Congenital Fibrosis Of The Extraocular Muscles Research Articles

MRI evaluation of cranial nerve abnormalities and extraocular muscle fibrosis in duane retraction syndrome and congenital extraocular muscle fibrosis.

To investigate the alterations in extraocular muscles (EOMs) by magnetic resonance imaging (MRI) among patients diagnosed with Duane retraction yndrome (DRS) and congenital fibrosis of the extraocular muscles (CFEOM), who present with various cranial nerve anomalies in an attempt to enhance the clinical diagnostic process. A case-control study was conducted to evaluate 27 patients with DRS and 14 patients with CFEOM. All patients underwent MRI scans of the brainstem and orbital examination. Neurodevelopmental assessments were conducted through MRI, and maximum cross-sectional area and volumes of EOMs were obtained. Three types of models were constructed using machine learning decision tree algorithms based on EOMs to predict disease diagnosis, cranial nerve abnormalities, and clinical subtypes. Patients with bilateral CN VI abnormalities had smaller volumes of LR, MR, and IR muscles compared to those with unilateral involvement (P < 0.05). Similarly, patients with CFEOM and unilateral third cranial nerve abnormalities had a smaller maximum cross-section of the affected eye's SR compared to the contralateral eye (P < 0.05). In patients with both CN III and CN VI abnormalities, the volume of SR was smaller than in patients with CN III abnormalities alone (P < 0.05). The prediction model using EOMs volume showed a diagnostic precision of 82.5% for clinical cases and 60.1% for predicting cranial nerve abnormalities. Nonetheless, the precision for identifying clinical subtypes was relatively modest, at only 41.7%. The distinctive volumetric alterations in EOMs among individuals exhibiting distinct cranial nerve anomalies associated with DRS or CFEOM provide valuable diagnostic insights into to Congenital Cranial Neurodevelopmental Disorders (CCDDs). MRI analysis of EOMs should thus be regarded as a crucial diagnostic modality.

The Frequency and Manifestations of Ocular Causes of Abnormal Head Posture

ABSTRACT Purpose To determine the frequency and manifestations of different ocular causes of abnormal head posture (AHP). Method This prospective, consecutive case series study was performed on 149 patients with ocular AHP at Farabi hospital, Iran, from February 2020 to June 2021. All patients underwent routine ophthalmic examinations. The manifestation of AHP was determined by direct observation from three viewing angles, while the patient read the smallest line on the vision chart that they could see. In front, above, and lateral gazes, observations were performed to find head tilt, head turn, and chin abnormal position, respectively. A picture with habitual AHP was taken from all patients. The amount of head tilt was measured by calculating the angle between the line that connects the lips center to the center of the eyebrows and the vertical line using the Corel Draw X7 computer software. Results The mean age of 149 patients with ocular AHP [101 (67.8%) males and 48 (32.2%) females] was 16.2 ± 12.2 (range, 2–57) years. The most common ocular sources of AHP were found to be superior oblique palsy (SOP) in 66 (44.3%) patients, 54 (36.2%) cases with Duane’s retraction syndrome (DRS), and 12 (8.1%) patients with nystagmus. Other frequent causes of ocular AHP were dissociated vertical deviation (DVD) in 5 (3.4%), A and V pattern strabismus in 3 (2.0%), and 2 cases (1.3%) in each of Brown syndrome, inferior rectus (IR) palsy, and congenital fibrosis of the extraocular muscles (CFEOM). The most common manifestations of AHP in all cases were “pure head turn” (48.3%), followed by “pure head tilt” (24.8%), “simultaneous head tilt and head turn” (20.8%), and “chin up” (6.0%). The mean head tilt among all patients with head tilt was 10.4° ± 8.9° (range, 5.0°−31.7°). Conclusion The most frequent ocular sources of AHP were SOP, DRS, and nystagmus, followed by DVD, A and V pattern strabismus, IR palsy, CFEOM, and Brown syndrome. In addition, pure head turn and pure head tilt were the most common manifestations of ocular AHP but were not always seen in the same direction or combination as previously reported with these etiologies.

Etiology of congenital ptosis - literature review

Karolina Ridikaitė1, Dovilė Bučaitė1, Dalia Jarušaitienė1, 2 1Lithuanian University of Health Sciences, Academy of Medicine, Faculty of Medicine, Kaunas, Lithuania 2Lithuanian University of Health Sciences Kauno klinikos, Department of Ophthalmology, Kaunas, Lithuania Abstract Background. Ptosis is abnormal drooping of the upper eyelid (> 2 mm). It is divided into two categories: congenital ptosis, which is present at birth, and acquired ptosis. The pathogenesis of congenital ptosis is thought to be due to a disorder of muscle development and damage to the innervation of the muscles. In contrast, there is currently no precise description of the pathogenesis of congenital eyelid ptosis. Aim. To present the main clinical manifestations of congenital ptosis, based on the available scientific literature. Material and methods. A literature review was conducted in the “PubMed” database using the terms “congenital ptosis” and “myogenic congenital ptosis” and “neurogenic congenital ptosis” from 2010 to 2023. Inclusion criteria was represented by articles relevant to these searches. Results. 1) Myogenic ptosis occurs when the development of the muscle responsible for elevating the upper eyelid is affected and replaced with other tissues. The condition is commonly seen as isolated congenital ptosis or blepharophimosis-ptosis-inverse epicanthal syndrome. 2) Neurogenic ptosis is characterized by an interruption in the nerve signals that control the muscles responsible for elevating the upper eyelid. The condition commonly presents as congenital fibrosis of the extraocular muscles, Marcus Gunn syndrome, Duane syndrome, Moebius syndrome, hereditary congenital facial paresis, Horner’s syndrome and congenital III cranial nerve palsy. Conclusions. Myogenic and neurogenic ptosis are most commonly described in the literature, with a higher prevalence in childhood. In contrast, the underlying mechanism of etiopathogenesis remains unclear. Keywords: congenital ptosis, myogenic congenital ptosis, neurogenic congenital ptosis Full article https://doi.org/10.53453/ms.2023.5.12

Pulled-in-two syndrome in strabismus surgery for congenital fibrosis of the extraocular muscles

ABSTRACT Purpose: The aim of this study is to present six cases of pulled-in-two syndrome (PITS) in strabismus surgeries and to discuss our prevention and management strategies. Methods: This is a retrospective study presenting cases of PITS during strabismus operations. The medical records of the subjects who underwent operation in the strabismus unit of Beyoglu Eye Training and Research Hospital were reviewed retrospectively, from January 2000 till March 2022. Detailed ophthalmological examination records and angle of deviation were noted. Results: A total of six cases (four males and two females) with a mean age of 37.2 ± 28.0 (min 9–max 71) years were included in this study. All of the cases had congenital fibrosis of extraocular muscles (CFEOM). The most commonly involved muscle was medial rectus (83%). Majority of cases (67%) were adults. In all cases, the muscle was found and reattached to the globe. No patients had diplopia after surgery. Conclusion: PITS is a rare complication that can be seen during strabismus surgeries, and CFEOM patients are in the risk group. Therefore, surgeons should be cautious and prepared in risky patients to be able to manage this complication.

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management.

Congenital fibrosis of the extraocular muscles (CFEOM) is a genetic disorder belonging to the congenital cranial dysinnervation disorders and is characterized by nonprogressive restrictive ophthalmoplegia. It is phenotypically and genotypically heterogeneous. At least seven causative genes and one locus are responsible for the five subtypes, named CFEOM-1 to CFEOM-5. This review summarizes the currently available molecular genetic findings and genotype-phenotype correlations, as well as the advances in the management of CFEOM. We propose that the classification of the disorder could be optimized to provide better guidance for clinical interventions. Finally, we discuss the future of genetic-diagnosis-directed studies to better understand such axon guidance disorders.

EP145: Severe Pierre Robin sequence and hydrocephalus in infant with TUBB3 variant

Pathogenic variants in TUBB3 are associated with congenital fibrosis of the extraocular muscles 3 (CFEOM3) and cortical dysplasia, complex, with other brain malformations 1 (CDCBM1). CDCBM1 is considered a tubulinopathy. Tubulinopathies are a group of conditions that include a large spectrum of brain malformations that are caused by pathogenic variants in genes encoding different tubulin isotypes. There are at least nine different alpha and ß tubulin isotypes, which are closely related subunits that are major components of microtubules (MTs).

Ocular Manifestations of Two Filipinos with Congenital Fibrosis of the Extraocular Muscles

Congenital fibrosis of the extraocular muscles (CFEOM) is a rare, congenital, non-progressive disorder presenting with partial or total ophthalmoplegia, with variable degrees of ptosis in both eyes. We present the clinical manifes tations of congenital fibrosis of the extraocular muscles in two patients. Both patients presented with bilateral ptosis and variable ophthalmoplegia with a chin-up posture. The ocular deviations have been noted since birth. No patient demonstrated a Marcus-Gunn jaw-winking phenomenon. Both patients had a mild refractive error with with-the-rule astigmatism. Deviation for both patients revealed exotropia with varying amounts of hypotropia and limitations in the movement of extraocular muscles. Both patients presented no abnormalities in the pupils. Neuroimaging revealed atrophy of the extraocular muscles. Diagnosis of CFEOM in a resource-poor setting is also challenging due to inaccessible gene testing. Manifestations of CFEOM vary across affected patients. CFEOM proposes challenges to the ophthalmologist with regards to management.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Congenital fibrosis of the extra-ocular muscles (CFEOM) and the cranial dysinnervation disorders.

Congenital fibrosis of the extraocular muscles (CFEOM) is one of the congenital cranial dysinnervation disorders (CCDDs). This review discusses the characteristics of the CFEOM phenotypes and the CCDDs, the fibrosis associated with these disorders and the processes, and genes involved in the embryological development of cranial neuromuscular units. In particular, it focuses on the genetics of neural crest identity, axon guidance, and axon construction in relation to the CFEOMs and some consideration of treatment strategies.

Anomalous superior oblique muscles and tendons in congenital fibrosis of the extraocular muscles

To evaluate the finding of anomalous superior oblique muscles in congenital fibrosis of the extraocular muscles (CFEOM), a feature not previously emphasized in this condition. The medical records of all patients clinically or genetically diagnosed with CFEOM at Boston Children's Hospital between 2010 and 2018 were reviewed retrospectively. Those who underwent strabismus surgery during the study period were included in the analysis. Baseline patient characteristics, type of CFEOM, results of genetic testing, and intraoperative features of the superior oblique muscle or tendon were recorded. Of 24 patients identified (age range, 1month to 62years), 10 (42%) had genetically confirmed CFEOM, and 22 underwent strabismus surgery, 14 (64%) involving the superior oblique muscle. Of these, 7 (50%) had anomalously inserted tendons (most commonly attached nasal to the superior rectus muscle), whereas 7 (50%) had increased superior oblique muscle tension. Half of CFEOM patients who underwent superior oblique surgery had abnormally inserted superior oblique tendons, and 50% had tight muscles or abnormally thin tendons, findings that have not been well-characterized in this condition. The findings suggest that abnormal insertion of the superior oblique muscles and tendons are additional features of the disease process in CFEOM that have not been described previously. These features may contribute to the severe upgaze limitation in CFEOM and highlight the importance of superior oblique tenotomy in surgical management.

Congenital fibrosis of the extraocular muscles in a Czech family and its molecular genetic cause

Congenital fibrosis of the extraocular muscles in a Czech family and its molecular genetic cause

Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles

To detail surgical strategy and strabismus outcomes in a genetically defined cohort of patients with congenital fibrosis of the extraocular muscles (CFEOM). A total of 13 patients with genetically confirmed CFEOM (via genetic testing for mutations in KIF21A, PHOX2A, and TUBB3) were retrospectively identified after undergoing strabismus surgery at Boston Children's Hospital and surgical outcomes were compared. Age at first surgery ranged from 11months to 63years, with an average of 3 strabismus procedures per patient. Ten patients had CFEOM1, of whom 9 had the KIF21A R954W amino acid substitution and 1 had the M947T amino acid substitution. Of the 3 with CFEOM3, 2 had the TUBB3 E410K amino acid substitution, and 1 had a previously unreported E410V amino acid substitution. CFEOM1 patients all underwent at least 1 procedure to address chin-up posture. Chin-up posture improved from 24° ± 8° before surgery to 10.0° ± 8° postoperatively (P<0.001). Three CFEOM1 patients developed exotropia after vertical muscle surgery alone; all had the R954W amino acid substitution. Postoperatively, 1 CFEOM1 patient developed a corneal ulcer. All CFEOM3 patients appeared to have underlying exposure keratopathy, successfully treated with prosthetic replacement of the ocular surface ecosystem (PROSE) lens in 2 patients. CFEOM is a complex strabismus disorder for which surgical management is difficult. Despite an aggressive surgical approach, multiple procedures may be necessary to achieve a desirable surgical effect. Knowledge of the underlying genetic diagnosis may help to inform surgical management.

Congenital fibrosis of the extraocular muscles: review of recent literature.

Congenital fibrosis of the extraocular muscles (CFEOM) is caused by abnormal development of the innervation of extraocular muscles. We update the recent literature regarding the clinical, anatomic, genetic, and molecular characteristics of CFEOM. Surgical considerations are addressed. CFEOM is broken down into three main subtypes, CFEOM1, CFEOM2, and CFEOM3. Several recent reports of individuals, as well as family pedigrees, highlight the phenotypic heterogeneity of CFEOM. Intracranial and intraorbital radiologic findings have enhanced our understanding of the disease pathophysiology. Molecular genetics research has increased our understanding of the development of extraocular muscles and their innervation as well as pathophysiology of CFEOM. Our understanding of the pathophysiology of CFEOM has increased with the recent contributions from neuroimaging, molecular genetics, and pedigree analysis. Surgical management of patients with CFEOM continues to be challenging.

Anomalous superior oblique muscle in congenital fibrosis of the extraocular muscles

Anomalous superior oblique muscle in congenital fibrosis of the extraocular muscles

Don’t Miss This! Red Flags in the Pediatric Eye Examination: Ophthalmoplegia in Childhood

ABSTRACTParalytic strabismus in children is rare, occurring in about 0.1% of children. This rate is far less common than the 3% rate usually noted for comitant strabismus. The relative rates of ocular motor pareses were fourth nerve palsies in 36%, sixth in 33%, third in 22%, with multiple ocular motor nerve palsies in 9%. In a single population series from Minnesota, few cases were associated with neoplasm. However, institutional case series reports a high rate of neoplasm for acquired third nerve and sixth nerve palsies after excluding trauma and congenital causes. Tumor is rare in children with fourth cranial nerve palsies, usually associated with other neurologic disease. Rare causes of external ophthalmoplegia, to be considered when the motility pattern is variable or not fitting an ocular motor nerve pattern, include myasthenia gravis and congenital fibrosis of the extraocular muscles. Myasthenia most often presents as ptosis with exotropia. Rarer still is involvement of the extraocular muscles in childhood thyroid disease.

112 Axonal polyneuropathy with onset in young adulthood due to TUBB3 mutation

IntroductionThe TUBB3 gene encodes the protein Beta-tubulin isotype III, a component of the microtubule cytoskeleton. Mutations in this gene have been associated with axonal polyneuropathy, however usually associated with congenital fibrosis of the extraocular muscles (CFOEM) and other abnormalities of cerebral development.1 2 We report a case of isolated neuropathy associated with a TUBB3 mutation.MethodsCase report - clinical information and next generation sequencing results were obtained.ResultsA 64 year old man presented with a severe, progressive, length dependent sensorimotor polyneuropathy which commenced in his late twenties. There was no clinical involvement of the extraocular muscles and cognition was normal. Family history was limited, but there were no other members affected.The patient had previously been extensively investigated including sural nerve biopsy, which confirmed axonal neuropathy without a specific diagnosis. Intravenous immunoglobulins and steroids had been trialled without benefit.A neuromuscular gene panel utilising next generation sequencing was performed and demonstrated heterozygosity for a variant of the TUBB3 gene (D417N substitution).Case series describing TUBB3 mutations show a large heterogeneity in phenotypic expression depending on the amino acid substitution.2–4 There is also heterogeneity in patients with D417N mutations, although a small number have been reported to develop a polyneuropathy without CFOEM1.ConclusionsThis case strengthens previous reports that TUBB3 mutation can be associated with a pure, axonal, sensorimotor polyneuropathy and highlights the use of next generation sequencing in streamlining the diagnostic process.ReferenceTischfield M, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 2010;140(1):pp.74–87.Ncbi.nlm.nih.gov. (2019). Congenital fibrosis of the extraocular muscles - Conditions - GTR - NCBI. [online] Available at: https://www.ncbi.nlm.nih.gov/gtr/conditions/CN043677/ [Accessed 14 Feb. 2019].Omim.org. (2019). OMIM Entry - * 602661 - TUBULIN, BETA-3; TUBB3. [online] Available at: https://www.omim.org/entry/602661 [Accessed 14 Feb. 2019].Krupa, K. and Bekiesinska-Figatowska, M. (2013). Congenital and Acquired Abnormalities of the Corpus Callosum: A Pictorial Essay. BioMed Research International, 2013, pp.1–14.

Study of de novo point mutations in known genes among patients with unexplained intellectual disability or developmental delay

Objective: To analyze the de novo point mutations in known genes among patients with unexplained intellectual disability (ID) or developmental retardation (DD). Methods: A total of 120 outpatients with ID or DD were recruited in the Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics between September 2015 and April 2017. Target gene sequencing was used to screen the candidate gene. The sequencing data were analyzed by a variety of bioinformatics software. Combining with the phenotypes of the patients, the candidate genetic/genomic variants were identified from next-generation sequencing data. The final pathogenicity of the genetic/genomic variants were interpreted according to the guideline of the American College of Medical Genetics and Genomics (ACMG) for variants after segregation analysis in the parents and necessary family members by Sanger sequencing. The comprehensive physiological function and signaling pathways of 20 disease genes with de novo point mutation discovery was also studied. Results: Among the 120 patients, 23 patients were found to carry clear pathological changes, and the incidence of de novo point variation was 19.2%. The patients included 12 males and 11 females, with an age of 2 months to 6-year-6-month. Five patients were diagnosed with early onset of epileptic encephalopathy. Seven had mental retardation type 5, 6, 8, 19, 20, 22, 39, respectively. Weill-Marchesani syndrome type 2 was found in one case, Wiedemann-Steiner syndrome in one case, Coffin-Siris syndrome in two cases, Rubinstein-Taybi syndrome in one case, GLUT1 deficiency syndrome in one case, Rett syndrome in one case, cardio-facio-cutaneous syndrome 3 in one case, neurodegeneration with brain iron accumulation in one case, corpus callosum local dysplasia in one case, and congenital fibrosis of the extra-ocular muscles in one case. A total of 20 novel mutations were reported in this study. No somatic mutation was found in the samples of 6 patients with mutation and their parents' peripheral blood DNA samples by amplicon-based deep sequencing. This study found that the main disease genes were involved in chromatin remodeling, transcriptional regulation, autophagy body assembly, MAPK signal pathway, DNA methylation, potassium, sodium ion transport, cell skeleton assembly and skeletal muscle development. These genes were significantly enriched in the following biological processes: Ras signaling pathways, transcription factor binding and cancer related signaling pathway. Conclusions: The etiology of children affected with intellectual disability or developmental delay is complex. Harmful de novo point mutation plays an important role in these diseases. Targeted exome/genome sequencing based on the core family is helpful for the molecular diagnosis of patients and the discovery of more genes.

Vertical Strabismus - Indication of Surgical Techniques on the Inferior Rectus Muscle.

Surgery technique &#8220;cul-de-sac&#8221; is aprocedure with fixed adjustable sutures (non-absorbable suture), which are guided in parallel on both peaks original insertion of inferior rectus muscle. The node itself of suture is done in cutting the muscle and through the original insertion only leads arc suture. During &#8222;counterclockwise transposition&#8220; procedure sec. Knapp, the horizontal rectus muscles are fixed at the straight inferior rectus muscle level. The author included their graphical diagrams. At the Department of Ophthalmology in the Faculty Hospital Královské Vinohrady in Prague (Czech Republic, EU) in the years 1996 - 2014 arelease relaxing operation of the inferior rectus musle by the technique &#8220;cul-de-sac&#8221; on 49 eyes. Indication was double elevator palsy in 31 patients, congenital fibrosis of the extraocular muscles in 15 patients and in 3 cases, it was thyroid eye disease. &#8220;Counterclockwise transposition&#8221; procedure sec. Knapp was indicated twice for paresis of the inferior rectus muscle in 2015 and 2016. For the first time, it was acongenital form. It was detected histologically atrophy of stripped muscle with hypertrophy collagen. The second traumatic form was formed after an orbital injury. We provided adequate relaxation of the inferior rectus muscle and practical restoration of eye elevation by the technique &#8220;cul-de-sac&#8220; in 18 preschool children with the double elevator palsy and three adult patients with thyreiod eye disease. We had to restore motility to complete the procedure by classical transposition procedure sec. Knapp of both horizontal rectus muscles to the direct superior rectus muscle in elderly children and adults with the double elevator palsy, as well as in all patients with the congenital fibrosis of the extraocular muscles. Indicate the inclusion of this transposition influenced the degree of fibrotic rectus inferior muscle given by age. &#8220;Counterclockwise transposition&#8220; procedure sec. Knapp ensured the practical disappearance hypertropie in both cases of paresis of the inferior rectus muscle. The alignment of the position of the eyes without diplopia in the direct view was ensured by prismatic correction. To release the fibrotically altered inferior rectus muscle in the double elevator palsy, the congenital fibrosis of the extraocular muscles and the thyroid eye disease, the operation of adjustable sutures was necessary in accordance with our experience with the technigue &#8220;cul-de-sac&#8220; in its own modification. The transposition procedure sec. Knapp, either classical or &#8220;&#8221;counterclockwise&#8221; &#8220; in its own modification, was of paramount importance for the solution of the vertical deviation of aparetic ethiology. Key words: adjustable sutures, congenital fibrosis of the extraocular muscles, double elevator palsy, thyroid eye disease, transposition procedure sec. Knapp, vertical strabismus.

Comparison of Clinical and Radiological Findings between Congenital Orbital Fibrosis and Congenital Fibrosis of the Extraocular Muscles

ABSTRACT Purpose/Aims To compare the clinical and radiological findings of the two rare entities of congenital orbital fibrosis and congenital fibrosis of the extraocular muscles (CFEOM). Materials Methods Clinical characteristics and magnetic resonance imaging (MRI) findings of three congenital orbital fibrosis patients were analyzed and compared to 13 CFEOM patients. Results In all three patients with congenital orbital fibrosis, unilateral EOM limitation and enophthalmos were found with a retrobulbar infiltrating mass and normal oculomotor and abducens nerves on MRI. Conversely, most of the patients with CFEOM showed bilateral involvement with hypoplasia of oculomotor nerves and/or abducens nerves and hypotrophic EOM on MRI. Conclusion All the patients with congenital orbital fibrosis had normal oculomotor and abducens nerves with a retrobulbar mass infiltrating between EOMs, suggesting that congenital orbital fibrosis is a unique disease entity distinguished from CFEOM.

A TUBB6 mutation is associated with autosomal dominant non-progressive congenital facial palsy, bilateral ptosis and velopharyngeal dysfunction.

Congenital cranial dysinnervation disorders (CCDDs) comprise a heterogeneous spectrum of diseases characterized by congenital, non-progressive impairment of eye, eyelid and/or facial movements including Möbius syndrome, Duane retraction syndrome, congenital ptosis, and congenital fibrosis of the extraocular muscles. Over the last 20 years, several CCDDs have been identified as neurodevelopmental disorders that are caused by mutations of genes involved in brain and cranial nerve development, e.g. KIF21A and TUBB3 that each plays a pivotal role for microtubule function. In a five-generation pedigree, we identified a heterozygous mutation of TUBB6, a gene encoding a class V tubulin which has not been linked to a human hereditary disease so far. The missense mutation (p.Phe394Ser) affects an amino acid residue highly conserved in evolution, and co-segregates with a phenotype characterized by congenital non-progressive bilateral facial palsy and congenital velopharyngeal dysfunction presenting with varying degrees of hypomimia, rhinophonia, impaired gag reflex and bilateral ptosis. Expression of the mutated protein in yeast led to an impaired viability compared to wildtype cells when exposed to the microtubule-poison benomyl. Our findings enlarge the spectrum of tubulinopathies and emphasize that mutations of TUBB6 should be considered in patients with congenital non-progressive facial palsy. Further studies are needed to verify whether this phenotype is indeed part of the CCDD spectrum.