Cardiomyocyte Ogt is essential for postnatal viability.

The singly coded gene O-linked-ß-N-acetylglucosamine (O-GlcNAc) transferase (Ogt) resides on the X chromosome and is necessary for embryonic stem cell viability during embryogenesis. In mature cells, this enzyme catalyzes the posttranslational modification known as O-GlcNAc to various cellular proteins. Several groups, including our own, have shown that acute increases in protein O-GlcNAcylation are cardioprotective both in vitro and in vivo. Yet, little is known about how OGT affects cardiac function because total body knockout (KO) animals are not viable. Presently, we sought to establish the potential involvement of cardiomyocyte Ogt in cardiac maturation. Initially, we characterized a constitutive cardiomyocyte-specific (cm)OGT KO (c-cmOGT KO) mouse and found that only 12% of the c-cmOGT KO mice survived to weaning age (4 wk old); the surviving animals were smaller than their wild-type littermates, had dilated hearts, and showed overt signs of heart failure. Dysfunctional c-cmOGT KO hearts were more fibrotic, apoptotic, and hypertrophic. Several glycolytic genes were also upregulated; however, there were no gross changes in mitochondrial O2 consumption. Histopathology of the KO hearts indicated the potential involvement of endoplasmic reticulum stress, directing us to evaluate expression of 78-kDa glucose-regulated protein and protein disulfide isomerase, which were elevated. Additional groups of mice were subjected to inducible deletion of cmOGT, which did not produce overt dysfunction within the first couple of weeks of deletion. Yet, long-term loss (via inducible deletion) of cmOGT produced gradual and progressive cardiomyopathy. Thus, cardiomyocyte Ogt is necessary for maturation of the mammalian heart, and inducible deletion of cmOGT in the adult mouse produces progressive ventricular dysfunction.

Congenital fibrosis of the extraocular muscles: magnetic resonance imaging findings and surgical treatment.

PURPOSE: We analyzed findings of orbital and cranial magnetic resonance imaging (MRI) in patients with congenital fibrosis of the extraocular muscles (CFEOM). We described surgery and its outcome. MATERIAL AND METHOD: Nine out of 10 patients with clinical findings of CFEOM underwent orbital and cranial MRI to perform a study of the extraocular muscles and cranial nerves. A multimodality workstation platform developed by the imaging laboratory of our hospital for PC computer allowed us to visualize and measure the cross sections of the extraocular muscles in a coronal section. Surgery was indicated to resolve strabismus. Outcome was considered favorable if the final deviation was < 10 pd in the primary position without head turn. RESULTS: In 8 cases (6 males, 5 unilateral [3 left eye]), MRI revealed atrophy of at least 1 of the extraocular muscles supplied by the third nerve. Five patients had third nerve aplasia or hypoplasia. Clinical findings were compatible with a probable diagnosis of CFEOM in all 10 patients. Four patients underwent ptosis surgery before being diagnosed with CFEOM. Four patients underwent surgery to correct strabismus and, of these, 2 required multiple interventions (1 needed 4 interventions). Outcome was successful in only 2 cases. CONCLUSION: Orbital and cranial MRI provided useful information about extraocular muscles and cranial nerves in CFEOM. Surgery must be performed on an individual basis; the number of reoperations is high. The outcome of surgery was favorable in half of the cases.

Congenital orbital fibrosis associated with fibrosis of extraocular muscle.

Congenital orbital fibrosis is a non-familial, unilateral, distinct clinical entity, characterised by the presence of a diffusely infiltrating orbital mass and is extremely a rare disease. Congenital orbital fibrosis with combined fibrosis of extraocular muscles have not been reported previously. We treated an 8-year-old boy with the presence of a diffusely infiltrating orbital mass and fibrosis of extraocular muscles with secondary involvement of extraocular muscles. Clinical examination revealed left exotropia, hypotropia and fibrosis of extraocular muscle, an irregular, retrobulbar mass located within the orbit, incorporating the optic nerve, medial, superior, inferior and lateral rectus muscle. The CT, MRI and light microscopic studies confirmed the diagnosis. We performed exploration of the orbit, release and biopsy of scar tissue and strabismus surgery. Unlike other reported cases, our case was a progressive congenital disorder with combined fibrosis of extraocular muscle.

Unilateral congenital fibrosis of the extraocular muscles with lid retraction: surgical treatment with a silicon plate on the orbital floor.

Fibrosis of the extraocular muscles can be an acquired or congenital disorder (CFEOM). The congenital disorder(1) is a complex strabismus with congenital restrictive ophthalmoplegia with or without ptosis. The surgery is challenging because the eye muscles are replaced by fibrous tissue or fibrous bands and in most cases the results are not satisfactory. We present the first case report of unilateral CFEOM with palpebral adherence and hypotropia, which was managed with our technique of a silicon plate implant on the orbital floor. The purpose of the implantation of the silicon plate in the orbital floor is to improve the hypotropia caused by CFEOM.

Imaging findings in congenital cranial dysinnervation disorders.

In 2002, the term congenital cranial dysinnervation disorders (CCDDs) was proposed to group heterogeneous syndromes with congenital abnormalities of ocular muscle and facial innervations. The concept of neurogenic etiology has been supported by discovery of genes that are essential to the normal development of brainstem, cranial nerves, and their axonal connections. The CCDDs include Duane retraction syndrome, congenital fibrosis of the extraocular muscles, Möbius syndrome, horizontal gaze palsy with progressive scoliosis, the human homeobox-related disorders, pontine cap tegmental dysplasia, and an expanding list. The purpose of this review was to update the imaging features, as well as clinical and genetic information, regarding cases of CCDDs.

Congenitally dysplastic inferior rectus muscle.

The authors report an unusual presentation of an idiopathic congenitally dysplastic inferior rectus muscle that responded well to surgical correction. Isolated unilateral enlargement of extraocular muscles is rare in children, and there is no definite logical explanation for its cause. A 20-month-old child presented with a congenitally enlarged posterior part of the right inferior rectus muscle with prominent hypotropia and enophthalmos since 10 months of age. Systemic disease work-up, ultrasound B-scan, computed tomography of the orbit and brain, and inferior rectus muscle biopsy were performed. Preoperatively, the child had severe hypotropia of the right eye with retraction of the globe. Work-up for systemic diseases was negative. Computed tomography scan showed thickening of the posterior two-thirds of the inferior rectus muscle. Muscle biopsy showed non-specific fibrotic changes. Strabismus surgery was undertaken at 2 years of age. Hypotropia was reduced significantly postoperatively. Compensatory head position was eliminated.

Renal dysplasia and nephrosclerosis in calves.

Renal dysplasia and nephrosclerosis in six calves, which were aged three to six months and from different farms in western Scotland and north-west England, was characterised clinically by stunted growth and renal failure with uraemia. Affected animals were depressed and one case exhibited severe neurological signs. Reduced erythrocyte counts were evident in three of four animals from which blood samples were submitted for haematology. At postmortem examination, the kidneys were bilaterally small, pale and firm, with marked fibrosis and sometimes contraction of the capsule. Histologically, affected calves had disorganised atrophic glomeruli, dilatation of tubules, loss of nephrons, areas of undifferentiated mesenchyme and diffuse interstitial and periglomerular fibrosis. There was minimal inflammation. Renal dysplasia and nephrosclerosis is a form of juvenile nephropathy of unknown aetiology that occurs sporadically in calves in the UK.

KIF21A variant R954W in familial or sporadic cases of CFEOM1.

PURPOSE: To demonstrate the clinical characteristics and determine mutations in the KIF21A gene, encoding a kinesin motor protein in patients with congenital fibrosis of the extraocular muscles (CFEOM) type 1. METHODS: Patients of five families with congenital fibrosis syndrome and two simplex patients with CFEOM underwent ophthalmologic examination and mutation analysis in the KIF21A gene. RESULTS: Clinical examination and passive motility testing prior to surgery met criteria for CFEOM. All patients had congenital restrictive ophthalmoplegia primarily affecting muscles innervated by the oculomotor nerve. Complete mutation screening in the KIF21A gene revealed the presence of the known and most common recurrent variant R954W in three families and in two simplex cases. Two families demonstrated linkage to chromosome 16. CONCLUSIONS: The patients included in the study had marked restriction of movement bilaterally with nearly complete loss of vertical ocular motility, graded reduction of horizontal motility, ptosis, and compensatory chin elevation. The phenotype was variable in patients carrying the same mutation. In one family, all patients were diagnosed with mental retardation, indicating that this syndrome might not only affect the development of cranial nerves, but can also be responsible for general neurologic dysfunction. The screening data suggest frequent and exclusive appearance of the R454W variant in sporadic and familial cases of CFEOM1 in Germany.

[Central nervous system abnormalities related to congenital fibrosis of extraocular muscles]. / Alteraciones del sistema nervioso central asociadas a fibrosis congénita de músculos extraoculares.

OBJECTIVE: We undertook this study to describe central nervous system (CNS) abnormalities associated with congenital cranial dysinnervation disorders (CCDD). METHODS: This was a retrospective, observational, transversal and descriptive study including patients with congenital fibrotic strabismus. We analyzed clinical files of patients from 2001 to 2006. Neurological lesions were reported. RESULTS: Restrictive strabismus was demonstrated in all cases. Sixteen patients were included: nine males and seven females. Different neurological lesions were reported: corpus callosum anomalies, severe cortipathy, epilepsy, cavum vergae, nystagmus, occipital subarachnoid cyst, and hydrocephalus. Mental retardation was reported in 56% of patients. Different malformations were reported: genital malformations, trigonocephalus, camptodactyly, mild facial hypoplasia, low set ears, and agenesis of left ear. Blepharoptosis was present in 81% of patients. The most frequent form of strabismus was exotropia (56%), hypotropia in 37.5%, hypertropia 18.7%, "A" pattern 18.7%, and esotropia in 6.25%. Affection was cranial nerve III, 93.75%; cranial nerve VI, 6.25%; cranial nerve VII, 6.25%; and lesion to cranial nerve II in eight cases (50%). CONCLUSIONS: We have suggested that failure in early stages of embryology of the CNS can lead to the development of paralytic strabismus and generate secondary fibrotic changes, not only in muscle structures but also in other orbital tissues. That is the reason why we have used the term "congenital fibrotic strabismus" to report cases included in CCDD. We have demonstrated the strong association of mental retardation and neurological alterations. Multidisciplinary rehabilitation is relevant for these patients.

Alteraciones del sistema nervioso central asociadas a fibrosis congénita de músculos extraoculares / Central nervous system abnormalities related to congenital fibrosis of extraocular muscles

Objetivo: Describir las alteraciones del sistema nervioso central asociadas a dismorfogenesias de los nervios craneales. Material y métodos: Estudio retrospectivo, observacional, transversal y descriptivo de pacientes con estrabismo por fibrosis congénita de los músculos extraoculares, atendidos entre enero de 2001 y enero de 2006. Fueron identificadas las lesiones neurológicas y se analizó su asociación. Resultados: Todos los pacientes tuvieron estrabismos fibróticos. Se incluyeron 16 pacientes, nueve hombres y siete mujeres. Las lesiones neurológicas asociadas fueron anomalías de cuerpo calloso, cortipatía severa con sordera, epilepsia, cavum vergae, nistagmo, quiste subaracnoideo occipital e hidrocefalia. Se demostró retraso psicomotor en 56 % de los pacientes. Se identificaron malformaciones congénitas como trigonocefalia, camptodactilia, hipoplasia facial, implantación baja de orejas. La ptosis palpebral se encontró en 81 % de los casos. El estrabismo más frecuente fue la exotropía (56 %) seguida de hipotropía (37.5 %), hipertropía (18.7 %), anisotropía en “A” (18.7 %) y endotropía (6.25 %). Los nervios craneales afectados fueron el III (93.75 %), VI (6.25 %) y VII (6.25 %); además, se encontró lesión a II nervio en 50 %. Conclusiones: La falla en los estadios tempranos del desarrollo del sistema nervioso central puede provocar estrabismo paralítico que secundariamente puede manifestarse como estrabismo fibrótico que afecta músculos y tejidos orbiculares, por lo que el término más apropiado sería “estrabismo fibrótico congénito como causa de dismorfogenesia de los nervios craneales”. Encontramos alta incidencia de retraso psicomotor y alteraciones neurológicas. Es importante la rehabilitación temprana y multidisciplinaria en estos pacientes.

OBJECTIVE: We undertook this study to describe central nervous system (CNS) abnormalities associated with congenital cranial dysinnervation disorders (CCDD). METHODS: This was a retrospective, observational, transversal and descriptive study including patients with congenital fibrotic strabismus. We analyzed clinical files of patients from 2001 to 2006. Neurological lesions were reported. RESULTS: Restrictive strabismus was demonstrated in all cases. Sixteen patients were included: nine males and seven females. Different neurological lesions were reported: corpus callosum anomalies, severe cortipathy, epilepsy, cavum vergae, nystagmus, occipital subarachnoid cyst, and hydrocephalus. Mental retardation was reported in 56% of patients. Different malformations were reported: genital malformations, trigonocephalus, camptodactyly, mild facial hypoplasia, low set ears, and agenesis of left ear. Blepharoptosis was present in 81% of patients. The most frequent form of strabismus was exotropia (56%), hypotropia in 37.5%, hypertropia 18.7%, "A" pattern 18.7%, and esotropia in 6.25%. Affection was cranial nerve III, 93.75%; cranial nerve VI, 6.25%; cranial nerve VII, 6.25%; and lesion to cranial nerve II in eight cases (50%). CONCLUSIONS: We have suggested that failure in early stages of embryology of the CNS can lead to the development of paralytic strabismus and generate secondary fibrotic changes, not only in muscle structures but also in other orbital tissues. That is the reason why we have used the term "congenital fibrotic strabismus" to report cases included in CCDD. We have demonstrated the strong association of mental retardation and neurological alterations. Multidisciplinary rehabilitation is relevant for these patients.

Unilateral restrictive ophthalmoplegia and enophthalmos associated with an intraorbital tissue band.

Fibrosis of the extraocular muscles can be congenital or acquired. Acquired causes include trauma, myositis, thyroid eye disease, infection, and metastases. Congenital fibrosis of the extraocular muscles (CFEOM) runs in families and is known to have a genetic basis. It has been classified by Brown, Hansen, and Harley et al into the five following types: general fibrosis syndrome; fibrosis of the inferior rectus (IR) with blepharoptosis; strabismus fixus; vertical retraction syndrome; and unilateral fibrosis, blepharoptosis, and enophthalmos syndrome. In this report, a case of unilateral fibrosis with enophthalmos and blepharoptosis due to a fibrous band is described.

Simultaneous pediatric kidney transplantation and ureterocystoplasty in a 20-month-old boy.

Kidney transplantation (KT) in children with end-stage renal disease and an abnormal bladder poses a complex management challenge. Ureterocystoplasty (UC) has been previously reported in older children with non-compliant bladders, but the timing and technique of repair are controversial. This case reports the youngest patient, a 20-month-old boy to undergo successful single-stage UC and living-related KT. UC was performed because of a fibrotic, non-compliant bladder. A temporary vesicostomy was placed to provide adequate drainage in the presence of urethral stenosis. The patient developed a single episode of pyelonephritis within the first six months post-operatively, but there were no other urologic complications. At 13 months, the renal function is excellent with a mean glomerular filtration rate of 100 mL/min/1.73 m(2) and no clinical evidence of rejection. This case demonstrates that simultaneous UC and KT can be safely performed even in infants with non-compliant bladders and renal failure.

Long-term outcome of strabismus and ptosis surgery in a mother and daughter with congenital fibrosis of extraocular muscles.

BACKGROUND: Congenital fibrosis of extraocular muscles (CFEOM) is a very rare congenital condition, characterized by variable amounts of restriction of the extraocular muscles, with or without ptosis. The aim of this report was to describe a severe, atypical, exposure-induced corneal stromal lysis in two patients. CASE REPORT: A mother and a daughter with a severe CFEOM were presented. The surgery of both extraocular muscles and ptosis led to a fair outcome in mother even 30 years after, and a very good outcome in daughter 4 years after the treatment. CONCLUSION: Though frequently challenging and dissapointing the outcome of surgery of both extraocular muscles and ptosis in CFEOM can be favorable even in rather severe cases. To the best of our knowledge, the atypical keratolysis we described has not been highlighted in the literature on CFEOM so far.

Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A.

Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a complex strabismus syndrome that results from mutations in the homeodomain transcription factor PHOX2A. To define the clinical and neuroimaging features of patients with this autosomal recessive syndrome, we studied 15 patients with genetically defined CFEOM2. All patients underwent full neurological, neuro-ophthalmological and orthoptic assessments. Twelve patients had pupillary pharmacological testing and nine had 3.0 tesla MRI of the brain, brainstem and orbits. Patients were born with severe bilateral ptosis and exotropia with almost complete bilateral absence of adduction, elevation, depression and intorsion. Variable abduction was present prior to strabismus surgery in 14 patients, and central ocular motility reflexes (smooth pursuit, saccades, vestibulo-ocular reflex and optokinetic reflex) were intact except for convergence. Pupillary light and near reflexes were not present, but irises were anatomically normal and responded to pupillary pharmacology. Neuroimaging of brain and brainstem was remarkable for the anatomical absence of cranial nerve (CN) 3 and probably CN 4 bilaterally. Therefore, the CFEOM2 phenotype and neuroimaging are both consistent with the congenital absence of CNs 3 and 4. Additional features included presence of most central ocular motility reflexes, a central lack of pupillary responsiveness of uncertain aetiology and modest phenotypic variability that does not correlate with specific PHOX2A mutations. Clinical presentation, neuroimaging and Phox2a-/- animal models all support the concept that CFEOM2 is a primary neurogenic abnormality with secondary myopathic changes.

Congenital unilateral ocular fibrosis syndrome secondary to benign congenital tumor.

Congenital unilateral fibrosis, blepharoptosis and enophthalmos syndrome is one of the rare forms of congenital fibrosis of extraocular muscles. The nature and cause of such unilateral inflammation leading to fibrosis is unknown. Prenatal orbital penetration has been proposed as a cause of this syndrome. We report a case of this rare syndrome associated with an adjacent sinus tumor.

Hallazgos en la RNM en pacientes con fibrosis congénita generalizada de los músculos extraoculares (CFEOM) / Findings on MRI in patients with congenital generalized fibrosis of the extraocular muscles (CFEOM)

Objetivo: Mostrar los hallazgos en la RNM de pacientes afectados de CFEOM Pacientes y métodos: Se presentan las RNM de 4 pacientes afectados de CFEOM Resultados: En todos se observa una marcada atrofia del recto superior y los otros músculos extraoculares inervados por el III nervio se ven adelgazados. El recto lateral en 1 paciente aparece bilobulado. En un paciente con oftalmoplegia, en la T1 se observa una señal brillante en el interior del cuerpo muscular. Conclusiones: La RNM de estos pacientes con CFEOM muestra 2 características: atrofia muscular del recto superior, elevador del párpado superior y señal brillante en el interior del cuerpo muscular.

Objectives: To show the findings on MRI in patients affected by CFEOM Patients and methods: The MRI of four patients affected by CFEOM were revieved Results: In all cases a significant atrophy of the superior rectus can be seen, and the other extraocular muscles, inervated by the III nerve, are visibly thinner. The lateral rectus, in one patient, appears bilobulated. In another patient with ophthalmoplegy, in T1, a brilliant signal in the interior of the muscular body can be observed. Conclusions: Two characteristics were found on the MRI in these patients with CFEOM. One is the muscular thinness of the PSL and SR, and the other is the brilliant signal in the interior of the muscular body. Also, some structural anomalies can be observed in other extraocular muscles.

Correlación clínico-genética en una familia portadora de fibrosis muscular congénita tipo 1 / Clinical and genetic correlation in a family with congenital muscular fibrosis type 1

Objetivo: Correlacionar tipo clínico de fibrosis muscular congénita (CFEOM tipo 1) y falla genética en los miembros afectados en tres generaciones de una familia chilena. Metodología: enrolamiento de portadores de fibrosis muscular congénita tipo clínico 1 (CFEOM 1) según protocolo. Fotografía y video, pedigrí familiar, obtención de muestra de sangre, extracción del DNA linfositario de casos/control, Linkage análisis de DNA. Resultados: Identificación de mutación AD en cromosoma 11, gen KIF21A en todos los afectados en una familia con tres generaciones con CFEOM tipo 1. Codifica proteína motora kinesina, que participa en el desarrollo del III par craneal. Conclusiones: En este tipo de estrabismo la alteración primaria es inervacional y no muscular. Relación entre forma clínica y cromosoma afectado permite caracterizar genéticamente las distintas formas clínicas de la enfermedad. Se propone una clasificación clínica nueva de los estrabismos restrictivos congénitos.

Aim: To correlate a clinical type of congenital muscular fibrosis (CFEOM type 1) with a genetic flaw in the affected members of three generations of a single Chilean family. Methods: Clinical type 1 congenital muscular fibrosis carriers were enrolled according to protocol. For each patient, the following information was collected: Video and pictures, family pedigree, blood samples, case/ control lymphocytes DNA, and DNA linkage analysis. Results: An AD mutation in chromosome 11 was identified. KIF21A gene was found in all affected members of the family over the three generations. It codified The motor protein kinesin, which is involved in the development of the third cranial nerve. Conclusions: In this form of strabismus, the primary dysfunction is innervational rather than muscular. The relationship between the clinical form and the affected chromosome permits identification of the various clinical forms of the disease. We propose a new clinical classification of the congenital restrictive strabismus.

Congenital trismus secondary to masseteric fibrous bands: a 7-year follow-up report as an approach to management.

A 7-year prospective follow-up report, which was previously presented in this journal as an initial pediatric case report, is presented as an approach to management of congenital trismus secondary to masseteric fibrous bands. Adams and Rees discussed management, including endoscopic exploration at 18 months of age with early recurrence of trismus. Under the care of the same plastic surgeon and his team, the progress of this patient over 7 years has given us an insight into management. The cause of trismus is not fully elucidated, but the condition can result in compromised caloric intake, speech development, facial appearance, dental care, and oral hygiene. The decreased oral opening may be secondary to shortening of the muscles of mastication, which may cause tension moulding and distortion of the coronoid process; yet, there is no consensus on the optimal management of temporomandibular joint trismus and all its causes. The patient presented in this report, now aged 7 years, has proceeded through to open surgery on two occasions yet, regrettably, has persistently tight masseter muscles and only 8 mm of jaw opening.