Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission. The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete CSNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel alpha1-subunit genes. Mutation analysis of this new alpha1-subunit gene, CACNA1F, in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation. These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina.

X-linked retinitis pigmentosa: re-evaluation of fundus findings and the use of haplotype analysis in clarification of carrier female status.

The identification by fundus examination of those females carrying an X-linked retinitis pigmentosa (RP) gene can reportedly be as high as 87%. In genetic counselling sessions with young females with a 50% risk of being a carrier who wished to know their status, it has not been possible to achieve such a level of success. A review and reanalysis of previous reports indicated that if a tapetal-like reflex was not present in those age 35 years or less, the likelihood of identifying a carrier by fundus examination was small. A family with 7 females with a 50% risk of being a carrier of X-linked RP was evaluated using haplotype analysis in an attempt to identify the X chromosome carrying the RP gene. In the family described, it was possible to establish that a mutation in the RP3 locus most likely causes the disease. This has permitted the determination of the carrier status in each of the females with a high degree of certainty.

Histopathology and molecular basis of iridogoniodysgenesis syndrome.

Iridogoniodysgenesis is an autosomal dominant disorder in which there are abnormalities in the development of the iris stroma and trabecular meshwork tissues commonly resulting in glaucoma. The unoperated eye from an affected member of a family with iridogoniodysgenesis syndrome (IGDS) was removed shortly after death. Histopathological studies showed an incomplete, normally positioned line of Schwalbe and iris stromal hypoplasia. The molecular basis underlying the disorder is a missense mutation in the RIEG gene at 4q25, mutations of which have been previously shown to cause Axenfeld-Rieger syndrome (ARS). Coupled with another report of a missense mutation of the RIEG gene in a family with IGDS, we suggest that these mutations may interfere less with gene function and thereby may be responsible for a milder phenotype than occurs in the more characteristic ARS.

Senior-Loken syndrome. Case reports of two siblings and association with sensorineural deafness.

Two siblings with Senior-Loken syndrome are described. The need for a full evaluation of renal function and hearing in children with a retinal dystrophy is emphasised.

Corneal involvement in autosomal dominant coloboma/microphthalmos.

Peripheral corneal opacification in the line of closure of the embryonic fissure associated with hyperopic astigmatism and anisometropic amblyopia was identified in two eyes of two members of a family with isolated autosomal dominant coloboma-microphthalmos. A review of the literature disclosed no previously reported cases. It would appear that the gene for isolated coloboma-microphthalmos can affect the growth and differentiation of mesenchymal cells of neural crest origin, as well as the neuroectodermal tissues of the embryonic fissure.

Autosomal dominant megalocornea with congenital glaucoma: evidence for germ-line mosaicism.

After the presentation of a newborn with congenital glaucoma, four additional members in two generations of a family were found to be affected with megalocornea. The absence of the disorder in the parents of three affected siblings can be explained by autosomal recessive inheritance, autosomal dominant inheritance or germ-line mosaicism. Each affected member showed iris stroma hypoplasia, miotic pupils and defects of the iris pigment epithelium. Less frequently encountered features included increased axial length, high myopia and congenital cataract. Most of the abnormalities can be accounted for by a disturbance in the growth and development of neural crest cells of the anterior chamber angle.

Congenital nystagmus--genetic and environmental causes.

A survey of 40 individuals registered with the Canadian National Institute for the Blind (CNIB) as blind from congenital nystagmus revealed that an abnormal single gene was responsible for the disorder in 33 patients. Fifteen of these were due to autosomal recessive conditions while X-linked disorders accounted for another 15 patients. In 3 cases the pedigrees were consistent with both autosomal recessive or X-linked inheritance. A clearly defined environmental origin was present in 1 case while specific genetic or environmental factors were not detected in the remaining six patients. The albinism, achromatopsia and Leber's congenital amaurosis groups of disorders were those most frequently detected.

Causes of blindness in children. 1046 cases registered with the Canadian National Institute for the Blind 1970-1973.

During the period 1970-73, 1,046 children under 20 years of age were registered with the Canadian National Institute for the Blind. The three most common registration diagnoses were Cataract (13%), Optic Atrophy (12%) and Nystagmus (10%); Retrolental Fibroplasia was responsible for a smaller proportion (6%). Twenty per cent of the registration diagnoses were non-specific and included "Nystagmus", "Site or Type not Established", "Affection of Visual Centre" and "Amblyopia". Without a specific diagnosis one could not decide whether the blindness was due to genetic or environmental causes. It is recommended that the C.N.I.B. establish a procedure by which children with a non-specific registration diagnosis can be referred for further investigation.

Hereditary macular dystrophy. A clinical and genetic study of two specific forms.

Four families with nine members affected with autosomal recessive macular dystrophy (Stargardt's Disease) and one family with six members affected with autosomal dominant macular dystrophy have been examined. Age of onset, rate of visual deterioration, fundus appearance, electroretinography and dark adaptometry have been compared in the various families. Some differences, particularly in the rate of visual deterioration and in the fundus appearance were noted between the recessive and dominant forms. Despite these differences in the clinical and related features, the genetic implications are of greater importance to the affected individuals. Genetic counselling which provides recurrence risks of the disorder in the affected individuals' siblings and children should be included in the assessment of patients with these forms of hereditary ocular disease.

Muscle recession with a suture loop in rabbits.

We recessed extraocular muscles in rabbits using loops of silk sutures. The effectiveness of the pseudotendons produced depended on their relation to the functional equator of the eye and on the length adherent to the sclera. Loops about 5 mm long inserted at or near the functional equator produced effective pseudotendons. If the loops were inserted in front of the functional equator they adhered to the sclera and the advantage of using them was negated.

Incidence of accommodative impairment following traumatic hyphema.

To examine the effect of traumatic hyphema on accommodation, we reviewed the records of 158 patients (159 eyes) admitted to hospital between Jan. 1, 1988, and Dec. 31, 1989, for treatment of traumatic hyphema. A sample of 30 patients were examined an average of 29.6 months after injury, and 2 (7%) were found to have accommodative impairment of greater than 2.5 dioptres. Post-traumatic accommodative impairment may cause prolonged reading disability requiring asymmetric spectacle correction.

Inferior rectus muscle restriction after retrobulbar anesthesia for cataract extraction.

Among the recognized complications of retrobulbar anesthesia, postoperative permanent diplopia has rarely been reported. We describe two patients with inferior rectus muscle restriction after retrobulbar anesthesia for cataract extraction and intraocular lens implantation. Both did well after inferior rectus recession with placement of an adjustable suture.

Adjustable sutures: experimental assessment of final muscle position.

The likelihood of forward "creep" of muscles recessed with the use of adjustable loops of suture in the correction of strabismus was investigated. Twelve orthotropic dogs underwent both regular and loop recessions of the lateral and medial rectus muscles; the data for two of the dogs were excluded because of loss of muscles. Three months later it was found that in the majority of cases the recessed muscles had minimally advanced from the position of surgical placement. Although the type of recession made little difference to the results, the mean forward creep was much greater for the medial rectus muscles (1.55 +/- 0.68 mm [p less than 0.01] and 2.00 +/- 2.44 mm [p = 0.09] for those undergoing regular and loop recessions respectively) than for the lateral rectus muscles (0.35 +/- 0.58 mm and 0.60 +/- 0.62 mm respectively). During the operations the amount of contraction of the medial rectus muscle had been noted to vary. It is likely that in some instances the tension on the suture loops was insufficient to hold them taut, and the muscles therefore adhered to the sclera at variable sites. Hence, adequate intrinsic muscle tone may be important for predictable clinical results of loop recession.

Extraocular muscle recession with a suture loop in dogs.

Extraocular muscle recessions with loops of silk suture were performed in 10 dogs. When, after a 5-mm section of the medial rectus muscle was resected, suture loops 5 mm long were inserted near the functional equator (8 mm behind the muscle's original insertion) an effective pseudotendon was produced in 71% of the eyes. This procedure may be a useful addition to the surgical methods of correcting horizontal strabismus.

End-stage cytomegalic inclusions retinitis and disseminated intravascular coagulation.

Areas of necrosis of the retinal pigment epithelium developed in each eye of a 40-year-old renal transplant recipient. Myocardial infarctions supervened and eventually caused his death. Autopsy demonstrated cytomegalic inclusion bodies in the lungs and liver, and areas of retinal scarring and fibrin thrombi in the choriocapillaris of both eyes. The ocular features likely resulted from the resolved retinitis and preterminal disseminated intravascular coagulation.

Unexpected stereoacuity following surgical correction of long-standing horizontal strabismus.

Eight patients with long-standing large-angle constant tropias unexpectedly achieved stereoacuity (40 seconds of arc in six patients and 60 seconds of arc in two patients) following strabismus surgery. There are few reports in the literature documenting this finding. The authors found that if excellent postoperative alignment can be achieved in patients with good bilateral visual acuity, some of these patients will demonstrate high-grade stereoacuity even if the preoperative findings suggest this outcome to be unlikely.

Variable expressivity in X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a well-documented disorder in which the most striking clinical features are impaired night vision, nystagmus and myopia. Recent reports have highlighted differing features between families, and it has been suggested that these discrepancies may be the result of two loci on the X chromosome or of two mutant alleles. We outline the clinical and visual function findings in 42 affected members from 10 families and 1 adopted person. There was a relative unawareness of the disorder in clinical practice. At least one of the main features of CSNB was absent in 75% of the patients. The visual function values varied widely, both between and within families (visual acuity 20/30 to 20/400, refractive error +1.50 to -22.50 and rod segment elevation 1.5 to 3.0 log units). The findings are consistent with a single allele exhibiting a wide variation in clinical expression.

Bardet-Biedl syndrome and retinitis punctata albescens in an isolated northern Canadian community.

Autosomal recessive inheritance of various conditions is well documented among inbreeding groups. In northern Canada inbreeding occurs in communities as a result of language and cultural uniqueness as well as geographic isolation. In one such community--Rae, in the Northwest Territories--two autosomal recessive disorders, the Bardet-Biedl syndrome and retinitis punctata albescens, are segregating. This report outlines the major clinical features of the disorders, establishes for both conditions the high frequency of the heterozygous carrier genotype in the community and suggests a possible way to reduce the likelihood of increased numbers of affected individuals in forthcoming generations.

Recession of the superior oblique tendon in A-pattern strabismus.

We performed 9 to 12 mm of recession of the superior oblique tendon for A-pattern strabismus in 10 patients. The average preoperative A-pattern measured 29.4 prism dioptres (PD), and the average pattern correction was 29.3 PD. All patients had a residual pattern of 6 PD or less (average 2.3 PD). No patient experienced significant underaction of the superior oblique, and other surgical complications, such as ptosis, Brown's syndrome, and laceration of the vortex vein or superior rectus, did not occur. The procedure corrected 14 to 40 PD of A-pattern. The amount of pattern corrected was correlated with the size of the preoperative A-pattern but not with the total amount of recession done. No significant shift in esodeviation in primary position was noted in the patients who underwent only superior oblique recession. The procedure appears to be of particular value in patients with moderate superior oblique overaction. The advantages of recession of the superior oblique tendon include the potential for reversibility and reoperation, low risk of induced superior oblique palsy, allowance for asymmetric surgery and potential for adjustable suture technique.

Clinical variability among patients with incomplete X-linked congenital stationary night blindness and a founder mutation in CACNA1F.

BACKGROUND: Incomplete X-linked congenital stationary night blindness (CSNB) is a clinically variable condition that has been shown to be caused by mutations in the calcium-channel CACNA1F gene. We assessed the clinical variability in the expression of the incomplete CSNB phenotype in a subgroup of patients of Mennonite ancestry with the same founder mutation. METHODS: Sixty-six male patients from 15 families were identified with a common mutation in exon 27 of CACNA1F (L1056insC). Clinical variability in night blindness, reduced visual acuity, myopia, nystagmus and strabismus was examined. RESULTS: At least one of the major features of CSNB (night blindness, myopia and nystagmus) was absent in 72% of the patients. All the examined features varied widely, both between and within families. INTERPRETATION: Although the patients shared a common CACNA1F mutation, there was considerable variability in the clinical expression of the incomplete CSNB phenotype. These findings suggest the presence of other genetic factors modifying the phenotype of this disorder.