Roles of Collagen XXV and Its Putative Receptors PTPσ/δ in Intramuscular Motor Innervation and Congenital Cranial Dysinnervation Disorder.

Intramuscular motor innervation is an essential process in neuromuscular development. Recently, mutations in COL25A1, encoding CLAC-P/collagen XXV, have been linked to the development of a congenital cranial dysinnervation disorder (CCDD). Yet the molecular mechanisms of intramuscular innervation and the etiology of CCDD related to COL25A1 have remained elusive. Here, we report that muscle-derived collagen XXV is indispensable for intramuscular innervation. In developing skeletal muscles, Col25a1 expression is tightly regulated by muscle excitation. In vitro and cell-based assays reveal a direct interaction between collagen XXV and receptor protein tyrosine phosphatases (PTPs) σ and δ. Motor explant assays show that expression of collagen XXV in target cells attracts motor axons, but this is inhibited by exogenous PTPσ/δ. CCDD mutations attenuate motor axon attraction by reducing collagen XXV-PTPσ/δ interaction. Overall, our study identifies PTPσ/δ as putative receptors for collagen XXV, implicating collagen XXV and PTPσ/δ in intramuscular innervation and a developmental ocular motor disorder.

Outcome of inferior oblique disinsertion versus myectomy in the surgical treatment of unilateral congenital superior oblique palsy.

PURPOSE: To compare the outcome of inferior oblique disinsertion and myectomy in patients with unilateral congenital superior oblique palsy. METHODS: In this prospective study, consecutive patients with superior oblique palsy underwent either myectomy or disinsertion of the inferior oblique muscle. Success was defined as postoperative hypertropia of ≤5Δ in primary position and no hypotropia. In cases with preoperative hypertropia of ≤5Δ, success was defined as improved hypertropia and resolution of abnormal head position (AHP). RESULTS: A total of 62 patients were included: 34 underwent myectomy; 28, disinsertion. Preoperative primary position hypertropia was 15.8Δ ± 7.4Δ in the myectomy group and 14.5Δ ± 7.3Δ in the disinsertion (P = 0.756). AHP was present in 85.3% and 85.7% of patients, respectively (P = 1). Mean follow-up was in the myectomy group 7.5 ± 6.7 months and 6.9 ± 3.0 months in the disinsertion group (P = 0.637). Correction of hypertropia in primary position was more pronounced in the myectomy group (14.3Δ ± 7.4Δ vs 10.0Δ ± 5.4Δ; P = 0.013). Success was achieved in 91.2% of myectomy and 60.7% of disinsertion patients (P = 0.006). Persistence of AHP did not differ between groups (8.8% in the myectomy group vs 7.1% in the disinsertion group [P = 1]). Comparison of patients with preoperative hypertropia of ≤15Δ revealed nonsignificant differences between groups in rate of success (100% vs 81.3% [P = 0.226]) and correction of primary position hypertropia (8.8Δ ± 3.2Δ vs 7.6Δ ± 4.0Δ [P = 0.336]). CONCLUSIONS: In our study cohort, inferior oblique myectomy had a greater effect in reduction of primary position hypertropia; however, disinsertion proved as effective as myectomy if preoperative vertical deviation was ≤15Δ. Both procedures effectively corrected AHP and demonstrated self-adjustment.

Trochlear-oculomotor synkinesis: another congenital cranial dysinnervation disorder? / Sincinesia troclear-oculomotora: outro distúrbio congênito de denervação craniana?

ABSTRACT This report documents an unusual phenomenon. A 6-year-old girl with trochlear-oculomotor synkinesis presented with superior oblique and palpebral levator co-contraction. The literature was reviewed and the possibility of classifying this entity as a congenital cranial dysinnervation disorder was speculated.

RESUMO Este relato descreve um fenômeno incomum. Uma menina de 6 anos com sincinesia troclear-oculomotora apresentou co-contração do oblíquo superior e do levantador da pálpebra. A literatura foi revisada e especulou-se a possibilidade de classificar essa desordem como um distúrbio da congenital cranial dysinnervation disorder.

Trochlear-oculomotor synkinesis: another congenital cranial dysinnervation disorder?

This report documents an unusual phenomenon. A 6-year-old girl with trochlear-oculomotor synkinesis presented with superior oblique and palpebral levator co-contraction. The literature was reviewed and the possibility of classifying this entity as a congenital cranial dysinnervation disorder was speculated.

Long-term follow-up of torsional augmentation surgery in a case of congenital ocular tilt reaction with head tilt.

Torsional augmentation surgery was used to correct the anomalous head position (AHP) in a child with congenital ocular tilt reaction (OTR). The underlying neuropathology was hypoplasia involving the right hemicerebellum and contralateral brainstem. Postoperatively there was an acceptable and variable resolution of head tilt sustained over a 25-year follow-up period. These findings suggest that early torsional augmentation surgery can effectively correct stable OTR head tilt in congenital cases over the long term.

Atypical Presentation of Giant Aneurysm in Pediatric Patient with Duane Syndrome.

BACKGROUND: Duane syndrome is a congenital eye movement disorder characterized by congenital malformation of the abducens nucleus. Thrombogenic conditions during development may lead to vascular anomalies in Duane syndrome; however, the presence of a giant aneurysm in this patient population is a rarely documented phenomenon. CASE DESCRIPTION: We reported a case of a large cerebral aneurysm in a pediatric patient with Duane syndrome and performed a review of the literature to identify other potential cases and associations. The pathophysiologic hallmarks of Duane syndrome that lead to alterations in the fetal cerebral vasculature and that may form the basis for a potential mechanism for aneurysm formation were reviewed in this study. The patient was an 11-year-old female with Duane syndrome who presented with seizures. Computed tomography and magnetic resonance imaging demonstrated a large, heterogeneously enhancing right temporal mass. Intraoperatively, the mass was revealed to be a partially thrombosed giant middle cerebral artery aneurysm. After surgery, the patient had an uneventful postoperative course without residual aneurysm presented on postoperative angiogram. No clinical or radiographic appearance of recurrent aneurysm was evident at her 6-month follow-up. CONCLUSIONS: The pathophysiology of vascular anomalies with Duane syndrome may be related to thrombogenic conditions during development leading to alterations in cerebral fetal vasculature. Strong consideration for vascular anomaly should be given when evaluating cerebral masses in patients with Duane syndrome.

Horizontal Deviations in Congenital Brown Syndrome.

PURPOSE: To report the incidence of horizontal deviations requiring surgical correction in patients with congenital Brown syndrome. METHODS: In a retrospective study, the medical records of all children who underwent a surgical correction of congenital Brown syndrome at Schneider Children's Medical Center of Israel from 1998 to 2016 were reviewed, analyzing the presence of preoperative primary position horizontal misalignment. RESULTS: Overall, 19 eyes (8 right and 11 left eyes) of 16 patients (7 males, 9 females; mean age: 4.2 ± 2.6 years) were included in this study. Fourteen patients (88%) had surgery for correction of a compensatory head position, including 8 patients (50%) with a head tilt and 6 patients (38%) with a chin-up position, and 2 patients had surgery for primary position hypotropia. All of them underwent a weakening procedure of the superior oblique tendon, by either Z-tenectomy (81%, n = 13) or suture elongation of the superior oblique tendon (19%, n = 3). Fifty-six percent of patients (n = 9) had primary position horizontal deviation before surgery, including 50% (n = 8) exodeviations, ranging from exophoria of 4 prism diopters (PD) to exotropia of 30 PD, and one esotropia of 14 PD. Fifty percent of patients (n = 8) had surgery to correct the horizontal deviation by a recession of either one (31%, n = 5) or two (19%, n = 3) muscles. Mean preoperative horizontal deviation (9.3 ± 3.4 PD) decreased significantly following surgery (1.7 ± 1 PD, P = .001) (paired t test). CONCLUSIONS: Significant horizontal misalignment is often present in patients with congenital Brown syndrome and its correction should be considered at the time of surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(2):113-116.].

Congenital Cranial Dysinnervation Disorders: A Literature Review.

Congenital cranial dysinnervation disorders (CCDD) is a new term describing a collection of non-progressive neurogenic syndromes. Initially referred to as congenital fibrosis syndrome, it was thought that the primary problem was extraocular muscular maldevelopment. Recent advancements in genetics and neuro-radiology have now determined the initial observation of fibrotic muscles is secondary to a primary lack of innervation from deficient, absent, or misguided cranial nerves. This presentation provides an overview of the known genes and phenotypes currently recognized within the CCDD domain. It will also highlight areas of current research being done in the area of cranial nerve development. Increased knowledge and awareness of these disorders has resulted in more research being conducted. These studies have provided a more complete understanding of efferent motor system development and are leading to improved treatment strategies for patients.

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.

Unidirectional abnormal eye movement without gaze nystagmus - Report of a case.

We report here a case with unidirectional abnormalities of smooth eye movements without gaze nystagmus. Abnormalities of eye movements were confined to unidirectional (leftward) horizontal pursuit and slow phase of OKN; however, horizontal VOR (slow phase of caloric nystagmus) and saccade were normal, and vertical eye movements were also normal. No lesions were detected in the central nervous system, and any history of drug intake was denied. Although the cause of the unidirectional abnormality in eye movement of this case is still not clear, a congenital origin seems to be the most probable.

Congenital and Genetic Ocular Motility Disorders: Update and Considerations.

Concepts regarding certain forms of congenital eye movement disorders have recently changed, due in large part to new genetic evidence identifying causative genes and their role in the development of extraocular muscle innervation. This group is now referred to as the Congenital Cranial Dysinnervation Disorders (CCDDs). Careful assessment of phenotypic features that include both ophthalmological and non-ophthalmological features in genetically defined individuals has led to the development of a more robust classification system. Correlating phenotypes with new genetically defined syndromes has improved the ability of the clinician/researcher to better determine a definitive diagnosis in patients with complex ocular motility disorders. Nevertheless, more work is still required.

[Brown syndrome: clinical and radiological correlation].

OBJECTIVE: Brown syndrome is characterized by limitation of elevation in adduction, with complex mechanisms involving muscle, tendon, and trochlea. Here, we investigated mechanisms of Brown syndrome by magnetic resonance (MR) imaging. METHODS: It was a retrospective case series study. Fourteen patients with unilateral Brown syndrome between 3 and 54 years of age (10 cases of congenital and 4 cases with acquired disease) were included in the study. All patients underwent complete ophthalmic and orthoptic evaluation. Imaging of the ocular motor nerves at the brainstem was performed on 3D-FIESTA sequence, the orbits were imaged with FSE T1, T2WI using surface coils. RESULTS: Nine of 10 with congenital Brown syndrome demonstrated hypoplasia of the superior oblique (SO) of the affected side. Abnormal low signal intensity in the trochlea area was found in one patient. Three of 4 acquired patients had a history of trauma and were demonstrated fracture of the trochlea, extensive scarring, and superior orbital fracture. One acquired case was demonstrated scarring of anterior part of the SO and hypoplasia of the posterior part. CONCLUSION: Brown syndrome consists of a series of diseases. Their clinical features are quite similar while their anatomical mechanism varies in numerous ways. Therefore, based on patient's individual pathophysiology, the management in Brown syndrome should be personalized.

Considerations on the etiology of congenital Brown syndrome.

PURPOSE OF REVIEW: Brown syndrome is an ocular motility disorder characterized by limited volitional and passive elevation of the eye in adduction. Although originally thought due to abnormalities in the trochlea or tendon sheath (limiting the free movement of the tendon through the trochlea), recent evidence suggests that some cases of congenital Brown syndrome may be related to neurodevelopmental abnormalities of the extraocular muscles (congenital cranial dysinnervation disorders, CCDD). RECENT FINDINGS: CCDD is a term encompassing congenital abnormalities of eye movements caused by congenital innervational abnormalities. The abnormal development of cranial nerve nuclei or abnormalities in cranial nerve axonal transport affects the development of the extraocular muscle(s). Currently, congenital fibrosis of the extraocular muscles, Duane syndrome, Moebius syndrome, Horizontal gaze palsy and progressive scoliosis, and synergistic divergence are included as CCDDs. In addition, congenial ptosis, Jaw Wink ptosis, and congenital superior oblique palsy are also included. Recently, it has been suggested that some cases of congenital Brown syndrome and congenital superior oblique paresis are related, and these entities may be part of the CCDDs spectrum. SUMMARY: Important findings regarding the cause of congenital Brown syndrome will be reviewed.

Magnetic resonance imaging in congenital Brown syndrome.

AIMS: Our aim was to elucidate the etiology of Brown syndrome by evaluating the trochlea position, morphologic characteristics of the extraocular muscles including superior oblique muscle/tendon complex, and the presence of the cranial nerves (CN) III, IV, and VI using magnetic resonance imaging (MRI) in eight patients with unilateral congenital Brown syndrome and one patient with bilateral congenital Brown syndrome. METHODS: Nine consecutive patients diagnosed with congenital Brown syndrome had a comprehensive ocular examination and MRI for the CN III, CN VI, and the extraocular muscles. Five of the nine patients underwent additional high resolution MRI for CN IV. The distance from the annulus of Zinn to the trochlea was measured. RESULTS: Normal sized CN III, IV, and VI, as well as all extraocular muscles, could be identified bilaterally in all patients with available MRI. The distance from the annulus of Zinn to the trochlea was the same in both eyes. CONCLUSIONS: The findings for our patients, particularly in those who underwent additional high resolution MRI, did not provide evidence of a lack of CN IV as a cause of Brown syndrome.

A rare cause of severe diarrhoea diagnosed by urine metabolic screening: aromatic L-amino acid decarboxylase deficiency.

A 15-year-old Chinese male with infantile-onset hypotonia, developmental delay, ptosis, and oculogyric episodes presented with a history of chronic diarrhoea since the age of 5 years. At presentation, he had an exacerbation of diarrhoeal symptoms resulting in dehydration and malnutrition with a concurrent severe chest infection. In view of his infantile-onset hypotonia, oculogyric crises, and protracted diarrhoea, an autonomic disturbance related to neurotransmitters was suspected. Urine organic acid profiling was compatible with aromatic L-amino acid decarboxylase deficiency. The diagnosis was confirmed based on cerebrospinal fluid analysis and genetic mutation analysis. The patient was treated with a combination of bromocriptine, selegiline, and pyridoxine; a satisfactory reduction in diarrhoea ensued. Our report highlights the importance of urine organic acid screening in infantile-onset hypotonia, especially when accompanied by oculogyric crises, and severe diarrhoea which could manifest as a result of autonomic disturbance.

The results of Brown syndrome surgery with superior oblique split tendon lengthening.

PURPOSE: To report the surgical outcome of superior oblique tendon split lengthening for management of patients with severe type of congenital Brown syndrome. Brown syndrome is characterized by hypotropia in primary position and limitation of elevation in adduction more than -4. MATERIALS AND METHODS: Fourteen consecutive patients with severe congenital Brown syndrome underwent superior oblique split lengthening surgery (10 mm). The amount of hypotropia in primary gaze and the degree of elevation in adduction were compared before and after the surgery. Any surgical complications were also recorded. RESULTS: Surgery was performed on 15 eyes in 11 female and 3 male subjects. Mean postoperative follow-up time was 12.93 ± 1.79 months (ranging from 10 to 16 months). Average hypotropia in primary gaze improved from 16.2 ± 5.5 prism diopters (range: 10-25 prism diopters) preoperatively to 5.9 ± 4.0 prism diopters (range: 0-18 prism diopters) postoperatively recorded at final follow-up examination (p < 0.001). The limitation in adduction improved from -7.2 ± 4.5 (range: -6 to -8) preoperatively to -1.8 ± 1.3 (range: zero to -5) postoperatively (p < 0.001). No surgical complications were noted. CONCLUSION: Superior oblique split lengthening has a significant effect on reducing primary gaze hypotropia and improving elevation in adduction. This technique should be considered for the treatment of patients with severe congenital Brown syndrome.

Congenital trochlear-oculomotor synkinesis.

Synkinesis of the extraocular muscles forms a subset of congenital ocular motility abnormalities termed congenital cranial dysinnervation disorders. Synkinesis most frequently involves the abducens or oculomotor nerves and rarely the trochlear nerve. Only 3 such patients have been described in the literature. We report an isolated case of trochlear-oculomotor synkinesis in a healthy 6-year-old boy and discuss the proposed pathophysiology of this disorder.

Congenital cranial dysinnervation disorders: a concept in evolution.

PURPOSE OF REVIEW: We review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs). RECENT FINDINGS: Recent literature contains new genotypic and phenotypic descriptions of Duane retraction syndrome, Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been identified, permitting a better understanding of associated phenotypes. More information is available regarding neurodevelopmental and clinical effects of various gene mutations associated with individual CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the genotype, and conversely, the genotype may not always predict the phenotype. SUMMARY: The CCDD concept has focused attention on specific congenital disturbances of human ocular motility and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid evolution within this field with the last 2 years yielding additional information about existing diagnoses, genes, and phenotypes that may result in better classification of these disorders and new genotype-phenotype correlations in the future.