Genetic basis of total colourblindness among the Pingelapese islanders.

Complete achromatopsia is a rare, autosomal recessive disorder characterized by photophobia, low visual acuity, nystagmus and a total inability to distinguish colours. In this disease, cone photoreceptors, the retinal sensory neurons mediating colour vision, seem viable but fail to generate an electrical response to light. Achromatopsia, or rod monochromatism, was first mapped to 2p11-2q12 (MIM 216900; ref. 3), where it is associated with missense mutations in CNGA3 (ref. 4). CNGA3 encodes the alpha-subunit of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A second locus at 8q21-q22 has been identified among the Pingelapese islanders of Micronesia, who have a high incidence of recessive achromatopsia (MIM 262300). Here we narrow the achromatopsia locus to 1.4 cM and show that Pingelapese achromatopsia segregates with a missense mutation at a highly conserved site in CNGB3, a new gene that encodes the beta-subunit of the cone cyclic nucleotide-gated cation channel. Two independent frameshift deletions establish that achromatopsia is the null phenotype of CNGB3. Combined with earlier findings, our results demonstrate that both alpha- and beta-subunits of the cGMP-gated channel are essential for phototransduction in all three classes of cones.

Molecular genetics of human blue cone monochromacy.

Blue cone monochromacy is a rare X-linked disorder of color vision characterized by the absence of both red and green cone sensitivities. In 12 of 12 families carrying this trait, alterations are observed in the red and green visual pigment gene cluster. The alterations fall into two classes. One class arose from the wild type by a two-step pathway consisting of unequal homologous recombination and point mutation. The second class arose by nonhomologous deletion of genomic DNA adjacent to the red and green pigment gene cluster. These deletions define a 579-base pair region that is located 4 kilobases upstream of the red pigment gene and 43 kilobases upstream of the nearest green pigment gene; this 579-base pair region is essential for the activity of both pigment genes.

A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis.

PURPOSE: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. MATERIALS AND METHODS: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. RESULTS: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. CONCLUSION: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers.

A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype.

PURPOSE: To identify and characterize new cone rod homeobox (CRX) mutations associated with the Leber congenital amaurosis phenotype. METHODS: The human CRX gene was sequenced in 74 consecutive patients carrying the diagnosis of Leber congenital amaurosis. RESULTS: Two mutations were identified in CRX that cause frameshifts and predict severe truncations of the encoded protein. One of these, a 1-bp insertion, spares only nine N-terminal amino acids, removing the homeodomain, WSP motif, and conserved OTX domain at the C terminus. Of the CRX mutations described in the literature, this is the first that convincingly represents a null allele of the gene. Although the patient heterozygous for this null allele is affected with Leber congenital amaurosis, it was surprising that her father, who had normal vision, was heterozygous for the same mutation. CONCLUSIONS: These results strongly suggest that haploinsufficiency of CRX is not sufficient to cause a retinal disorder. Loss of function alleles of CRX appear to cause Leber congenital amaurosis through a recessive or multigenic mechanism.

Microphthalmos in the presumed homozygous offspring of a first cousin marriage and linkage analysis of a locus in a family with autosomal dominant cerulean congenital cataracts.

A family with autosomal dominant congenital cataracts was studied to determine clinical variability. A total of 159 relatives was ascertained; 17 affected and 19 normal individuals were evaluated and their blood sampled for inclusion in the linkage analysis. The disease was compatible with normal to mildly decreased visual acuity until adult life in all affected except the product of a consanguineous marriage of affected first cousins who was born with bilateral microphthalmos and dense congenital cataracts, attributed to homozygosity of the cataract gene. There were no extraocular abnormalities; the patient was of normal intelligence. Twenty-three markers were typed, 18 of which were informative. Linkage could be excluded for all 18 markers at short distances.

Mitochondrial DNA mutation and heteroplasmy in type I Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by bilateral acute or subacute loss of central vision, primarily in young males. A G----A single base mutation at 11778nt of the mitochondrial genome which eliminates a SfaNI restriction site [Wallace et al., 1988; Holt et al., 1989; Hotta et al., 1989; Singh et al., 1989; Vilkki et al., 1989; Yoneda et al., 1989; Stone et al., 1990; Lott et al., 1990.] has been found in more than 60% of the families with LHON studied. We studied 25 persons from 4 families with LHON using SfaNI and Mae III digestion of a 201 base pair polymerase chain reaction (PCR) product encompassing the 11778nt mutation. The loss of the SfaNI site and the acquisition of a Mae III site at 11778nt were identified in all maternal relatives of the LHON families studied. The mutation was heteroplasmic in all affected individuals, female carriers, and males at-risk. The heteroplasmy of mitochondrial DNA (mtDNA) was also identified by direct DNA sequencing of PCR amplified by direct DNA sequencing of PCR amplified mtDNA digested by SfaNI or Mae III. It appears that the proportion of the mutant mtDNA correlates with the severity of the disease.

Linkage analysis in lattice corneal dystrophy.

Two kindreds of lattice corneal dystrophy (LCD) [McKusick, 1983, catalog No. 12220] were studied for linkage. Fifty-one relatives were examined clinically, and 27 affected and 24 normal persons were ascertained. Tight linkage could be excluded for 15 informative markers with LOD scores of less than -2.0. The largest positive LOD score was 0.56 at 0 = 0.17 for linkage between haptoglobin and LCD. Combined with a previous study, the combined LOD score is 0.96.

Microdeletion in the X-chromosome and prenatal diagnosis in a family with Norrie disease.

We have studied a three-generation family in which Norrie disease is segregating and have performed prenatal diagnosis on the fetus of an obligatory carrier. Deletions at loci DXS7 and DXS77 defined by probes L1.28, L1.28-p59, and pX59 were detected in the affected male. DNA studies of chorionic villus biopsy material indicated that the male fetus had inherited the normal allele from the carrier mother. This prediction was confirmed on eye examination at age 5 months.

Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome.

Hepatoblastoma is a rare neoplasm of infants and children only recently documented in association with hereditary adenomatous polyposis of the colon [Kingston et al., 1983]. We report four children with hepatoblastoma from four unrelated families with Gardner syndrome (GS). One child, now 19 years old, survived after a resection of a hepatoblastoma in infancy and recently was found to have GS. He has an associated odontoma and pigmented ocular fundus lesions, both of which have been shown to be clinical markers of GS. Many individuals in these four GS families, both affected and at risk, have osteomatous jaw lesions and pigmented ocular fundus lesions. A search for colonic polyps should be made in families of infants and children with hepatoblastoma. If the child survives, he or she should be monitored for the later appearance of colonic polyps. The finding of jaw lesions and/or pigmented ocular fundus lesions in relatives at risk are indications of the possible presence of the GS gene.

Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.

Fibroblast growth factor receptor (FGFR) mutations have been found in craniosynostosis syndromes with and without limb and/or dermatologic anomalies. Ocular manifestations of FGFR2 syndromes are reported to include shallow orbits, proptosis, strabismus, and hypertelorism, but no ocular anterior chamber, structural abnormalities have been reported until now. We evaluated three unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles. Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present. These patients had airway compromise, seizures, and two died by age 15 months. All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding. Seven patients with isolated Peters anomaly, two patients with Peters plus syndrome, and three cases with typical Antley-Bixler syndrome were screened for this mutation, but none was found. These phenotype/genotype data demonstrate that FGFR2 is involved in the development of the anterior chamber of the eye and that the Ser351Cys mutation is associated with a severe phenotype and clinical course.

Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes.

Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.

Peters' anomaly and associated congenital malformations.

We reviewed the clinical findings in 29 patients with Peters' anomaly. There was developmental delay in 15 patients, congenital heart disease in eight patients, external ear abnormalities in five patients, structural defects of the central nervous system in four patients, genitourinary malformations in four patients, cleft lip/palate in three patients, hearing loss in three patients, spinal defects in two patients, and single cases of other less common defects. One patient had fetal alcohol syndrome; one, Pfeiffer's syndrome; and one, short stature, ulnar hypoplasia, and joint laxity. Colobomatous microphthalmia was present in seven patients, and persistent hyperplastic primary vitreous in three patients. Ten patients developed glaucoma, and three had retinal detachment unrelated to ocular surgery. Peters' anomaly may be due to a developmental field defect, or the complex ocular and systemic malformations may be the result of a contiguous gene syndrome or of a defective homeotic gene controlling the development of the eye and other body structures.

Bardet-Biedl syndrome and related disorders.

The Bardet-Beidl and Laurence-Moon syndromes are distinct entities. The nosology of five syndromes combining ocular and/or auditory defects, mental retardation, genital hypoplasia, obesity, and digital anomalies is reviewed. A 32-month-old boy had an unusual condition that may represent a sixth entity.

Hereditary pigmented paravenous chorioretinal atrophy.

An affected, but asymptomatic, mother and her three sons presented with pigmented paravenous chorioretinal atrophy. The patients had coarse pigment clumps and areas of chorioretinal atrophy in a paravenous distribution. The severity of chorioretinal changes was variable; two of the patients had macular involvement. Signs of vitreoretinal degeneration were seen in all patients; the sons had associated hyperopia and esotropia. Electroretinography revealed decreased photopic responses with normal scotopic responses in five of six eyes tested. To our knowledge, this is the second account reported of familial occurrence of pigmented paravenous chorioretinal atrophy. The present pedigree is compatible with X-linked or dominant inheritance.

Vitreoretinal degeneration in spondyloepiphyseal dysplasia congenita.

Eighteen patients had ocular changes associated with spondyloepiphyseal dysplasia congenita, a rare cause of congenital dwarfism with normal mental development. Seven patients had nonprogressive myopia of 5.00 or more diopters. Vitreoretinal degeneration was encountered in six patients with high myopia, and vitreous syneresis was present in all patients. Corrected visual acuity was 20/50 or better in all patients. Retinal detachment was not encountered, although reports in the nonophthalmic literature claim up to 50% retinal detachment rate and poor visual prognosis in these patients.

Leber's congenital amaurosis. Retrospective review of 43 cases and a new fundus finding in two cases.

Leber's congenital amaurosis is a hereditary clinical disorder that may be associated with several different diseases. This study consists of a retrospective review of 43 cases. Twenty of our patients had fundus appearances that resembled retinitis pigmentosa. Five had normal-appearing fundi. The remainder had other, previously reported fundus abnormalities, with the exception of two patients who demonstrated a new fundus finding, a nummular pigmentary pattern. Other associated eye anomalies included cataracts, keratoconus, ptosis, and strabismus. The most frequent systemic associations were mental retardation, cystic renal disease, skeletal disorders, and hydrocephalus.

Autosomal dominant congenital cataract associated with chromosomal translocation [t(3;4)(p26.2;p15)].

We studied a family in which congenital cataracts were found in a father and son who had a reciprocal translocation between the short arms of chromosomes 3 and 4 [t(3;4)(p26.2;p15)]. The father's parents and brother had normal chromosomes and no evidence of cataracts. While results of these studies do not prove a causal relationship, they do strongly suggest that the areas near the break points involved in the translocation (3p26.2 and 4p15) would be good sites for further investigations into the genetic basis of this type of cataract.

Cataract extraction and intraocular lens implantation in patients with retinitis pigmentosa or Usher's syndrome.

We report the results of cataract extraction in 26 eyes of 16 patients with retinitis pigmentosa or Usher's syndrome. There was no unusual incidence of intraoperative or postoperative complications in this group. After adequate preoperative counseling, and after we made certain that the patients' expectations were in line with anticipated results, 15 of our 16 patients were satisfied with the surgical outcome. Four patients who had a conventional cataract extraction with postoperative contact lens wear in one eye and an intraocular lens implanted in the other eye preferred the eye with the implant. There was no evidence that intraocular lens implantation interfered with the post-cataract-extraction care of the patients.

Olivopontocerebellar atrophy with retinal degeneration. A clinical and ocular histopathologic study.

The ocular histopathologic and electron microscopic findings were determined in eyes obtained at autopsy from twins with dominant olivopontocerebellar atrophy (OPCA) and retinal degeneration (OPCA type III). On light microscopy, a retinal degeneration that involved primarily the photoreceptor layer was present and appeared to start in the macular area and spread to involve the peripheral fundus. The retinal pigment epithelium was variably hypopigmented and hyperpigmented. On electron microscopy, osmiophilic, multimembranous, and complex lipofuscin inclusions were present in conjunctival cells, keratocytes, lens epithelium, iris and ciliary body fibrocytes, occasional outer retinal cells, and retinal pigment epithelial cells. The twins' father and an older sister were also affected and had classic neurologic and ophthalmologic abnormalities. The similarities were noted between the clinical and ultrastructural findings between OPCA type III and the neuronal ceroid lipofuscinoses.

Mucolipidosis IV. Histopathology of conjunctiva, cornea, and skin.

The condition of a 4-year-old white girl of Ashkenazi Jewish parents was diagnosed as mucolipidosis IV on the basis of marked corneal clouding and severe psychomotor retardation, in the absence of facial-skeletal dysplasia or abnormal mucopolysacchariduria. The results of histochemical and ultrastructural studies of conjunctiva, skin, and corneal epithelium confirmed the combined storage of acid mucopolysaccharide and complex lipid substances. An unusual histopathologic feature of mucolipidosis IV is the predisposition of extreme storage involvement of corneal epithelial cells with relative sparing of the keratocytes, which is a finding of potential therapeutic implication. In addition, application of electron microscopic study of cultured amniotic cells and conjunctival biopsy specimens to assess for the parents the mother's subsequent pregnancy additional emphasizes the value of ultrastructural studies in the diagnosis of lysosomal storage disease.