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Molecular Vision 2014To describe the phenotypic characteristics and clinical course of a sporadic case of congenital fibrosis of the extraocular muscles (CFEOM) and Möbius syndrome with a...
PURPOSE
To describe the phenotypic characteristics and clinical course of a sporadic case of congenital fibrosis of the extraocular muscles (CFEOM) and Möbius syndrome with a de novo mutation in the KIF21A gene encoding a kinesin motor protein.
METHODS
An individual with the rare combination of CFEOM and Möbius syndrome underwent comprehensive ophthalmologic and neurological evaluations. Magnetic resonance imaging (MRI) including diffusion tensor imaging (DTI) tractigraphy at 3T field strength was used to evaluate orbital, encephalic, and intracranial nerve integrity. The proband and her healthy parents underwent screening for mutations in the KIF21A, PHOX2A, and TUBB3 genes.
RESULTS
The patient exhibited congenital, nonprogressive, bilateral external ophthalmoplegia, bilateral ptosis, bilateral facial palsy, and developmental delay. Her inability to blink resulted in severe exposure keratopathy and subsequent corneal perforation requiring a penetrating keratoplasty. MRI revealed an unremarkable configuration of the axial central nervous system and preservation of the intracranial portion of cranial nerves I, II, III, V, VI, VII, and VIII (cranial nerve IV is not normally visualized by MRI). A novel and de novo heterozygous KIF21A mutation (c.1056C>G, p.Asp352Glu) in a highly conserved region of the gene was present in the proband.
CONCLUSIONS
The reported KIF21A D352E mutation and associated phenotype further expand the clinical and mutational spectrum of CFEOM and Möbius syndrome.
Topics: Amino Acid Sequence; Base Sequence; Child; Conserved Sequence; DNA Mutational Analysis; Eye Diseases, Hereditary; Female; Fibrosis; Fixation, Ocular; Humans; Kinesins; Magnetic Resonance Imaging; Mobius Syndrome; Molecular Sequence Data; Mutation; Ocular Motility Disorders
PubMed: 24715754
DOI: No ID Found -
Ophthalmology Jul 2014To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort. (Observational Study)
Observational Study
OBJECTIVE
To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort.
DESIGN
Prospective, observational study.
PARTICIPANTS
Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate.
METHODS
Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations.
MAIN OUTCOME MEASURES
The number of patients meeting MDC and the number of patients with confirmed genetic mutation.
RESULTS
A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored a HOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation.
CONCLUSIONS
Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may have TUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome.
Topics: Adolescent; Adult; Blepharoptosis; Child; Child, Preschool; DNA Mutational Analysis; Exotropia; Eye Diseases, Hereditary; Eye Movements; Female; Fibrosis; Homeodomain Proteins; Humans; Infant; Male; Middle Aged; Mobius Syndrome; Mutation; Ocular Motility Disorders; Polymerase Chain Reaction; Prospective Studies; Transcription Factors; Tubulin; Young Adult
PubMed: 24612975
DOI: 10.1016/j.ophtha.2014.01.006 -
Anales de Pediatria (Barcelona, Spain :... Nov 2014Mobius syndrome is characterized by damage in the nucleus of the sixth and seventh cranial nerves, with subsequent facial palsy and abduction limitation of the eyes. The... (Observational Study)
Observational Study
INTRODUCTION
Mobius syndrome is characterized by damage in the nucleus of the sixth and seventh cranial nerves, with subsequent facial palsy and abduction limitation of the eyes. The aim of this article is to describe the ophthalmological findings of the Mobius syndrome in Mexican children.
PATIENTS AND METHODS
A cross-sectional, retrospective, observational and descriptive study was conducted. A review was made of the clinical charts of patients with Mobius syndrome who were seen in the National Institute of Pediatrics in Mexico, between the years 2000 and 2010.
RESULTS
A total of 64 charts were reviewed. The most important findings were eye abduction limitation (100%), facial palsy (100%), esotropia (54%), epicanthus (51.5%), entropion (22%), and history of use of abortion inducers in the mother in the first trimester of pregnancy (28%). We also found exotropia and hypertropia in some cases.
CONCLUSIONS
Mobius syndrome has a wide spectrum of ophthalmological manifestations that are important to detect early in order to improve function and esthetics.
Topics: Child; Child, Preschool; Cross-Sectional Studies; Eye Diseases; Female; Humans; Infant; Male; Mobius Syndrome; Retrospective Studies
PubMed: 24581746
DOI: 10.1016/j.anpedi.2013.10.023 -
Brain : a Journal of Neurology Apr 2014Congenital facial weakness is present in a heterogeneous group of conditions. Among them is Moebius syndrome, which has been defined as a disorder with congenital,... (Observational Study)
Observational Study
Congenital facial weakness is present in a heterogeneous group of conditions. Among them is Moebius syndrome, which has been defined as a disorder with congenital, non-progressive facial weakness and limited abduction of one or both eyes. It is typically attributed to agenesis of the abducens and facial cranial nerves. This paper details ocular motor findings of 40 subjects (23 months to 64 years; 24 females, 16 males) with congenital facial weakness: 38 presented at a Moebius Syndrome Conference and two were clinic patients. A new classification scheme of patterns based on ocular motor phenotype is presented. Of 40 subjects, 37 had bilateral and three had unilateral facial weakness. The most common ocular motor pattern (Pattern 1, n=17, 43%) was bilateral horizontal gaze palsy with intact vertical range. Pattern 2 (n=10, 26%) was bilateral horizontal gaze palsy with variable vertical limitations. Pattern 3, which was rare, was isolated abduction deficits (n=2, 5%). Others had full motility range and did not meet minimal criteria for the diagnosis of Moebius syndrome (Pattern 4, n=10, 26%). One subject was too severely affected to characterize. Abnormal vertical smooth pursuit was present in 17 (57%) of 30 subjects: nine with Pattern 1, five with Pattern 2, and three with Pattern 4. Abnormal vertical saccades were present in 10 (34%) of 29 subjects. Vertical saccades appeared slow in nine: six with Pattern 1 and three with Pattern 2. Vertical saccades were absent in one subject with Pattern 2. Abnormal vertical optokinetic nystagmus was present in 19 (68%) of 28 subjects: 10 with Pattern 1, six with Pattern 2, one with Pattern 3, and two with Pattern 4. Reduced convergence was present in 19 (66%) of 29 subjects: nine with Pattern 1, six with Pattern 2, one with Pattern 3, and three with Pattern 4. The most common pattern of ocular motor deficit in Moebius syndrome is bilateral horizontal gaze palsy from pontine abducens nuclear defects, rather than abducens nerve involvement. Defects in the range or dynamic properties of vertical movements in subjects with congenital facial weakness may suggest involvement of ocular motor structures in the midbrain, including oculomotor nerves or nuclei, vertical supranuclear saccadic centres, and convergence neurons. Such deficits were found even in subjects with full vertical motility range. Classification of patterns of ocular motor deficits in congenital facial weakness may assist with further delineation of anatomic localization and identification of genetic deficits underlying these disorders.
Topics: Adolescent; Adult; Child; Child, Preschool; Cross-Sectional Studies; Eye Movements; Female; Humans; Infant; Male; Middle Aged; Mobius Syndrome; Muscle Weakness; Ocular Motility Disorders; Young Adult
PubMed: 24561559
DOI: 10.1093/brain/awu021 -
Journal of Clinical and Experimental... Oct 2013Möbius syndrome is a congenital condition, the etiology when is not associated with misoprostol is not well defined. Signs and symptoms include difficulty swallowing,... (Review)
Review
Möbius syndrome is a congenital condition, the etiology when is not associated with misoprostol is not well defined. Signs and symptoms include difficulty swallowing, speech problems, drooling, strabismus, limitation of eye movement and more importantly, the facial blankness that these individuals have, result of the facial paralysis, due to atrophy of the cranial nerves that are involved in this condition. The ability to express emotions is affected and are considered "children without a smile." There is currently no treatment to solvent the birth defects, the treatment options for reduce these alterations is the surgical option that has as main objective to restore muscle function through various techniques, used as required, the possibilities of applying them, is taking into consideration the outcome of the procedure to execute. Among the surgical techniques used mainly: the lengthening myoplasty of the temporal muscle,muscle transfers, cross-facial grafting, neurorrhaphy and nerve transposition, of which latter are the best performers, giving the patient a more natural, in as far as regards expression and function. Key words:Möbius syndrome, surgery, smile, facial nerve, muscle transfer, transfer nerve, temporalis muscle.
PubMed: 24455082
DOI: 10.4317/jced.51116 -
Cellular and Molecular Life Sciences :... Jun 2014The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal... (Review)
Review
The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.
Topics: Adult; Animals; Axons; Cranial Nerves; Face; Humans; Maxillofacial Development; Mouth Mucosa; Regeneration; Salivary Glands; Taste Buds
PubMed: 24395053
DOI: 10.1007/s00018-013-1549-0 -
Case Reports in Ophthalmology 2013Möbius syndrome is a heterogeneous congenital disorder that is linked to bilateral palsies of the cranial nerves VI and VII, resulting in congenital facial paralysis...
INTRODUCTION
Möbius syndrome is a heterogeneous congenital disorder that is linked to bilateral palsies of the cranial nerves VI and VII, resulting in congenital facial paralysis sometimes associated with impaired ocular abduction.
CASE REPORT
We present the case of a 44-year-old woman with Möbius syndrome and inferior recurrent keratitis secondary to scleral show in both eyes. We decided to use a cartilage graft from the ear in the inferior eyelid to avoid eyelid retraction and scleral show.
DISCUSSION
Patients with Möbius syndrome have a severe dysfunction of their facial mimic. Their treatment must be individualized, depending on their age, clinical examination and symptoms.
PubMed: 24348407
DOI: 10.1159/000356528 -
Seminars in Ophthalmology 2013In recent years, our understanding of the genetic foundations of incomitant strabismus has grown significantly. Much new understanding has been gleaned since the concept... (Review)
Review
In recent years, our understanding of the genetic foundations of incomitant strabismus has grown significantly. Much new understanding has been gleaned since the concept of congenital cranial dysinnervation disorders (CCDDs) was introduced in 2002, and the genetic basis of CCDDs continues to be elucidated. In this review, we aim to provide an update of the genetic and clinical presentation of these disorders. Disorders reviewed include Duane syndrome (DS), HOXA1 and HOXB1 syndromes, Moebius syndrome, congenital fibrosis of the extraocular muscles (CFEOM), and horizontal gaze palsy with progressive scoliosis (HGPPS).
Topics: Duane Retraction Syndrome; Eye Diseases, Hereditary; Fibrosis; Homeodomain Proteins; Humans; Mobius Syndrome; Ophthalmoplegia; Ophthalmoplegia, Chronic Progressive External; Scoliosis; Strabismus; Transcription Factors
PubMed: 24138051
DOI: 10.3109/08820538.2013.825288 -
JAMA Ophthalmology Dec 2013Total ophthalmoplegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopathy. Patients carrying RYR1 mutations are at high risk...
IMPORTANCE
Total ophthalmoplegia can result from ryanodine receptor 1 (RYR1) mutations without overt associated skeletal myopathy. Patients carrying RYR1 mutations are at high risk of developing malignant hyperthermia. Ophthalmologists should be familiar with these important clinical associations.
OBJECTIVE
To determine the genetic cause of congenital ptosis, ophthalmoplegia, facial paralysis, and mild hypotonia segregating in 2 pedigrees diagnosed with atypical Moebius syndrome or congenital fibrosis of the extraocular muscles.
DESIGN, SETTING, AND PARTICIPANTS
Clinical data including medical and family histories were collected at research laboratories at Boston Children's Hospital and Jules Stein Eye Institute (Engle and Demer labs) for affected and unaffected family members from 2 pedigrees in which patients presented with total ophthalmoplegia, facial weakness, and myopathy.
INTERVENTION
Homozygosity mapping and whole-exome sequencing were conducted to identify causative mutations in affected family members. Histories, physical examinations, and clinical data were reviewed.
MAIN OUTCOME AND MEASURE
Mutations in RYR1.
RESULTS
Missense mutations resulting in 2 homozygous RYR1 amino acid substitutions (E989G and R3772W) and 2 compound heterozygous RYR1 substitutions (H283R and R3772W) were identified in a consanguineous and a nonconsanguineous pedigree, respectively. Orbital magnetic resonance imaging revealed marked hypoplasia of extraocular muscles and intraorbital cranial nerves. Skeletal muscle biopsy specimens revealed nonspecific myopathic changes. Clinically, the patients' ophthalmoplegia and facial weakness were far more significant than their hypotonia and limb weakness and were accompanied by an unrecognized susceptibility to malignant hyperthermia.
CONCLUSIONS AND RELEVANCE
Affected children presenting with severe congenital ophthalmoplegia and facial weakness in the setting of only mild skeletal myopathy harbored recessive mutations in RYR1, encoding the ryanodine receptor 1, and were susceptible to malignant hyperthermia. While ophthalmoplegia occurs rarely in RYR1-related myopathies, these children were atypical because they lacked significant weakness, respiratory insufficiency, or scoliosis. RYR1-associated myopathies should be included in the differential diagnosis of congenital ophthalmoplegia and facial weakness, even without clinical skeletal myopathy. These patients should also be considered susceptible to malignant hyperthermia, a life-threatening anesthetic complication avoidable if anticipated presurgically.
Topics: Amino Acid Substitution; Blepharoptosis; Child; Consanguinity; DNA Mutational Analysis; Diseases in Twins; Exome; Eye Diseases, Hereditary; Female; Fibrosis; Genotype; Homozygote; Humans; Infant; Magnetic Resonance Imaging; Male; Malignant Hyperthermia; Mobius Syndrome; Mutation, Missense; Ophthalmoplegia; Pedigree; Ryanodine Receptor Calcium Release Channel; Twins, Dizygotic
PubMed: 24091937
DOI: 10.1001/jamaophthalmol.2013.4392 -
Arquivos Brasileiros de Oftalmologia 2013To assess the prevalence of refractive errors in Möbius sequence.
PURPOSE
To assess the prevalence of refractive errors in Möbius sequence.
METHODS
This study was carried out during the Annual Meeting of the Brazilian Möbius Society in November 2008. Forty-four patients diagnosed with the Möbius sequence were submitted to a comprehensive assessment, on the following specialties: ophthalmology, neurology, genetics, psychiatry, psychology and dentistry. Forty-three patients were cooperative and able to undertake the ophthalmological examination. Twenty-two (51.2 %) were male and 21 (48.8%) were female. The average age was 8.3 years (from 2 to 17 years). The visual acuity was evaluated using a retro-illuminated logMAR chart in cooperative patients. All children were submitted to exams on ocular motility, cyclopegic refraction, and fundus examination.
RESULTS
From the total of 85 eyes, using the spherical equivalent, the major of the eyes (57.6%) were emmetropics (>-0.50 D and <+2.00 D). The prevalence of astigmatism greater than or equal to 0.75 D was 40%.
CONCLUSION
The prevalence of refractive errors, by the spherical equivalent, was 42.4% in this studied group.
Topics: Adolescent; Brazil; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Male; Mobius Syndrome; Prevalence; Refraction, Ocular; Refractive Errors; Visual Acuity
PubMed: 24061836
DOI: 10.1590/s0004-27492013000400010