The effect of dyskinesia on postural control, balance, gait, and fall risk in people with Parkinson's disease: a systematic review protocol

Dyskinesia affects the limbs, trunk, and head and is more prevalent in people with Parkinson's disease (PD) and a history of falls. More evidence about the effects of dyskinesia on postural control, balance, gait, and fall risk could help improve the quality of life of individuals with PD. This review aims to examine associations between dyskinesia and postural control, balance, gait, and fall risk in individuals with PD. Such information could lead to new approaches to quality of life improvement among individuals with PD. PubMed, CINAHL, PsycInfo, Scopus, and SciELO will be searched for longitudinal, cohort, and case-control studies published in English or Portuguese in any year that investigated the association between dyskinesia and postural control, balance, gait, and fall risk in individuals with PD. Two reviewers will independently evaluate the titles, abstracts, and full texts according to PRISMA guidelines to select eligible studies for the review. Data on participants, dyskinesia, postural control, balance, gait, and fall risk will be extracted and summarized in tables. Two reviewers will independently assess the methodological quality of each study using the Newcastle Ottawa quality assessment scale. Meta-analysis will not be performed. The results of this systematic review will offer insight into the effects of dyskinesia on postural control, balance, gait, and fall risk. Such information could significantly contribute to informed decisions about early motor intervention in individuals with PD. (AU)

Alternativa terapéutica para mejorar la calidad de vida en pacientes con fibrosis quística y discinesia ciliar primaria / Therapeutic alternative to improve quality of life in patients with cystic fibrosis and primary ciliary dyskinesia

Objective: To evaluate the clinical response of patients with cystic fibrosis and primary ciliary dyskinesia after endoscopic sinus surgery at the Dr. Robert Reid Cabral Children's Hospital from September 2021 to February 2022. Methods: An ambispective, cross-sectional, observational case series study was conducted, where the study population was made up of patients with cystic fibrosis and primary ciliary dyskinesia at the Dr. Robert Reid Cabral children's hospital during the study period. Inclusion criteria: Patients older than 6 years with a confirmed diagnosis of cystic fibrosis and primary ciliary dyskinesia (Genetic test with 2 homozygous mutations, positives electrolytes in sweat), severe respiratory symptoms of CRS that did not improve with conventional treatment and underwent endoscopic surgery for sinuses. Results: Of a total of 41 patients, only 10 met the inclusion criteria, the most prevalent age range was 14 to 18 years. Both CF and PCD patients decreased the frequency of CRS symptoms. After ENC, there were discrete changes in lung function, and only patients with severe to moderate disease increased % of FEV1. Most of the patients did not require admission after surgery. The most common germ found in nasopharyngeal and sputum cultures in preoperative patients was Pseudomonas aeruginosa in 86%; after ESS there was a significant increase in MRSA colonization in both CF and PCD patients. More than 50% of postoperative patients improved their quality of life, so endoscopic sinus surgery is effective in this population in the treatment of chronic rhinosinusitis.

Objetivo: Evaluar la respuesta clínica de los pacientes con fibrosis quística y discinesia ciliar primaria posterior a la cirugía endoscópica de senos paranasales en el Hospital Infantil Dr. Robert Reid Cabral en el período septiembre 2021 a febrero 2022. Métodos: Se realizó un estudio observacional tipo serie de casos, de corte transversal y ambispectivo, donde la población estudiada estuvo conformada por los pacientes con fibrosis quística y discinesia ciliar primaria del hospital infantil Dr. Robert Reid Cabral en el período de estudio. Criterios de inclusión: Pacientes mayores de 6 años con diagnóstico confirmado de fibrosis quística y discinesia ciliar primaria (Prueba genética con 2 mutaciones homocigotas, electrolitos en sudor positivos), síntomas respiratorios severos de RSC que no mejoraron con tratamiento convencional y sometidos a la cirugía endoscópica de senos paranasales. Resultados: De un total de 41 pacientes, sólo 10 cumplieron con los criterios de inclusión, el rango de edad más prevalente fue de 14 a 18 años. Tanto los pacientes con FQ como los de DCP disminuyeron la frecuencia de los síntomas de RSC. Posterior a la CEN hubo cambios discretos en la función pulmonar, y sólo los pacientes con enfermedad grave a moderada aumentaron el % de FEV1. La mayoría de los pacientes no ameritaron ingresos posterior a la cirugía. El germen más común encontrado en los cultivos nasofaríngeo y esputo en los pacientes preoperatorios fue la Pseudomonas aeruginosa en el 86%, luego de la CEN hubo un aumento significativo de la colonización por MRSA tanto en los pacientes con FQ como en los de DCP. Más del 50% de los pacientes postquirúrgicos mejoraron su calidad de vida, por lo que la cirugía endoscópica de senos paranasales es efectiva en dicha población en el tratamiento de la rinosinusitis crónica.

Outcomes of Endoscopic Sinus Surgery for Chronic Rhinosinusitis in Adults with Primary Ciliary Dyskinesia

Abstract Introduction Primary ciliary dyskinesia (PCD) is a rare inherited disease associated with impairment of mucociliary transport and, consequently, with a high incidence of chronic rhinosinusitis. For patients with chronic rhinosinusitis who remain symptomatic despite medical treatment, endoscopic sinus surgery is a safe and effective therapeutic option. However, to date, no studies have been found evaluating the effect of surgery on the quality of life associated with the effect on olfaction and nasal endoscopy findings of patients with primary ciliary dyskinesia and chronic rhinosinusitis. Objective To describe the effect of endoscopic sinus surgery on the quality of life, on olfaction, and on nasal endoscopy findings of adults with PCD and chronic rhinosinusitis. Methods Four patients who underwent endoscopic sinus surgery were included. The Sinonasal Outcome Test-22 (SNOT-22) score, the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire, and the Lund-Kennedy score were collected preoperatively and at 3 and 6 months postoperatively. The olfaction as assessed with the University of Pennsylvania Smell Identification Test (UPSIT), which was administered preoperatively and 3 months postoperatively. Results A total of 4 patients with a mean age of 39.3 years old (3 men and 1 woman) completed the study. All patients showed clinically significant improvement in the SNOT-22, NOSE, and Lund-Kennedy scores at 3 months postoperatively, and this improvement was sustained throughout the follow-up period. However, olfaction did not improve after surgery. Conclusion The endoscopic sinus surgery treatment of chronic rhinosinusitis in adults with PCD was associated with improvement in quality of life and endoscopic findings. However, no improvement in olfaction was demonstrated. Studies with a larger number of patients and control groups should help confirm these findings.

A rare case of primary ciliary dyskinesia with Kartagener抯 syndrome - A case report

Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease that includes various forms of ciliary ultrastructural defects. The most serious form is Kartagener syndrome (KS), which accounts for 50% of all cases of PCD. Kartagener?s syndrome is a rare disorder and the prevalence is about 1 in 30,000. It is autosomal recessive ciliary disorder comprising the triad of situs inversus totalis, chronic sinusitis, and bronchiectasis. The defective movement of cilia leads to recurrent respiratory infections, and ear/ nose/ throat infections, and infertility. The diagnosis is made clinically and confirmed through electron microscopy, which reveals abnormalities of structural organization of the axoneme in cilia from respiratory epithelia and in spermatozoa. Underlying structural defects include 1) absent inner and/or outer dynein arms, 2) tubular defects, and 3) radial spoke defects. We hereby report a rare case of Kartagener?s syndrome, in an infertile male with immotile sperms. The clinician should have a high index of suspicion, so as to make an early diagnosis. An early diagnosis helps in making the options for timely treatment of infertility may be offered and unnecessary evaluation is avoided.

Computed Tomography Evaluation of the Paranasal Sinuses in Adults with Primary Ciliary Dyskinesia

Abstract Introduction Primary ciliary dyskinesia is a rare inherited disease that results in a malfunction of mucociliary clearance and sinonasal complaints. Aplasia/hypoplasia of the frontal and sphenoid sinuses has been described as more frequent in this population. However, to date, no studies have provided a detailed description of computed tomography findings in adult patients with a diagnosis of this condition. Objective To describe the computed tomography (CT) findings of adult patients with primary ciliary dyskinesia. Methods Retrospective observational study of adult patients with primary ciliary dyskinesia who underwent CT. Results Twenty-one adults were included in the study. Aplasia occurred in 38.1% of frontal sinuses and in 14.3% of sphenoid sinuses. Likewise, hypoplasia occurred in 47.6% of the frontal sinuses, in 54.8% of the sphenoid sinuses and in 40.5% of the maxillary sinuses. Furthermore, trabecular loss was identified in 61.9% ethmoidal sinuses. The mean Lund-Mackay score was 13.5. In addition, 9.5% of the patients had concha bullosa, 47.6% had marked bilateral inferior turbinate hypertrophy, 38.1% had marked middle turbinate hypertrophy, and 47.6% had marked septal deviation. Finally, we identified images suggestive of fungus ball, mucocele, osteoma, a possible antrochoanal polyp, and frontal bone erosions. Conclusion The present study provides a detailed description of CT findings in patients with primary ciliary dyskinesia. We also describe abnormalities that must be identified for safer surgical planning and that suggest a diagnosis of primary ciliary dyskinesia if found in patients with a consistent clinical picture.

Research progress on primary ciliary dyskinesia in children / 中华实用儿科临床杂志

Primary ciliary dyskinesia (PCD) is an inherited disease characterized by impaired ciliary ultrastructure and function.Respiratory symptoms are the most important clinical manifestations of PCD.More than 50 pathogenic genes responsible for PCD have been identified, which have been contributed to clarify the etiology of PCD.At present, special therapy and gold standard for the diagnosis of PCD are scant.Gene therapy can restore ciliary function.Gene testing can identify the genetic etiology of PCD, and promote the development of individualized gene therapy.This review aims to summarize the research progress on genetic etiology of PCD and its genetic testing and gene therapy.

Developmental and epileptic encephalopathy with dyskinesia caused by the FRRS1L gene mutation: a case report and literature review / 中华实用儿科临床杂志

The clinical characteristics and gene mutation profiles of a child who was treated in Xuzhou Children′s Hospital, Xuzhou Medical University in June 2022 due to developmental and epileptic encephalopathy (DEE) combined with dyskinesia caused by the FRRS1L gene mutation was analyzed retrospectively.A male case 1 year and 9 months old presented developmental delay since childhood, hypotonia at the age of 6 months, treatment-resistant seizures (focal clonic seizures) at the age of 1 year and 7 months that were unable to be controlled by antiepileptic drugs, and developmental regression and abnormal movements of the hands and feet during the attack.Whole exome sequencing showed 2 heterozygous variants (missense mutation and deletion mutation) in the FRRS1L gene of the child.The missense mutation c. 754C>T (p.R252C) located in the 4 th exon was inherited from his mother, and the deletion mutation c. 438_c.459del (p.I146fs*4) located in the 2 th exon was inherited from his father, thus constituting a compound heterozygous mutation.Through literature review, all 6 relevant literatures involving 31 children with DEE were published in foreign countries.They presented similar clinical manifestations to this case, but the genotypes were different, all of which were homozygous mutations.The FRRS1L gene mutation can lead to DEE, which is characterized by the autosomal recessive inheritance pattern, refractory epilepsy onset in infancy, developmental regression and prominent dyskinetic movements with hyperkinesia, and poor long-term prognosis.

Primary ciliary dyskinesia in children: a case report and literature review / 中国综合临床

Objective:To explore the clinical features and diagnostic methods of primary ciliary dyskinesia (PCD).Methods:A case of PCD diagnosed by Kunming Children's Hospital was analyzed retrospectively (including general information, clinical characteristics, auxiliary examination results), and the literature was reviewed.Results:The patient, an 8-year-old female, went to hospital for repeated cough and suffered from pneumonia and sinusitis repeatedly in the past. The electron microscope of cilia biopsy showed that the number of cilia was reduced. The mutation of c.7615T>C (p.W2539R) in DNA H5 gene located in chr5-13,809,290 was detected by gene test, so the patient was diagnosed as PCD.The mutation site was a new mutation site.Conclusion:PCD is a rare disease in children. Electron microscopy and genetic examination are helpful to the diagnosis of PCD. Children with recurrent respiratory tract infection and wet cough should be alert to the possibility of PCD.

Clinical phenotype and genetic characteristics of patients with typical 16p11.2 microdeletion syndrome / 中华神经科杂志

Objective:To analyze the clinical phenotype, copy number variation, treatment and follow-up characteristics of children with typical 16p11.2 deletion syndrome.Methods:The clinical data of 10 children with typical 16p11.2 deletion syndrome who were treated in the Department of Neurology, Children′s Hospital of Fudan University from August 2011 to December 2021 were retrospectively collected, and their clinical phenotype, copy number variation, treatment and follow-up were summarized.Results:Among the 10 children, 4 are female and 6 are male, all with epilepsy. Nine patients had epilepsy in infancy, and the age of onset was 6.0 (4.0, 8.5) months. Four cases had focal seizures (1 with fever), 4 had generalized tonic-clonic seizures, and 2 had focal seizures with generalized tonic-clonic seizures. Eight cases had cluster seizures (more than 2 to 10 seizures within 24 hours), and 1 case had 1 status epilepticus. Nine children did not show obvious developmental delay at the onset of epilepsy, and 1 child had developmental delay at the onset of epilepsy at 14 months of age. One child had parallel toes at left foot, and 1 had macrocephaly and low limb muscle tone. Genetic testing found that 10 children carried typical 16p11.2 heterozygous deletion, the starting position of the deletion fragment was Chr16:29478119-29675016, the ending position was Chr16:30125670-30206112, and the deletion length was 525-712 kb, all of which were considered pathogenic variants. In the antiepileptic drug treatment, 4 children were treated with oxcarbazepine, 2 with sodium valproate, 2 was switched to oxcarbazepine after levetiracetam was ineffective, 1 with levetiracetam combined with sodium valproate, and 1 with levetiracetam in combination with sodium valproate and ketogenic diet, and all 10 children had no seizures. One patient developed episodic exercise-induced dyskinesia at school age, and the seizures decreased after treatment with oxcarbazepine. Follow-up of 10 children found that 9 children had different degrees of developmental delay (language was significantly affected), 3 cases were combined with autism-like manifestations, and 1 case had poor comprehension, learning difficulties, and repeated grades after entering regular primary schools.Conclusion:The typical 16p11.2 microdeletion syndrome has the deletion of gene fragments in the proximal region of 16p11.2, characterized by drug-responsive cluster seizures with onset in infancy, which may be accompanied by language delay, autism spectrum disorder and nonspecific malformations.

A pedigree study of paroxysmal exercise-induced dyskinesia with Parkinson-like symptoms associated with the expression of the PRRT2 gene in the elderly / 中华老年医学杂志

Objective:To study the clinical and genetic characteristics of familial paroxysmal exercise-induced dyskinesia with Parkinson-like manifestations in the elderly.Methods:Clinical data of 9 family members were analyzed, including 2 patients(both received treatment)consenting to appropriate therapy and prediction protocols.DNA was extracted from peripheral blood samples, and then second-generation sequencing mutation screening.Results:The tremor of two probands in the family was completely brought under control by oxcarbazepine treatment.In 5 family members, a heterozygous mutation of base G>C in exon 2 c. G366C: P.QCon122H at position 29824741 of the PRRT2 gene was found, resulting in the mutation of the amino acid at 122 from glutamine to histidine, which was predicted by SIFT and M-CAP to be harmful.Sanger sequencing of pedigree samples showed that the sisters, brothers and nephews of the proband were heterozygous and their nieces were of the wild type.Conclusions:Q122 of PRRT2 protein can cause the Parkinson-like limb tremor phenotype, and antiepileptic drugs are also effective for paroxysmal exercise-induced dyskinesia in the elderly.

Neuromyelitis optica spectrum disease starting as paroxysmal dyskinesia： A case report and literature review / 中风与神经疾病杂志

@#Neuromyelitis optica spectrum disease （NMOSD） is an inflammatory demyelinating disease of the central nervous system that preferentially affects the optic nerves and spinal cord， characterized by the presence of aquaporin-4 autoantibodies. NMOSD can result in a variety of forms of dyskinesia， including secondary paroxysmal dyskinesia （sPxD）， but sPxD usually occurs during the recovery period. Cases with PxD as the initial presentation have rarely been reported. We present a case of NMOSD starting as PxD， which lasted for nearly a month before the onset of limb weakness and other symptoms. A correct understanding of the relationship between PxD and NMOSD will contribute to the early diagnosis and treatment of the disease.

Clinical features of facial myokymia and its treatment with botulinum toxin A / 中风与神经疾病杂志

@#Objective To investigate the clinical features of facial myokymia (FM),assess the therapeutic effect of botulinum toxin A for this condition,and offer clinical guidance for the treatment of this rare disease. Methods A retrospective analysis was performed on the clinical data of 17 patients who visited the Dyskinesia Outpatient Clinic of the Department of Neurology in Peking Union Medical College Hospital and were diagnosed with FM or facial peristalsis from March 2018 to March 2023,and the patients were followed up for the therapeutic effect of botulinum toxin A. Results Among the 17 patients with FM,12 were female and 5 were male;the mean age of onset was (31.4±9.3) years,and the duration of disease ranged from 1.5 months to 22 years. Unilateral onset was seen in all the cases;the onset in 3 cases was associated with trauma or extreme fatigue,while the cause was unclear in the remaining cases. The initial symptoms affected the lower eyelid,temporal muscle,and masseter muscle;symptoms progressed to the muscles on the same side of the face in 6 cases and involved the lower eyelid on the opposite side in 1 case;6 cases had concomitant pain;9 cases experienced functional impairment;12 cases had worsening symptoms due to coldness,tension,excitement,or strong light stimulation;1 case had head MRI results which revealed abnormal signals in the right insula,possibly due to abnormal congenital development (gray matter heterotopia);1 case had MRI results which revealed multiple intracranial ischemic foci. Seven cases showed improved symptoms after the use of carbamazepine,oxcarbazepine,phenytoin sodium,baclofen,and nicergoline during the course of disease;4 cases showed no response;6 cases did not receive any medication. Ten cases received treatment with BTX-A injection,with a mean onset of action of (5.0±2.7) days,a mean time to best effect of (8.5±4.9) days,a mean improvement rate of (78.5±15.8)%,and a mean maintenance time of (7.1±2.9) months. Following BTX-A injection,all patients experienced alleviation of anxiety and pain. Five cases who received regular BTX-A injections had a mean maintenance time of (6.3±3.4) months and a mean improvement rate of (85±13.7)%. Conclusion FM is a rare disease,lacking effective treatment consensus. Botulinum toxin A injection is a safe and effective treatment and is considered a first-line treatment for various types of focal dystonia. Based on limited case reports in the literature and our clinical research experience,botulinum toxin A injection can be recommended for the symptomatic treatment of FM.

Association between neurotransmitters and dyskinesia in patients with vascular Parkinson syndrome and the predictive value of neurotransmitters / 中风与神经疾病杂志

@#Objective To investigate the association between neurotransmitters and dyskinesia in patients with vascular Parkinson syndrome(VPS) and the predictive value of neurotransmitters. Methods A retrospective analysis was performed for 60 patients with VPS who were hospitalized in Department of Neurology in our hospital from December 2020 to December 2022,and they were enrolled as observation group;60 patients with Parkinson disease who were hospitalized in our hospital during the same period of time were enrolled as control group;60 patients who underwent physical examination in the Physical Examination Center of our hospital during the same period of time were enrolled as healthy group. The simplified Fugl-Meyer Assessment(FMA) score was used to evaluate the motor function of patients. The above three groups were compared in terms of serum neurotransmitters[5-hydroxytryptamine(5-HT),dopamine(DA)] and FMA score;the VPS patients with different Hoehn-Yahr stages were compared in terms of serum neurotransmitters and FMA score;the VPS patients with different severities of dyskinesia were compared in terms of serum neurotransmitters. A Pearson correlation analysis was used to investigate the correlation of serum 5-HT and DA with FMA score;the receiver operating characteristic(ROC) curve was plotted and the area under the ROC curve(AUC) was calculated to analyze the efficacy of 5-HT and DA in predicting dyskinesia. Results The observation group had significantly lower serum 5-HT and DA and FMA score than the control group and the healthy group(P<0.05),and the control group had significantly lower serum 5-HT and DA and FMA score than the healthy group(P<0.05). The stage Ⅳ group had significantly lower serum 5-HT and DA and FMA score than the stage Ⅲ group,and the stage Ⅲ group had significantly lower serum 5-HT and DA and FMA score than the stage Ⅱ group(P<0.05). The severe dyskinesia group had significantly lower serum 5-HT and DA than the obvious dyskinesia group(P<0.05),the obvious dyskinesia group had significantly lower serum 5-HT and DA than the moderate dyskinesia group(P<0.05),and the moderate dyskinesia group had significantly lower serum 5-HT and DA than the mild dyskinesia group(P<0.05). Serum 5-HT and DA were positively correlated with FMA score(r=0.411 and 0.403,P<0.05). The combined measurement of 5-HT and DA had an AUC of 0.803(95% CI 0.713-0.938) in predicting dyskinesia,with higher sensitivity and specificity than the measurement of each index alone(sensitivity:92.72% vs 75.27%/72.87%,P<0.05;specificity:90.83% vs. 72.64%/70.09%,P<0.05). Conclusion Dyskinesia in VPS patients is closely associated with the abnormally low expression of serum 5-HT and DA,both of which are involved in dyskinesia. The combined measurement of serum 5-HT and DA can improve the predictive efficacy of dyskinesia and thus has a certain reference value.

ZHUANG Lixing's Experience in Differentiating and Treating Levodopa-Induced Dyskinesia in Parkinson's Disease / 中医杂志

This paper summarized Professor ZHUANG Lixing's clinical experience in differentiating and treating levodopa-induced dyskinesia （LID） in Parkinson's disease. It is believed that the fundamental pathogenesis of LID lies in the disharmony or malnourishment of tendons and vessels. Based on the clinical manifestations， peak-dose LID is differentiated into two syndromes： syndrome of hyperactive liver yang causing wind and syndrome of deficiency of both liver and kidney. For the syndrome of hyperactive liver yang causing wind， the treatment focuses on calming the liver to stop the wind， and relaxing the tendons to stop tremors. The main prescription used is Zhengan Xifeng Decoction （镇肝熄风汤） with the addition of Shijueming （石决明） and Zhenzhumu （珍珠母）. For the syndrome of deficiency of both liver and kidney， the treatment focuses on nourishing the liver and kidneys， and replenishing yin to stop the wind. The main prescription used is Dabuyin Pills （大补阴丸） with modification. LID in the acoustic phase is differentiated into syndrome of phlegm-damp blocking middle jiao and syndrome of deficiency of both qi and yin. For the syndrome of phlegm-damp blocking middle jiao， the treatment focuses on dissipating phlegm and eliminating dampness， and nurturing tendons and vessels. Wendan Decoction （温胆汤） or Erchen Decoction （二陈汤） with modification is used. For the syndrome of deficiency of both qi and yin， the treatment focuses on replenishing qi and nourishing blood， and nurturing tendons and vessels. The main prescriptions used are Buzhong Yiqi Decoction （补中益气汤） or Bazhen Decoction （八珍汤） or Shenling Baizhu Powder （参苓白术散） with modification. Biphasic LID is differentiated as the Shaoyang pivot disadvantageousness， and the treatment focuses on harmonizing Shaoyang and regulating the pivot. The main prescription used is Xiaochaihu Decoction （小柴胡汤） with modification.

ZHUANG Li-xing's experience in treatment of dyskinesia of Parkinson's disease with acupuncture at triple-acupoint prescription / 中国针灸

The paper introduces professor ZHUANG Li-xing's clinical experience in treatment of dyskinesia of Parkinson's disease with acupuncture at triple-acupoint prescription. In pathogenesis, dyskinesia of Parkinson's disease refers to yang deficiency and disturbing wind. In treatment, acupuncture focuses on warming yang, promoting the circulation of the governor vessel, regulating the spirit and stopping trembling; and Baihui (GV 20), Suliao (GV 25) and Dingchanxue (Extra) are selected to be "trembling relief needling". In combination with Jin's three needling, named "three-trembling needling" "three-governor-vessel needling" and "three-spasm needling", the triple-acupoint prescription is composed. To ensure the favorable therapeutic effect, this prescription is modified according to the symptoms and the specific techniques of acupuncture are combined such as conducting qi, harmonizing yin and yang, and manipulating gently for reinforcing and reducing.

The Dynamics of Dopamine D2 Receptor-Expressing Striatal Neurons and the Downstream Circuit Underlying L-Dopa-Induced Dyskinesia in Rats / 神经科学通报·英文版

L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D2 receptor (D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D2R+ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D2R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D2-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D2R+ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D2R+ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D2R+ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D2R+ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.

Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice / 医学前沿

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients / 医学前沿

Primary ciliary dyskinesia (PCD) is a highly heterogeneous recessive inherited disorder. FAP54, the homolog of CFAP54 in Chlamydomonas reinhardtii, was previously demonstrated as the C1d projection of the central microtubule apparatus of flagella. A Cfap54 knockout mouse model was then reported to have PCD-relevant phenotypes. Through whole-exome sequencing, compound heterozygous variants c.2649_2657delinC (p. E883Dfs*47) and c.7312_7313insCGCAGGCTGAATTCTTGG (p. T2438delinsTQAEFLA) in a new suspected PCD-relevant gene, CFAP54, were identified in an individual with PCD. Two missense variants, c.4112A>C (p. E1371A) and c.6559C>T (p. P2187S), in CFAP54 were detected in another unrelated patient. In this study, a minigene assay was conducted on the frameshift mutation showing a reduction in mRNA expression. In addition, a CFAP54 in-frame variant knock-in mouse model was established, which recapitulated the typical symptoms of PCD, including hydrocephalus, infertility, and mucus accumulation in nasal sinuses. Correspondingly, two missense variants were deleterious, with a dramatic reduction in mRNA abundance from bronchial tissue and sperm. The identification of PCD-causing variants of CFAP54 in two unrelated patients with PCD for the first time provides strong supportive evidence that CFAP54 is a new PCD-causing gene. This study further helps expand the disease-associated gene spectrum and improve genetic testing for PCD diagnosis in the future.

Clinical phenotypes of primary ciliary dyskinesia / 中南大学学报(医学版)

Primary ciliary dyskinesia (PCD) is a hereditary disease characterized by airway mucociliary clearance dysfunction. The estimated prevalence of PCD is 1꞉10 000 to 1꞉20 000. The main respiratory manifestations in children are cough, expectoration, chronic rhinitis, sinusitis, and chronic otitis media, while the most common symptoms in adults are chronic sinusitis, bronchiectasis, and infertility. About 50% of patients with certain PCD-related gene variants are combined with situs inversus, and the incidence of congenital heart disease is also high. The pathogenesis behind PCD is that gene variants cause structural or functional disorders of respiratory cilia and motile cilia of other organs, leading to a series of heterogeneous clinical manifestations, which makes it difficult to identify and diagnose PCD. Combining different disease screening tools and understanding the relationship between genotypes and phenotypes may facilitate early diagnosis and treatment for PCD.

Advance in role of cilia in the pathogenesis of congenital heart disease / 国际儿科学杂志

Congenital heart disease(CHD)is one of the most common genetic diseases, mainly refers to the abnormal cardiovascular development caused by various abnormal factors during fetal development.Studies have found that the normal development of cardiovascular functional structure requires accurate positioning of the left-right asymmetry.As an essential link in body material metabolism and signal-transducing mechanism, cilia may participate in the pathogenesis of CHD by affecting the distribution of the left-right asymmetry of human organs and tissues during embryonic development.Therefore, a thorough understanding of the role, molecular mechanism, and related regulatory genes of cilia in CHD can provide accurate diagnosis and treatment for clinical work to obtain a better prognosis.Here we review the effects of cilia on the positioning of the left-right asymmetry during embryo development and its role in the pathogenesis of CHD.