Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.     

Characteristics of infantile convulsions and choreoathetosis syndrome caused by PRRT2 mutation

Importance:Infantile convulsions and choreoathetosis(ICCA)is a rare neurological disorder.Many affected patients are either misdiagnosed or prescribed multiple antiepileptic drugs.Objective:To explore therapeutic drug treatments and dosages for ICCA in children.Methods:Detailed clinical features(e.g.,past medical history and family history),genetic features,and treatment outcomes were collected from the records of six patients with ICCA.Results:Mean age at paroxysmal kinesigenic dyskinesia(PKD)onset was 8 years 8 months(range,3-12 years);the clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia.All patients had infantile convulsions at less than 1 year of age,and the mean onset age was 5.5 months(range,4-7 months).Two patients had a family history of ICCA,PKD,or benign familial infantile epilepsy.Whole exome sequencing identified the c.649-650insC mutation in PRRT2 in six patients;three mutations were inherited and three were de novo.All patients were prescribed low-dose carbamazepine and showed dramatic improvement with the complete disappearance of dyskinetic episodes after 3 days.They attended follow-up for 5-17 months and were attack-free until the final follow-up.Interpretation:PRRT2 mutations are the primary cause of ICCA.Lowdose carbamazepine monotherapy is effective and well-tolerated in children.     

传统抗精神病药物所致迟发性运动障碍的药理遗传学初步研究

目的：进一步探讨多巴胺D2、D3受体（dopamine D2,D3 receptor,DRD2,DRD3)功能基因多态性与迟发性运动障碍(tardive dyskinesia,TD）的相关性及各候选基因，同时包括五羟色胺2C受体（5－hydroxytryptamine 2C receptor,HTR2C）和锰超氧化物歧化酶（manganese superoxide dismutase,MnSOD）基因的相互作用对TD发生的影响。方法：使用异常不自主运动量表（abnormal involuntary movement scale,AIMS)评定精神分裂症（schizophrenia,CSH)患者有无TD及其严重程度，并采用简明精神病评定量表评定患者精神症状；应用聚合酶链反应－限制性片段长度多态性技术分析TD组和非TD组各候选基因等位基因和（或）基因型分布频率及其结合分布频率，并分析对AIMS总分值的影响。结果：各候选基因在SCH患者组以及TD和非TD组基因型分布均符合Hardy-Weinberg平衡定律；TD组HTR2C基因－697C（突变型）等位基因频率高于非TD组，差异有显著性（P＜0．05）；DRD2基因Taq I A1/A2、DRD3基因Ser9Gly和MnSOD基因Ala-9Val等位基因频率和基因型分布在TD组与非TD组之间差异均无显著性（P＞0．05）；仅DRD3突变型（Gly）和MnSOD野生型（Val）结合分布频率高于其它结合型，差异有显著性（P＜0．05）；但上述各候选基因不同等位基因和（或）基因型亚组间的临床学资料和AIMS总分值（TD值）差异均无显著性（P＞0．05）。结论：HTR2C基因启动区－697G→C单碱基置换可能是中国汉族男性SCH患者TD发生的易感因素；而SCH患者若同时携带DRD3基因9Gly突变型和MnSOD基因－9Val野生型等位基因可能增加了TD的易感性。     

Isomerism of the right atrial appendages: clinical,anatomical, and microscopic study of a long-surviving case with asplenia and ciliary abnormalities

This study describes a case of isomerism of the right atrial appendages (bilateral morphologically right atrial appendages associated with complex congenital cardiac lesions) with ciliary abnormalities. Detailed investigation included gross anatomic dissection, review of the clinical history, and light, confocal, and electron microscopy. Clinically, this 40-year-old, long-surviving male patient had relatively good health until 4 years before death, which was due to cardiac failure. Surgical intervention consisted only of a Blalock-Taussig shunt (anastomosis of the right subclavian artery to the right pulmonary artery) at 6 years of age. Despite the presence of complex cardiac malformations and asplenia, his longevity may be attributed to the connection of the pulmonary veins to the atrium without pulmonary venous obstruction, pulmonary valvar stenosis rather than atresia, no significant atrioventricular valve regurgitation, and no serious infections during his life. Microscopic examination of bronchial epithelium revealed a narrow, disorganized epithelium with abundant goblet cells and short, angulated cilia with a random orientation and possibly an abnormal central microtubule doublet. These abnormalities were not present in controls, and have been noted in primary ciliary dyskinesia (PCD) or Kartagener's syndrome. Because this syndrome has classically been thought to cause random lateralization resulting in a mirror-imaged arrangement of the organs, the occurrence of truly isomeric patterns is not widely recognized. Whereas polysplenia and left bronchial isomerism have been reported to occur in immotile cilia syndrome, this is the first report to present detailed postmortem anatomic evidence of isomerism of the right atrial appendages, right bronchial isomerism, and asplenia in association with microscopy suggesting ciliary abnormalities.     

An Overview of Curcumin in Neurological Disorders

Curcumin, the principal curcuminoid found in spice turmeric, has recently been studied for its active role in the treatment of various central nervous system disorders. Curcumin demonstrates neuroprotective action in Alzheimer''s disease, tardive dyskinesia, major depression, epilepsy, and other related neurodegenerative and neuropsychiatric disorders. The mechanism of its neuroprotective action is not completely understood. However, it has been hypothesized to act majorly through its anti-inflammatory and antioxidant properties. Also, it is a potent inhibitor of reactive astrocyte expression and thus prevents cell death. Curcumin also modulates various neurotransmitter levels in the brain. The present review attempts to discuss some of the potential protective role of curcumin in animal models of major depression, tardive dyskinesia and diabetic neuropathy. These studies call for well planned clinical studies on curcumin for its potential use in neurological disorders.     

An Update on the Phenotype,Genotype and Neurobiology of ADCY5-Related Disease

Adenylyl cyclase 5 (ADCY5)-related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5-related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, developmental delay, and intellectual disability may be present. The causative gene encodes adenylyl cyclase, the enzyme responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3′,5′-monophosphate (cAMP). cAMP is a second messenger that exerts a wide variety of effects via several intracellular signaling pathways. ADCY5 is the most commonly expressed isoform of adenylyl cyclase in medium spiny neurons (MSNs) of the striatum, and it integrates and controls dopaminergic signaling. Through cAMP pathway, ADCY5 is a key regulator of the cortical and thalamic signaling that control initiation of voluntary movements and prevention of involuntary movements. Gain-of-function mutations in ADCY5 have been recently linked to a rare genetic disorder called ADCY5-related dyskinesia, where dysregulation of the cAMP pathway leads to reduced inhibitory activity and involuntary hyperkinetic movements. Here, we present an update on the neurobiology of ADCY5, together with a detailed overview of the reported clinical phenotypes and genotypes. Although a range of therapeutic approaches has been trialed, there are currently no disease-modifying treatments. Improved in vitro and in vivo laboratory models will no doubt increase our understanding of the pathogenesis of this rare genetic movement disorder, which will improve diagnosis, and also facilitate the development of precision medicine approaches for this, and other forms of hyperkinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society     

Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia

Background

Current models of levodopa (L -dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L -dopa. However, patients with LID receive combination therapies that often include dopamine agonists.

Objective

Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.

Methods

Different regimens of L -dopa monotreatment and L -dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L -dopa monotreatment or L -dopa combined with ropinirole.

Results

We defined chronic regimens of L -dopa monotreatment and L -dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L -dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood–brain barrier hyperpermeability was markedly reduced after L -dopa-ropinirole cotreatment compared with L -dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L -dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L -dopa-ropinirole cotreated animals.

Conclusions

Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa-Induced Dyskinesia

Background

Degeneration of the substantia nigra (SN) may contribute to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear.

Objective

To further understand the pathogenesis of patients with PD with LID (PD-LID), we explored the structural and functional characteristics of SN in PD-LID using multimodal magnetic resonance imaging (MRI).

Methods

Twenty-nine patients with PD-LID, 37 patients with PD without LID (PD-nLID), and 28 healthy control subjects underwent T1-weighted MRI, quantitative susceptibility mapping, neuromelanin-sensitive MRI, multishell diffusion MRI, and resting-state functional MRI. Different measures characterizing the SN were obtained using a region of interest–based approach.

Results

Compared with patients with PD-nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast-to-noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD-LID. The intracellular volume fraction of the posterior SN in PD-LID was significantly higher compared with PD-nLID (P = 0.037). Resting-state fMRI indicated that PD-LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD-nLID (P = 0.031), and the functional connectivity changes in PD-LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042).

Conclusions

Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD-LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD-LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

迟发性运动障碍患者超氧化物歧化酶、ATP酶活性改变

目的探讨抗精神病药所致迟发性运动障碍（TD）患者体内自由基代谢状况与TD的关系。方法测定36例TD、36例非TD慢性精神分裂症患者及40名正常人血浆超氧化物歧化酶（SOD）、红细胞ATP酶及丙二醛（MDA）浓度,并进行三组间方差分析;生化指标与异常不自主运动量表（AIMS）总分间的相关性采用直线相关分析。结果对照组血清SOD活性、ATP酶活性均高于TD组及非TD组,对照组MDA浓度低于TD组及非TD组,差异均有统计学意义（均P〈0.05）,TD患者血清SOD活性、ATP酶活性、MDA浓度与非TD组间的差异均有统计学意义（均P〈0.05）。AIMS总分与SOD、ATP酶、MDA均有显著相关（r=-0.225,r=0.225,均P〈0.05）。结论TD患者的血清抗氧化酶、ATP酶活性、脂质过氧化物异常,自由基代谢障碍可能与TD关系密切。