Mutations in GAS8, a Gene Encoding a Nexin‐Dynein Regulatory Complex Subunit,Cause Primary Ciliary Dyskinesia with Axonemal Disorganization

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease characterized by chronic respiratory infections of the upper and lower airways, hypofertility, and, in approximately half of the cases, situs inversus. This complex phenotype results from defects in motile cilia and sperm flagella. Among the numerous genes involved in PCD, very few—including CCDC39 and CCDC40—carry mutations that lead to a disorganization of ciliary axonemes with microtubule misalignment. Focusing on this particular phenotype, we identified bi‐allelic loss‐of‐function mutations in GAS8, a gene that encodes a subunit of the nexin‐dynein regulatory complex (N‐DRC) orthologous to DRC4 of the flagellated alga Chlamydomonas reinhardtii. Unlike the majority of PCD patients, individuals with GAS8 mutations have motile cilia, which, as documented by high‐speed videomicroscopy, display a subtle beating pattern defect characterized by slightly reduced bending amplitude. Immunofluorescence studies performed on patients’ respiratory cilia revealed that GAS8 is not required for the proper expression of CCDC39 and CCDC40. Rather, mutations in GAS8 affect the subcellular localization of another N‐DRC subunit called DRC3. Overall, this study, which identifies GAS8 as a PCD gene, unveils the key importance of the corresponding protein in N‐DRC integrity and in the proper alignment of axonemal microtubules in humans.     

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.     

曲安奈德不同给药方式的临床观察

目的评价曲安奈德经不同给药方式治疗人工晶状体植入术后迟发性虹膜睫状体炎、早期甲状腺相关眼病及婴幼儿眼睑血管瘤的疗效。方法曲安奈德半球周注射治疗人工晶状体植入术后迟发性虹膜睫状体炎60例(60眼),曲安奈德眶周注射治疗早期甲状腺相关眼病38例(46眼),曲安奈德瘤体内注射治疗婴幼儿眼睑血管瘤16例(16眼)。结果迟发性虹膜睫状体炎60眼中56眼治愈,有效率93.33%;早期甲状腺相关眼病46眼中42眼有效,有效率91.30%;婴幼儿眼睑血管瘤16眼中14眼有效,有效率87.50%。结论曲安奈德经不同的给药方式局部注射能迅速而有效地治愈迟发性虹膜睫状体炎,早期甲状腺相关眼病及婴幼儿眼睑血管瘤,是治疗上述疾病可行而有效的方法。     

Dyskinetic and dystonic cerebral palsy and birth

Two hundred and nineteen cases of the dyskinetic and dystonic forms of cerebral palsy which were seen in the course of three decades at a single clinic have been analysed. Fifty-seven patients had kernicterus. In the remaining 162, 71% of whom were born at term, birthweight was below the expected mean in two-thirds. There was no relationship between birth weight, or abnormal birth, or asphyxia, and the ultimate clinical severity of the children. We conclude that abnormal birth and asphyxia are not direct causes of the cerebral damage, but are expressions of a pre-existing condition resulting in susceptibility to the stress of birth, whether it is normal or abnormal.     

Effects of melatonin on orofacial movements in rats

RATIONALE: While reserpine-induced oral movements (OM), an animal model of tardive dyskinesia, are more persistent in old than in adult rats, old animals present spontaneous OM, which are phenomenologically similar to those presented by reserpine-treated adult rats. We postulate that these OM may be the result of oxidative stress induced by both age and reserpine treatment.OBJECTIVES: We intended to determine the preventative effects of exogenous melatonin (one of the most important endogenous antioxidants) as well as suppression of endogenous melatonin via continuous exposure to light on reserpine- or age-induced OM in rats.METHODS: Adult (4 months of age) male Wistar rats were repeatedly treated with saline or melatonin (5 mg/kg, IP) and saline or reserpine and kept under a 12-h light/dark cycle for quantification of reserpine-induced OM as well as oxidative stress (via quantification of lipid peroxidation). To verify the effects of endogenous melatonin suppression on reserpine-induced OM, adult rats were repeatedly treated with saline or reserpine and continuously exposed to light. To verify the effects of exogenous melatonin on age-induced OM older (20 months of age) rats were long-term treated with saline or melatonin and kept under a 12-h light/dark cycle.RESULTS: Melatonin attenuated both reserpine- and age-induced OM. Reserpine enhanced striatal lipid peroxidation, that was prevented by melatonin co-administration. Continuous exposure to light increased spontaneous as well as reserpine-induced OM, indicating that endogenous melatonin may be involved in this movement disorder.CONCLUSIONS: We suggested that melatonin attenuates both reserpine- and age-induced OM in rats.     

Memantine attenuates the increase in striatal preproenkephalin mRNA expression and development of haloperidol-induced persistent oral dyskinesias in rats

Tardive dyskinesia (TD) is a serious motor side effect of long-term neuroleptic treatment that may persist after drug withdrawal. Alterations in striatal enkephalinergic neurons due to excessive glutamatergic activity is a possible pathogenetic mechanism. We studied the effect of the NMDA antagonist memantine in a rat model of TD, in which vacuous chewing movements (VCM) were induced by 20 weeks of haloperidol administration. The striatal density of preproenkephalin mRNA was measured and the number of neurons estimated. Haloperidol induced persistent VCM that was associated with increased striatal expression of preproenkephalin mRNA. Memantine inhibited the development of haloperidol-induced persistent VCM and attenuated the increase in preproenkephalin mRNA expression. This suggests that glutamate-mediated up-regulation of striatal enkephalin plays a role in the development of haloperidol-induced persistent oral dyskinesias.