symptom complex of Glut1 DS and can be effectively treated by KD. Paroxysmal dyskinesia trigged by the initiation of KD should not lead to the discontinuation of the diet in Glut1 DS.

PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?

BackgroundMutations in Proline-rich Transmembrane Protein 2 (PRRT2) have been primarily associated with individuals presenting with infantile epilepsy, including benign familial infantile epilepsy, benign infantile epilepsy, and benign myoclonus of early infancy, and/or with dyskinetic paroxysms such as paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, and exercise-induced dyskinesia. However, the clinical manifestations of this disorder vary widely. PRRT2 encodes a protein expressed in the central nervous system that is mainly localized in the pre-synaptic neurons and is involved in the modulation of synaptic neurotransmitter release. The anomalous function of this gene has been proposed to cause dysregulation of neuronal excitability and cerebral disorders.Case presentationWe hereby report on a young child followed-up for three years who presents with a spectrum of clinical manifestations such as congenital microcephaly, dysmorphic features, severe intellectual disability, and drug-resistant epileptic encephalopathy in association with a synonymous variant in PRRT2 gene (c.501C > T; p.Thr167Ile) of unknown clinical significance variant (VUS) revealed by diagnostic exome sequencing.ConclusionSeveral hypotheses have been advanced on the specific role that PRRT2 gene mutations play to cause the clinical features of affected patients. To our knowledge, the severe phenotype seen in this case has never been reported in association with any clinically actionable variant, as the missense substitution detected in PRRT2 gene. Intriguingly, the same mutation was reported in the healthy father: the action of modifying factors in the affected child may be hypothesized. The report of similar observations could extend the spectrum of clinical manifestations linked to this mutation.

The Spectrum of Paroxysmal Dyskinesias

Paroxysmal dyskinesias (PxD) comprise a group of heterogeneous syndromes characterized by recurrent attacks of mainly dystonia and/or chorea, without loss of consciousness. PxD have been classified according to their triggers and duration as paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia and paroxysmal exertion-induced dyskinesia. Of note, the spectrum of genetic and nongenetic conditions underlying PxD is continuously increasing, but not always a phenotype–etiology correlation exists. This creates a challenge in the diagnostic work-up, increased by the fact that most of these episodes are unwitnessed. Furthermore, other paroxysmal disorders, included those of psychogenic origin, should be considered in the differential diagnosis. In this review, some key points for the diagnosis are provided, as well as the appropriate treatment and future approaches discussed.

KCNMA1-linked channelopathy.

KCNMA1 encodes the pore-forming α subunit of the "Big K+" (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1-/- ) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as "KCNMA1-linked channelopathy." These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

Phenotypes, genotypes, and the management of paroxysmal movement disorders.

A growing number of genes have been associated with classic and newly described paroxysmal movement disorders. Paroxysmal movement disorders share common mechanisms and clinical features with other neurological paroxysmal phenomena including epilepsy and migraine.

Paroxysmal Dyskinesia in Children: from Genes to the Clinic.

Background and PurposeParoxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children.MethodsFifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records.ResultsForty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups.ConclusionsThis study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.

De novo KCNMA1 mutations in 3 children with paroxysmal nonkinesigenic dyskinesia and developmental delay

Objective To analyze the clinical characteristics of 3 unrelated boys with paroxysmal nonkinesigenic dyskinesia and developmental delay caused by de novo mutation in KCNMA1, and to expand the knowledge of clinical phenotype of KCNMA1 mutation. Methods Clinical data of patients were collected, including gender, age, condition of the perinatal period, personal history, and family history. And the features of genotype data were collected including features of attack, developmental milestones, physical examinations, treatments, and responses to treatment.The data including blood biochemical results, results of metabolic screening and genetic testing and the pedigree validation were collected, while the relationship between phenotype and genotype was analyzed. Results (1)Phenotypic features: 3 unrelated boys were diagnosed.The ages of disease onset were 20 days, 7 months and 13 months, respectively.All the patients manifested paroxysmal nonkinesigenic dyskinesia and were characterized by the episodes that occurred during wakefulness, presented with sudden onset of asymmetric limb dystonic posture, sometimes with nystagmus and strabismus, or sudden decrease of voluntary movement of limbs with hypotonia and occasional esotropia and yawning.There was no loss of awareness during attack.No precipitating factors were observed before attacks.The developmental milestones were delayed.Three children had no response to anti-epilepsy drug before diagnosis.After diagnosis, 2 cases used Clonazepam and 1 case showed less attack.There was not any epileptic seizure until the last follow-up at the ages of 3 years and 6 months old, 7 years old, and 5 years and 8 months old, respectively.The frequency of attacks was decreased.The episodes were recorded during video-electroencephalogram(EEG) monitoring, which showed normal ictal and interictal EEG.(2)Genotypic features: all 3 children were detected to have KCNMA1 genetic heterozygous missense mutation, while c. 2650G>A (p.Glu884Lys) mutation was identified in 1 patient, and c. 3158A>G(p.Asn1053Ser)mutation in the other 2 patients, but no such mutation was found in their parents. Conclusion This finding expands the phenotype of KCNMA1 mutation.KCNMA1 should be considered as one of the candidate genes for screening in patients with early onset of paroxysmal nonkinesigenic dyskinesia without triggers, or early-onset of developmental delay, with or without epilepsy. Key words: Paroxysmal nonkinesigenic dyskinesia; Developmental delay; Epilepsy; KCNMA1 gene

RSM22, mtYsxC and PNKD-like proteins are required for mitochondrial translation in Trypanosoma brucei

Mitochondrial ribosomes evolved from prokaryotic ribosomes, with which they therefore share more common features than with their counterparts in the cytosol. Yet, mitochondrial ribosomes are highly diverse in structure and composition, having undergone considerable changes, including reduction of their RNA component and varying degree of acquisition of novel proteins in various phylogenetic lineages. Here, we present functional analysis of three putative mitochondrial ribosome-associated proteins (RSM22, mtYsxC and PNKD-like) in Trypanosoma brucei, originally identified by database mining. While in other systems the homologs of RSM22 are known as components of mitochondrial ribosomes, YsxC was linked with ribosomes only in bacteria. The PNKD-like protein shows similarity to a human protein, the defects of which cause PNKD (paroxysmal non-kinesigenic dyskinesia). Here we show that all three proteins are important for the growth of T. brucei. They play an important function in mitochondrial translation, as their ablation by RNAi rapidly and severely affected the de novo synthesis of mitochondrial proteins. Moreover, following the RNAi-mediated depletion of RSM22, structure of the small subunit of mitochondrial ribosome becomes severely compromised, suggesting a role of RSM22 in ribosomal assembly and/or stability.

A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia

Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers of the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records and videos of episodes from 25 affected dogs were reviewed. The episodes of hyperkinesia and dystonia lasted from several minutes to several hours and could occur as often as >10/day. They were not associated with strenuous exercise or fasting but were sometimes triggered by excitement. The canine PxD phenotype most closely resembled paroxysmal non-kinesigenic dyskinesia (PNKD) of humans. Whole genome sequences were generated with DNA from 2 affected dogs and analyzed in comparison to 100 control canid whole genome sequences. The two whole genome sequences from dogs with PxD had a rare homozygous PIGN:c.398C > T transition, which predicted the substitution of an isoleucine for a highly conserved threonine in the encoded enzyme. All 25 PxD-affected dogs were PIGN:c.398T allele homozygotes, whereas there were no c.398T homozygotes among 1185 genotyped dogs without known histories of PxD. PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors a variety of proteins including CD59 to the cell surface. Flow cytometry of PIGN-knockout HEK239 cells expressing recombinant human PIGN with the c.398T variant showed reduced CD59 expression. Mutations in human PIGN have been associated with multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1). Movement disorders can be a part of MCAHS1, but this is the first PxD associated with altered GPI anchor function.

Mutation Analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients.

Background:Paroxysmal kinesigenic dyskinesia (PKD) is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry any PRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap.Methods:A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited. Clinical features were evaluated, and all subjects were screened for MR-1, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia, and myotonia congenita (MC), respectively. In addition, 200 genetically matched healthy individuals were recruited as controls.Results:A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G>A mutation was detected in one case, and CLCN1 c.1205C>T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A1 c.363G>A mutation was novel.Conclusions:The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2- negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.