先天性颅神经异常支配性疾病的分子遗传学新发现

先天性颅神经异常支配性疾病(congenital cranial dysinnervation disorders,CCDDs)是一组先天性、非进行性的眼球运动障碍,是由一条或多条颅神经发育异常或完全缺失,从而引起对肌肉的异常神经支配,伴或不伴全身系统异常.目前已发现的CCDDs致病基因包括SALL4、CHN1、HOXA1 、KIF21A、PHOX2A、TUBB3、TUBB2B、ROBO3及HOXB1等.虽然对CCDDs的认识不断深入,但同时发现根据CCDDs的临床表型不能完全预测基因型分类,而根据其基因型也无法完全预测临床表型.本文对不同类型CCDDs的临床表现及分子遗传学研究新发现进行了综述.     

先天性脑神经异常支配眼病的分子遗传学与神经科学研究进展

先天性脑神经异常支配眼病(CCDDs)为一组先天性、非进行性一条或多条脑神经发育异常或缺失,从而导致的原发或继发脑神经异常支配眼外肌的斜视综合征,可散发或家族遗传,可伴有全身系统异常。近年来随着神经病理学、神经影像学、遗传学的研究进展,不仅明确了CCDDs的病因是神经源性的眼球运动障碍,也发现了CCDDs的致病基因,包括SALL4、HOXA1、KIF21A、PHOX2A、TUBB3及HOXB1等。针对基因突变影响大脑神经发育从而进一步导致先天性脑神经支配异常性病变发生这一问题,文章回顾了近年国内外相关文献,就已知的CCDDs的分子遗传学和神经科学研究进展作一综述,以期为CCDDs的临床和基础研究提供参考。     

先天性眼外肌纤维化综合征研究进展

先天性眼外肌纤维化综合征（CFEOM）是临床少见的先天性非共同性斜视,临床表现为非进展性限制性眼肌麻痹,可伴有上睑下垂,以往被认为是原发性眼外肌纤维化所致,最近神经病理学、神经影像学和分子遗传学的研究显示CFEOM的病因为神经源性,为一种颅神经异常支配性疾病。分别对不同类型的CFEOM的神经病理学、神经影像学和分子遗传学研究进展进行综述。     

MRI多颅神经异常与斜视诊断

目的 运用MRI评价多条颅神经的形态学异常改变,分析其对斜视病因诊断的价值。设计 回顾性病例系列。研究对象 55例斜视患者。方法 患者行MRI检查,采用3D FIESTA序列,分析脑池段颅神经的MRI表现。主要指标 脑池段颅神经的发育情况。 结果 观察所有55例患者多对颅神经脑池段,发生颅神经异常的MRI表现包括：21例眼外肌纤维化综合征者中,脑池段动眼神经2条未显示,38条动眼神经纤细;16例双侧眼球后退综合征、15例眼外肌纤维化综合征和3例眼-面麻痹综合征中,脑池段外展神经41条未显示,19条纤细,2条脑池段外展神经走行区纤细索条影,1条起始位于脑干中部,1条走行区只见不规则形索条影。3例眼-面麻痹综合征和6例眼球后退综合征患者中,6条面神经、6条听神经、3条舌下神经脑池段未显示。结论 MRI能够清晰显示颅神经脑池段的异常改变,为神经源性斜视的诊断提供客观依据。（眼科,2013, 22： 299-303）     

异常神经支配造成眼与其他肌肉的异常运动

异常神经支配是指眼球运动神经或其各级分支损伤后,经过约半年时间恢复,由中枢端发出的再生神经纤维沿原有Schwan鞘下行,部分或全部误人其他Schwan鞘,或者沿包绕鞘的结缔组织延伸,下行至非相关肌肉,造成异常神经联合,当神经核向相关肌肉发出冲动时引起或伴随引起非相关肌肉收缩。     

特发性睑痉挛

痉挛可局限于眼轮匝肌局部或进而波及面神经支配的其它区域,如下面部和颈部肌肉。当下面部间歇性运动伴随眼睑痉挛,这种疾病称为自发性口面肌张力障碍或Meige综合征。倘波及下颌更大范围,则称为口下颌肌张力障碍或Breughel综合征。倘不随意肌收缩扩展到其它颅神经支配的肌肉(最常见的是第Ⅴ、Ⅸ、Ⅹ、Ⅺ和Ⅻ颅神经),则称为节段性颅神经肌张力障碍。看来好像这些肌张力障碍是表     

先天性颅神经异常支配综合征2例

我们报告两例在我们医疗中心治疗的先天性颅神经异常支配综合征(congenital cranial dysinnervation disorders,CCDD)。其中1例是7岁的中国女孩,无内科疾病,其父母注意到从婴孩时起患者习惯性向一侧倾斜头部,并伴有"眼懒惰"。双眼视力为斯内伦视力表6/6,头向右倾斜。水平或垂直注视时双眼外展受限,试图内转向下看时伴眼球内陷。另1例是10岁的马来西亚男孩,无内科疾病,其父母注意到自出生该男孩就"眼球运动差"。双眼视力为6/6,脸向左转并且双眼上睑下垂。在所有注视方位上眼球运动均受限,强制转向试验阳性。两个病例初步诊断均为先天性眼外肌纤维化(congenital fibrosis of extraocularmuscle,CFEOM),后来第一个病例的诊断修订为双侧Duane综合征。虽然Duane综合征和CFEOM都包括在CCDD内,但两种疾病病理不同。CCDD的表现非常多变,然而,治疗往往是有限的,且手术结果不可预测。因此,仍然需要进行大量研究以更深入了解CCDD,改善其治疗和结局。     

双眼不同类型Duane眼球后退综合征1例

0引言Duane眼球后退综合征(duange retraction syndrome,DRS)是一种眼球运动异常,多为先天性,占斜视患者的1%~4%[1,2]。其病因尚不明确,可能与结构异常和神经支配异常有关。其主要特点为眼球内转时患侧眼睑裂缩小,眼球后退,伴外转、内转受限或内外转均受限,或眼部及全身先天性发育异常,多为单眼受累。我院诊治1例双眼不同类型Duane眼球后退综合征患者,现报告如下。1临床资料患者,女,21岁,因发现右眼外斜,左眼不能外转20余年于2009-01来我院就诊。患者自小被发现左眼睑裂较右眼偏小,左眼不能外转;视物时头部向右偏斜。未诉有复视症状,否认眼外伤、头部外伤史及家     

关于Homer综合征瞳孔试验的质疑

Homer综合征是由于支配瞳孔运动的交感神经麻痹导致的传出性瞳孔运动障碍。眼交感神经通路三级神经元的任何一级受到损伤均可引起Homer综合征，典型表现为瞳孔缩小、瞳孔不等、瞳孔散大迟滞、眼睑下垂、眼球内陷、颜面无汗等，先天性者还伴有虹膜异色。     

神经嵴发育异常相关眼病

神经嵴是一个动态的胚胎干细胞群体，在眼部发育中起着关键作用。神经嵴与周围的神经外胚层、表面外胚层和中胚层相互作用，发育成眼球及其附属器的多种组织结构，包括角膜基质及内皮、小梁网、虹膜基质、睫状肌、玻璃体和脉络膜血管、Müller细胞等。眼部神经嵴细胞迁移和发育异常会引起一系列复杂的眼部疾病，包括影响眼前段的疾病，如Axenfeld-Rieger综合征、Peters异常、无虹膜、原发性先天性青光眼和指甲-髌骨综合征，以及影响眼后段的缺陷性疾病，如CHARGE综合征和鳃-眼-面综合征，此外还有一些罕见的神经嵴疾病的眼部异常，如Waardenburg综合征、Treacher-Collins综合征和Char综合征等。在这里我们将神经嵴细胞发育异常导致的眼部相关疾病做一综述，探讨与神经嵴迁移和发育相关的基因，以及这些基因的突变和缺陷如何导致眼部疾病。     

Congenital cranial dysinnervation disorders

The European Neuromuscular Centre (ENMC) derived the term Congenital Cranial Dysinnervation Disorders in 2002 at an international workshop for a group of congenital neuromuscular diseases. CCDDs are congenital, non-progressive ophthalmoplegia with restriction of globe movement in one or more fields of gaze. This group of sporadic and familial strabismus syndromes was initially referred to as the 'congenital fibrosis syndromes' because it was assumed that the primary pathologic process starts in the muscles of eye motility. Over the last few decades, evidence has accumulated to support that the primary pathologic process of these disorders is neuropathic rather than myopathic. This is believed that for normal development of extra ocular muscles and for preservation of muscle fiber anatomy, normal intra-uterine development of the innervation to these muscles is essential. Congenital dysinnervation to these EOMs can lead to abnormal muscle structure depending upon the stage and the extent of such innervational defects. Over last few years new genes responsible for CCDD have been identified, permitting a better understanding of associated phenotypes, which can further lead to better classification of these disorders. Introduction of high-resolution MRI has led to detailed study of cranial nerves courses and muscles supplied by them. Thus, due to better understanding of pathophysiology and genetics of CCDDs, various treatment modalities can be developed to ensure good ocular alignment and better quality of life for patients suffering from the same.     

Cranial nerve palsies in childhood

We review ocular motor cranial nerve palsies in childhood and highlight many of the features that differentiate these from their occurrence in adulthood. The clinical characteristics of cranial nerve palsies in childhood are affected by the child''s impressive ability to repair and regenerate after injury. Thus, aberrant regeneration is very common after congenital III palsy; Duane syndrome, the result of early repair after congenital VI palsy, is invariably associated with retraction of the globe in adduction related to the innervation of the lateral rectus by the III nerve causing co-contraction in adduction. Clinical features that may be of concern in adulthood may not be relevant in childhood; whereas the presence of mydriasis in III palsy suggests a compressive aetiology in adults, this is not the case in children. However, the frequency of associated CNS abnormalities in III palsy and the risk of tumour in VI palsy can be indications for early neuroimaging depending on presenting features elicited through a careful history and clinical examination. The latter should include the neighbouring cranial nerves. We discuss the impact of our evolving knowledge of congenital cranial dysinnervation syndromes on this field.     

CCDD Phenotype Associated with a Small Chromosome 2 Deletion

Abstract

Purpose: Some individuals are born with congenital limitation of ocular motility, often associated with ptosis and retraction of the globe. Many of these disorders are now known as the congenital cranial dysinnervation disorders (CCDDs). While several genes have been associated with CCDD phenotypes, there are still patients for whom the genetic basis has not been identified. Methods: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization (array CGH). Results: The patient was a four-year-old girl with mild dysmorphism; bilateral mild ptosis; substantial limitation of abduction OS with milder limitations of abduction OD, adduction OS, and vertical gaze OS; and retraction OS?>?OD on attempted adduction. No mutations were detected in the HOXA1, KIF21A, SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 8 Kb de novo deletion on chromosome 2 (2q24.3) that encompassed a portion of only one gene, the Xin Actin-binding Repeat containing 2 (Gene Symbol XIRP2; NM_001079810). This gene encodes a protein that is involved in muscle development and protecting actin filaments from depolymerization. It interacts functionally with 10 other proteins playing a similar role in muscle development. Conclusions: This patient’s chromosomal abnormality affected only one gene that currently seems involved only in muscle development. All other genes currently associated with the CCDDs affect neurologic development. Genetic information from this patient implies that genes involved in development and maintenance of extraocular muscles can cause congenital ocular motility disorders as well.     

Synergistic convergence and split pons in horizontal gaze palsy and progressive scoliosis in two sisters

Synergistic convergence is an ocular motor anomaly where on attempted abduction or on attempted horizontal gaze, both the eyes converge. It has been related to peripheral causes such as congenital fibrosis of extraocular muscles (CFEOM), congenital cranial dysinnervation syndrome, ocular misinnervation or rarely central causes like horizontal gaze palsy with progressive scoliosis, brain stem dysplasia. We hereby report the occurrence of synergistic convergence in two sisters. Both of them also had kyphoscoliosis. Magnetic resonance imaging (MRI) brain and spine in both the patients showed signs of brain stem dysplasia (split pons sign) differing in degree (younger sister had more marked changes).     

Angeborene Fehlinnervationssyndrome

Congenital cranial dysinnervation disorders (CCDDs) are responsible for 1–2% of infant strabismus cases. Insufficient innervation and misinnervation of aberrant nerve fibres lead to motility restrictions and synkinesis. We present the most common CCDDs and explain their pathogenesis and the resulting clinical features. Furthermore, we emphasize essential diagnostic steps and treatment aspects.     

Congenital cranial dysinnervation disorders

Congenital cranial dysinnervation disorders (CCDDs) are responsible for 1-2% of infant strabismus cases. Insufficient innervation and misinnervation of aberrant nerve fibres lead to motility restrictions and synkinesis. We present the most common CCDDs and explain their pathogenesis and the resulting clinical features. Furthermore, we emphasize essential diagnostic steps and treatment aspects.     

When straight eyes won't move: phenotypic overlap of genetically distinct ocular motility disturbances

Objective

To describe the phenotypic similarity in a series of patients with genetically distinct ocular motility disturbances involving straight eyes and different ocular motor pathology.

Design

Retrospective case series.

Participants

Clinical and genetic evaluation of 5 patients with straight eyes in the primary position and abnormalities of ocular motility.

Results

Patients with oculopharyngeal muscular dystrophy, congenital myasthenic syndrome, congenital fibrosis of the extraocular muscles type 3, Bosley-Salih-Alorainy syndrome, and horizontal gaze palsy and progressive scoliosis all had straight eyes in primary position and restricted ocular motility. History, ocular motility patterns, systemic features of individual syndromes, and genetic screening were important diagnostically.

Conclusions

A number of congenital and genetic ocular motility syndromes may result in substantial phenotypic overlap, particularly when eyes are straight in primary position and nonophthalmologic features are not apparent or not observed. The range of disorders that may fall into this category is discussed.     

Familial ptotic lid elevation during ipsilateral abduction

PURPOSE: To report and discuss the clinical findings of a 17-member family with 2 siblings who exhibit ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction. SUBJECTS AND METHODS: Sixteen members of the 17-member immediate family underwent ophthalmic examination. RESULTS: Two siblings exhibited ptosis and abnormal synkinetic lid elevation associated with ipsilateral abduction. One was bilaterally affected and the other had unilateral findings. A third sibling had isolated bilateral congenital ptosis. A fourth demonstrated classic Duane syndrome Type I in the right eye. Other family members did not have ophthalmic abnormalities. CONCLUSIONS: A unifying mechanism of congenital cranial dysinnervation may underlie these and similar phenotypes of oculomotor and/or abducens nerve abnormalities with or without abnormal synkinesis.