Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature.

BACKGROUND: The clinical phenotype of patients presenting with autosomal recessive CDHR1-related retinopathy has not been well described. MATERIALS AND METHODS: This is a retrospective case series of patients presenting to a single institution. Clinical data, including age, visual acuity, dilated fundus exam, fundus photos, fundus autofluorescence (FAF), optical coherence tomography, full-field electroretinograms (ERGs), and results of genetic testing, were collected. RESULTS: Four patients were identified to have biallelic mutations in the CDHR1 gene. All four patients were found to have at least one c.783G>A (p.Pro261 = ) mutation. A novel splice site mutation, c.152-2A>G, was identified in two patients. Patients became symptomatic between the fourth and sixth decades of life. Three patients presented initially with nyctalopia and peripheral visual field constriction, and one patient presented with simultaneous onset of photophobia and nyctalopia. The fundus appearance was characterized by macular atrophy with or without peripheral retinal pigment epithelium changes and arteriolar attenuation. FAF showed a hyperautofluorescent ring surrounding a central area of speckled hypoautofluorescence. Full-field electroretinography was available on three patients and showed decreased cone-and-rod responses. CONCLUSIONS: CDHR1-related retinal dystrophy should be considered in adult patients with a retinal dystrophy who present with symptoms of cone-and-rod dysfunction and macular atrophy on ophthalmoscopic examination.

Associated systemic and ocular disorders in patients with congenital unilateral cataracts: the Infant Aphakia Treatment Study experience.

PurposeFive-year prospective data on children enrolled in the Infant Aphakia Treatment Study (IATS) provided an opportunity to explore ocular and systemic associations in patients with a unilateral congenital cataract.MethodsInfants <7 months of age with a unilateral cataract were eligible for IATS screening. We reviewed data pertaining to the exclusion of patients as well as data collected on standardized study forms used at any time for documentation of ocular or systemic disorders.ResultsOverall, 227 infants were referred for possible enrollment. Of these, 10 had insignificant cataracts and 32 refused to participate. Of those excluded, 3 were premature, 27 had significant ocular disease (usually persistent fetal vasculature (PFV) or corneal diameter <9 mm), and 4 had systemic disorders. An additional 26 were excluded at the time of the first EUA, most often because of PFV or variants thereof. On follow-up, in the 114 enrolled patients, the following disorders were diagnosed: Stickler syndrome (1), mitochondrial disease (1), autism (1), and presumed congenital rubella syndrome (1). No patient developed a cataract in the fellow eye.DiscussionSome conditions that can feature unilateral cataracts are diagnosed at birth or very early in life, but others may be diagnosed at varying periods thereafter. PFV and its variants are the most common associated ocular findings in about a quarter of cases of unilateral congenital cataracts.ConclusionAlthough patients with a unilateral cataract may have significant associated abnormalities in the affected eye, most commonly PFV and its variants, the prevalence of associated significant systemic disease is quite low.

Histopathology of the Retina from a Three Year-Old Suspected to Have Joubert Syndrome.

PURPOSE: To define the retinal pathology in a 3 year-old eye donor who died from complications of an undiagnosed genetic syndrome. METHODS: Eyes were fixed and analyzed using macroscopic fundus photography (MF), confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT). Small areas from the perifovea and periphery were processed for histology and indirect immunofluorescence, using antibodies specific to retinal proteins such as rhodopsin, cone arrestin, RPE65 and others. Available medical records were also reviewed. RESULTS: With all three imaging modalities, the affected donor's eyes lacked the distinct morphological detail typically observed with these techniques in postmortem control eyes. MF images showed a "photonegative effect" due to a hypopigmented macula relative to a hyperpigmented retinal background. cSLO imaging demonstrated a weak autofuorescence signal that was largely devoid of the usual retinal structures compared to the control. SD-OCT suggested disorganization of the affected retina, absence of a photoreceptor layer, and degeneration of the choroid in the macular area. Histologic findings indicated a highly disorganized photoreceptor layer in the macula and periphery. The RPE layer displayed thinning in some regions of the periphery and decreased pigmentation in most areas. Rods and cones were significantly reduced in the affected retina but a few cones were detected in the perifovea. Centrin-2 labeling was mostly absent from the connecting cilium of the photoreceptor cells. Medical record review pointed to a possible clinical diagnosis of Joubert syndrome. CONCLUSIONS: The retinal degenerative findings, and absence of centrin-2 labeling are compatible with the expected retinal phenotype in patients with Joubert syndrome.

Spondylometaphyseal dysplasia with cone-rod dystrophy.

PURPOSE: To report on the clinical ophthalmologic and radiographic findings in spondylometaphyseal dysplasia with cone-rod dystrophy. BACKGROUND: The spondylometaphyseal dysplasias are a rare and heterogeneous group of disorders characterized by skeletal abnormalities of the spine and the metaphyses of long bones. In rare instances, spondylometaphyseal dysplasia can occur concomitantly with ocular abnormalities including a retinal degeneration of the cone-rod dystrophy type. METHODS: Retrospective review of affected twin females with serial radiographic imaging, comprehensive ophthalmologic examination, fundus photography, and electroretinography. RESULTS: The major radiographic findings involved bony abnormalities of the spine, metaphyses of the long bones and a distinctive shape to the bony pelvis. Both twins had a fine nystagmus that was present by 10 months of age. Dilated ocular fundus examination revealed similar appearing bilateral, large, excavated, well-circumscribed oval areas of chorioretinal atrophy occupying the macula between the aracades. Electroretinography showed a significant reduction in the photopic responses and slight reduction in the scotopic component of the waveforms consistent with cone-rod dystrophy. CONCLUSIONS: Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare congenital disorder of unknown inheritance pattern and pathophysiolgy. The ocular manifestations appear to stabilize in early adolescence whereas the skeletal abnormalities are progressive with age.

The Marshall M. Parks memorial lecture: making sense of early-onset childhood retinal dystrophies--the clinical phenotype of Leber congenital amaurosis.

A correct diagnosis of the early-onset childhood retinal dystrophies requires careful clinical evaluation, the detection of suggestive or pathognomonic ophthalmoscopic clues, the use of electrophysiology to document characteristic electroretinographic findings and, in some cases, the utilisation of newer diagnostic modalities such as optical coherence tomography. Molecular diagnosis confirms the clinical diagnosis and provides the basis for possible future gene therapy. A strict definition of early-onset childhood retinal dystrophies (EOCRDs) does not exist, but inherited retinal dystrophies that are diagnosed in the first few years of life could be included under this umbrella terminology. The clinical ophthalmological manifestations of these diseases may or may not be detected at birth, and include the triad of severe vision loss, sensory nystagmus and electroretinographic abnormalities. Their clinical manifestations are light sensitivity, night blindness, fundus pigmentary changes and other psychophysical and retinal anatomic abnormalities. Diseases that could be included in the EOCRDs are Leber congenital amaurosis, achromatopsia, congenital stationary night blindness, X-linked juvenile retinoschisis, Goldmann-Favre disease and other NR2E3-related disorders, and possibly some very early-onset forms of Stargardt disease and juvenile retinitis pigmentosa. In this paper, phenotypic clues to the diagnosis of the underlying molecular defect in patients with Leber congenital amaurosis are discussed and an overview of the clinical workup of the child with a retinal dystrophy is presented. An accurate diagnosis of individual EOCRD allows a better prediction of the clinical course and the planning of possible and emerging therapies.

Pituitary stalk duplication in association with moya moya disease and bilateral morning glory disc anomaly - broadening the clinical spectrum of midline defects.

BACKGROUND: Duplication of the pituitary stalk, morning glory disc anomaly and moya moya are rare malformations. The combination of these findings may be syndromic and may have an underlying genetic etiology. METHODS: Case report and review of the literature of neurological, ophthalmological, and neuroradiological findings including ophthalmic examination, MRI and MRA. CASE REPORT: A 2 year-old girl presented with reduced visual acuity and roving eye movements since birth. Ophthalmological workup revealed bilateral morning glory disc anomaly. MRI showed duplication of the pituitary stalk and caudal displacement of the floor of the third ventricle. MRA showed narrowing of the supraclinoid internal carotid arteries with focal narrowing of the proximal middle cerebral arteries consistent with early moya moya disease. CONCLUSIONS: Review of the literature of pituitary gland duplication and of the combination of morning glory disc anomaly and moya moya disease revealed only one previously reported case. However, the spectrum of this possibly syndromic presentation may be much broader and include various types of anterior midline defects and may have a common underlying genetic cause.

Idiopathic macular hypoplasia: a report of four cases and refinement of the phenotype of so-called ateliotic macula.

PURPOSE: To refine the phenotype of idiopathic macular hypoplasia, also referred to as ateliotic macula, by describing a series of cases with this diagnosis. METHODS: A review of the clinical characteristics of four patients as documented in medical records with regard to refractive error, visual acuity, anterior segment examination, retinal findings, and ancillary tests such as electroretinography (ERG). RESULTS: All patients had oval circumscribed or diffuse areas in the posterior pole where the retina appeared not to have developed normally; the fovea was involved in three patients with reduced visual acuity, and one patient had parafoveal lesions with preserved visual acuity. There were three males and one females. Patients' age ranged from 4 to 16 years. Errors of refraction ranged from severe myopia to hypermetropia and mild astigmatism. The anterior segment was normal in all patients. Three patients had strabismus and two had nystagmus. ERG was normal in the one patient in whom it was performed. One patient was mosaic for trisomy of chromosome 9. CONCLUSIONS: The term idiopathic macular hypoplasia can be applied to a spectrum of abnormalities in which a localized area of the posterior pole has a primordial or underdeveloped appearance. Lesions involving the fovea result in poor acuity. Generalized retinal dysfunction is absent. At least one of the genes involved in macular development may be located on chromosome 9.

Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28.

We have defined a new genetic locus for an X linked form of retinitis pigmentosa (RP) on chromosome Xq28. We examined 15 members of a family in which RP appeared to be transmitted in an X linked manner. Ocular examinations were performed, and fundus photographs and electroretinograms were obtained for selected patients. Blood samples were obtained from all patients and an additional seven family members who were not given examinations. Visual acuity in four affected individuals ranged from 20/40 to 20/80+. Patients described the onset of night blindness and colour vision defects in the second decade of life, with the earliest at 13 years of age. Examined affected individuals had constricted visual fields and retinal findings compatible with RP. Based on full field electroretinography, cone function was more severely reduced than rod function. Female carriers had no ocular signs or symptoms and slightly reduced cone electroretinographic responses. Affected and non-affected family members were genotyped for 20 polymorphic markers on the X-chromosome spaced at 10 cM intervals. Genotyping data were analysed using GeneMapper software. Genotyping and linkage analyses identified significant linkage to markers DXS8061, DXS1073, and DXS1108 with two point LOD scores of 2.06, 2.17, and 2.20, respectively. Haplotype analysis revealed segregation of the disease phenotype with markers at Xq28.

Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3.

BACKGROUND: Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder characterised by congenital absence of horizontal gaze, progressive scoliosis, and failure of the corticospinal and somatosensory axon tracts to decussate in the medulla. We previously reported that HGPPS patients from consanguineous pedigrees harbour homozygous mutations in the axon guidance molecule ROBO3. METHODS: We now report two sporadic HGPPS children of non-consanguineous parents who harbour compound heterozygous mutations in ROBO3. The mother of one of the children also had scoliosis DNA was extracted from a blood sample from each participant using a standard protocol, and the coding exons of ROBO3 were amplified and sequenced as previously described. RESULTS: Each patient harboured two unique heterozygous mutations in ROBO3, having inherited one mutation from each parent. CONCLUSIONS: HGPPS can result from compound heterozygous mutations. More comprehensive examinations of parents and siblings of HGPPS patients are required to determine if the incidence of scoliosis in individuals harbouring heterozygous ROBO3 mutations is greater than in the general population.

Ocular pathology in congenital heart disease.

PURPOSE: To describe the ocular findings in subjects with congenital heart disease (CHD). METHODS: In a prospective study, the same observer examined 240 consecutive patients with CHD admitted to the medical centre. Two independent geneticists performed identification of syndromes. RESULTS: The commonest anatomic cardiac anomalies were ventricular or atrial septal defects (62), tetralogy of Fallot (39), pulmonary stenosis (25), and transposition of the great arteries (24). The heart lesions were divided physiologically into volume overload (90), cyanotic (87), and obstructive (63). In all, 105 syndromic subjects included the velocardiofacial syndrome (18), Down's syndrome (17), CHARGE association (6), DiGeorge syndrome (5), Williams syndrome (3), Edwards syndrome (3), Noonan syndrome (3), VACTERL association (2), and Patau syndrome (trisomy 13) (2). The paediatric team recognized 51 patients as syndromic. Two independent geneticists recognized additional 54 patients as syndromic. Positive eye findings were present in 55% (132) and included retinal vascular tortuosity (46), optic disc hypoplasia (30), trichomegaly (15), congenital ptosis (12), strabismus (11), retinal haemorrhages (8), prominent eyes (7), and congenital cataract (6). There was a strong correlation between the retinal vascular tortuosity and both a low haematocrit (P=0.000) and a low arterial oxygen saturation (P=0.002). CONCLUSIONS: Patients with CHD are at a high risk for ocular pathology and need screening for various ocular abnormalities.

Bilateral microphthalmia with cyst, facial clefts, and limb anomalies: a new syndrome with features of Waardenburg syndrome, cerebro-oculo-nasal syndrome, and craniotelencephalic dysplasia.

We report a patient with bilateral microphthalmia with cyst, limb anomalies, and multiple facial malformations. This patient has clinical features similar to Waardenburg ophthalmo-acromelic syndrome, cerebro-oculo-nasal syndrome, and craniotelencephalic dysplasia. Although all of these syndromes are characterized by microphthalmia, the presently reported patient does not have the complete pattern of any of these syndromes, It is possible that he has a previously undescribed syndrome, most closely related to the cerebro-oculo-nasal syndrome with malformations outside the craniofacial region. More case reports are needed to further delineate this possibly new syndrome.

Clinical, genetic and histopathologic findings in two siblings with muscle-eye-brain disease.

PURPOSE: We present the clinical, genetic and histopathologic findings in two siblings with Muscle-Eye-Brain Disease (MEB-D), an autosomal recessive disease characterized by mental retardation, muscular dystrophy, retinal hypoplasia and brain abnormalities. METHODS: Clinical, histopathologic and gene mapping studies of a family with two normal and two children with MEB-D. RESULTS: Two siblings presented in the first few months of life with developmental delay, hypotonia, and strabismus. MRI of the brain showed colpocephaly, pontine and cerebellar atrophy, and diffuse white matter disease. Both patients were blind and had high myopia, strabismus, and retinal and optic nerve abnormalities. The older boy had glaucoma. Both children died from uncontrolled seizures. There was retinal, choroidal and RPE atrophy and optic nerve hypoplasia on ocular histopathology. Both patients shared the same parental haplotypes at the MEB locus on chromosome 1p, while an unaffected sibling did not, indicating possible linkage to the MEB locus. CONCLUSIONS: Patients with MEB-D have severe visual impairment from retinal and optic nerve hypoplasia. High myopia appears to be a consistent finding. The ocular manifestations of MEB-D appear to be distinct from those of patients with Walker-Warburg syndrome.

Update on the molecular genetics of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a heterogeneous group of retinal dystrophies characterized by photoreceptor cell degeneration. RP causes night blindness, a gradual loss of peripheral visual fields, and eventual loss of central vision. Advances in molecular genetics have provided new insights into the genes responsible and the pathogenic mechanisms of RP. The genetics of RP is complex, and the disease can be inherited in autosomal dominant, recessive, X-linked, or digenic modes. Twenty-six causative genes have been identified or cloned for RP, and an additional fourteen genes have been mapped, but not yet identified. Eight autosomal dominant forms are due to mutations in RHO on chromosome 3q21-24, RDS on 6p21.1-cen, RP1 on 8p11-21, RGR on 10q23, ROM1 on 11q13, NRL on 14q11.1-11.2, CRX on 19q13.3, and PRKCG on 19q13.4. Autosomal recessive genes include RPE65 on chromosome 1p31, ABCA4 on 1p21-13, CRB1 on 1q31-32.1, USH2A on 1q41, MERTK on 2q14.1, SAG on 2q37.1, RHO on 3q21-24, PDE6B on 4p16.3, CNGA1 on 4p14-q13, PDE6A on 5q31.2-34, TULP1 on 6p21.3, RGR on 10q, NR2E3 on 15q23, and RLBP1 on 15q26. For X-linked RP, two genes, RP2 and RP3 (RPGR), have been cloned. Moreover, heterozygous mutations in ROM1 on 11q13, in combination with heterozygous mutations in RDS on 6p21.1-cen, cause digenic RP (the two-locus mechanism). These exciting molecular discoveries have defined the genetic pathways underlying the pathogenesis of retinitis pigmentosa, and have raised the hope of genetic testing for RP and the development of new avenues for therapy.

Dominant radial drusen and Arg345Trp EFEMP1 mutation.

PURPOSE: To report a new North American family with dominant radial drusen and Arg345Trp mutation in the EFEMP1 gene. METHODS: Clinical and molecular genetic family study. RESULTS: Four family members had macular drusen, and one had submacular fibrosis and visual loss. An Arg345Trp mutation of the EFEMP1 gene was detected in three affected family members, but not in three unaffected members. CONCLUSION: The Arg345Trp mutation remains the only cause of Doyne hereditary macular dystrophy, also known as Malattia Leventinese or radial dominant drusen.

Confirmation of the autosomal recessive syndrome of ectopia lentis and distinctive craniofacial appearance.

We report four members of a Lebanese Druze family with the syndrome of lens dislocation, spontaneous filtering blebs, anterior segment abnormalities, and a distinctive facial appearance. The constellation of clinical abnormalities in these patients is not suggestive of the Marfan syndrome or other connective tissue disorders associated with ectopia lentis. We previously described this syndrome in another presumably unrelated and highly inbred Druze family from the mountains of Lebanon. We postulated autosomal recessive inheritance in a pseudo-dominant pedigree. A few isolated reports of similar cases are scattered in the world literature. We now confirm that this is a distinct autosomal recessive syndrome whose gene mutation is enriched in the Lebanese Druze community.

Comparison of clinical characteristics of familial and sporadic acquired accommodative esotropia.

PURPOSE: To compare the clinical characteristics of patients with familial and nonfamilial acquired accommodative esotropia. METHODS: We recruited 48 patients from 33 families with acquired accommodative esotropia (an inward deviation of the eyes of 10 PD or more, a hypermetropia greater than or equal to +1.50 D, and an onset of esotropia at, or later than, 1 year of age). Our control group consisted of 20 patients with no known family history. Spherical error of refraction, stereoacuity, and need for strabismus surgery were determined and the 2 groups were compared. RESULTS: No statistically significant difference was found between the spherical equivalent error of refraction in familial cases (mean = +4.50 OD, +4.63 OS; range = +1.50 to +10.30 OD, +2.00 to +9.38 OS) versus those with nonfamilial disease (mean = +4.93 OD, +5.02 OS; range = +2.50 to +11.00 OD, +2.50 to +10.90 OS) (P =.47 OD; P =.47 OS). There also was no difference between the percentage of patients with familial disease who had some degree of stereoacuity (58%) and those without a family history (59%) (P > .99). Patients with familial acquired accommodative esotropia did not require more surgical interventions (26%) than those with nonfamilial acquired accommodative esotropia (30%) (P = .79). CONCLUSIONS: The general clinical characteristics of familial and nonfamilial acquired accommodative esotropia are very similar.

Anterior transposition of the inferior oblique muscle as the initial treatment of a snapped inferior rectus muscle.

Snapping or tearing of an extraocular muscle refers to its rupture across its width, usually at the junction between muscle and tendon several millimeters behind the insertion. Tearing occurs during strabismus or retinal reattachment surgery, or after trauma. If the proximal end of the muscle cannot be located, transposition procedures are necessary to achieve ocular realignment. These surgical procedures carry the risk of anterior segment ischemia, especially in the elderly. Anterior transposition of the inferior oblique muscle has been used for the treatment of inferior oblique overaction, especially in the presence of a dissociated vertical deviation, and in patients with fourth nerve palsy. We transposed the inferior oblique muscle insertion in a 73-year-old woman with a snapped inferior rectus muscle.