Purpose: To report a family with unilateral isolated microphthalmia showing an autosomal recessive pattern of inheritance. Case report: We report a family in which three out of four children, one ...male and monozygotic female twins, were born with unilateral isolated microphthalmia to healthy consanguineous parents. One twin additionally had a horseshoe kidney. Rare cases of familial isolated microphthalmia/anophthalmia have been previously described. This is the first report of a family with autosomal recessive isolated microphthalmia occurring unilaterally in all affected individuals. It remains unknown how this inherited genetic disease results in unilateral manifestation. Conclusion: Mirror imaging of this condition in the monozygotic twins may help elucidate the underlying mechanism. The constellation of features in this family may contribute to solve remaining questions of research into symmetry and asymmetry.
Recessive mutations in GUCY2D, the gene encoding the retinal guanylyl cyclase protein, RetGC-1, have been shown to cause Leber Congenital Amaurosis (LCA), a severe retinal dystrophy. The purpose of ...this study was to determine the functional consequences of selected mutations in GUCY2Dlinked to LCA. The mutations investigated in this study map to the catalytic domain (P858S, L954P) and the extracellular domain (C105Y, L325P) of RetGC-1.
All four mutations were introduced into the in vitro expression plasmid, pRC-CMV human RetGC-1, and expressed in HEK-293 cells. We assayed the abilities of the mutant cyclases to generate cGMP (basal activity), and to be activated by guanylyl cyclase activating proteins (GCAP-1 and GCAP-2). Additionally, we co-expressed the catalytic domain mutations (P858S and L954P) with a wild-type allele to test for dominant negative effects on wild-type RetGC-1.
The P858S and L954P mutations, both in highly conserved residues of the catalytic domain of RetGC-1, severely impair basal, GCAP-1, and GCAP-2 stimulated catalytic activity of the enzyme. In addition, when co-expressed with the wild-type allele, both catalytic domain mutations act as dominant negative proteins and reduce the activity of wild-type RetGC-1. The basal activities of the C105Y and L325P mutants are unaltered, but GCAP-1 and GCAP-2 stimulated cyclase activities are reduced approximately 50%.
GUCY2D mutations from LCA patients have distinct functional consequences on RetGC-1 catalytic activity in vitro. Our analyses showed that the catalytic domain mutations cause a marked reduction in cyclase activity, while the extracellular domain mutations moderately reduce activity. The catalytic domain mutant alleles cause dominant negative effects, indicating that the functionality of RetGC-1 is compromised even in heterozygotes. This is consistent with abnormalities in cone electroretinograms (ERGs) detected in obligate heterozygous GUCY2D parents that carry the L954P mutation.
Objective: To report chronic fatigue syndrome (CFS) associated with both Ehlers-Danlos syndrome (EDS) and orthostatic intolerance.
Study design: Case series of adolescents referred to a tertiary ...clinic for the evaluation of CFS. All subjects had 2-dimensional echocardiography, tests of orthostatic tolerance, and examinations by both a geneticist and an ophthalmologist.
Results: Twelve patients (11 female), median age 15.5 years, met diagnostic criteria for CFS and EDS, and all had either postural tachycardia or neurally mediated hypotension in response to orthostatic stress. Six had classical-type EDS and 6 had hypermobile-type EDS.
Conclusions: Among patients with CFS and orthostatic intolerance, a subset also has EDS. We propose that the occurrence of these syndromes together can be attributed to the abnormal connective tissue in dependent blood vessels of those with EDS, which permits veins to distend excessively in response to ordinary hydrostatic pressures. This in turn leads to increased venous pooling and its hemodynamic and symptomatic consequences. These observations suggest that a careful search for hypermobility and connective tissue abnormalities should be part of the evaluation of patients with CFS and orthostatic intolerance syndromes. (J Pediatr 1999;135:494-9)
Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least a third of all cases are familial; autosomal dominant congenital cataract (ADCC) ...appears to be the most common familial form in the Western world. Cerulean cataracts have peripheral bluish and white opaci-fications in concentric layers with occasional central lesions arranged radially. Although the opacities may be observed during fetal development and childhood, usually visual acuity is only mildly reduced until adulthood, when lens extraction is generally necessary. We have been studying a family (ADCC-1) with cerulean blue ADCC, in which the affected daughter of a first cousin mating was presumed to be homozygous for the cataract gene. Recently, we mapped an ADCC gene in this family to a region of chromosome 22 containing three β-crystallin genes. Here we report that a chaintermination mutation in CRYBB2 is associated with ADCC in this family.
Congenital cataracts are clinically and genetically heterogeneous. Loci for autosomal dominant posterior polar cataracts have been mapped to chromosomes 1p36, 11q22-q22.3, 16q22, and 20p12-q12. We ...investigated a large four-generation family with 20 individuals affected with congenital posterior polar cataracts. After exclusion of known loci for posterior polar cataracts, a genome-wide screen was conducted. In this family, we mapped dominant congenital posterior polar cataracts to chromosome 10q24. On haplotype analysis, we identified an 11-cM interval between loci D10S1680 and D10S467, which included the PITX3 gene. On sequencing the coding region of PITX3, we found a 17-base-pair duplication in exon 4. Although the same genotype was described in a family with ASMD and cataracts, the common phenotype of this mutation is probably posterior polar cataract; a modifier gene is presumed to cause anterior segment abnormalities in the previously described patients. The same mutation was recently identified in four families with congenital cataracts. This study provides further evidence of genetic heterogeneity of autosomal dominant posterior polar cataract.
Leber congenital amaurosis (LCA, MIM 204001) is a clinically and genetically heterogeneous retinal disorder characterized by severe visual loss from birth, nystagmus, poor pupillary reflexes, retinal ...pigmentary or atrophic changes, and a markedly diminished electroretinogram (ERG). Purpose: To examine 100 consecutive patients with LCA in order to assess the relative burden of the three known genes involved in LCA, namely retinal guanylyl cyclase ( GUCY2D ), retinal pigment epithelium protein ( RPE65 ), and the cone-rod homeobox ( CRX ), and to define their clinical correlates. Methods: Mutational analysis and detailed clinical examinations were performed in patients diagnosed with LCA at the Johns Hopkins Center for Hereditary Eye Diseases and the Montreal Childrens Hospital. Results: Mutations were identified in 11% of our patients: GUCY2D mutations accounted for 6%, while RPE65 and CRX gene mutations accounted for 3% and 2%, respectively.
To describe the clinical features of a large pedigree with autosomal dominant congenital nystagmus linked to chromosome 6p12.
In a prospective evaluation of 54 living family members in a single ...pedigree, 21 persons were affected with autosomal dominant congenital nystagmus, and clinical examinations were performed on 14. Selected persons underwent further studies, including electroretinography, scanning laser ophthalmoscopy, nerve fiber layer studies, visual evoked potential studies, and eye movement recordings.
Among seven affected persons whose parents were able to report whether the nystagmus was present congenitally, onset at birth was noted in two persons and between 3 and 6 months in five persons. Best-corrected binocular Snellen visual acuity ranged from 20/30 to 20/100, with a mode of 20/50. Strabismus was present in 14 examined patients (36%). Eye movement recordings, performed on five persons, included asymmetric pendular (three), asymmetric pendular combined with dual waveform jerk (one), and unidirectional jerk nystagmus (one).
Autosomal dominant congenital nystagmus represents a disorder with variable expressivity. While onset is typically during infancy, it can be noted at birth. Intrafamilial variation in visual acuity, ocular alignment, and nystagmus waveform suggests a role for modifying influences on expression of disease.
We examined 25 patients from three pedigrees with dominant optic atrophy (Kjer type). Follow-up on 20 patients ranged from five to 40 years (mean, 16 years; median, 13 years). Visual acuity ranged ...from 20/20 (in one 58-year-old man with an affected father and three affected children) to 20/400. The median initial visual acuity was 20/60, and the median final visual acuity was 20/80. Visual acuity remained unchanged or decreased by one Snellen line in both eyes of 13 patients (65%); it decreased between two and four Snellen lines in only one eye in three patients (15%) and in both eyes in four patients (20%). The rate of visual loss was unrelated to initial visual acuity or the particular pedigree to which the patient belonged. There was functional and ophthalmoscopic heterogeneity between and within the pedigrees. Eight patients perceived moderate to severe social or occupational handicap. Visual prognosis is relatively good in Kjer's dominant optic atrophy with stable or slow progression of visual loss.
Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the ...fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at θ = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor nystagmus to an 18-cM region between D6S271 and D6S455.
Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy and the most frequent cause of inherited blindness in children. LCA is usually inherited in an autosomal ...recessive fashion, although rare dominant cases have been reported. One form of LCA, LCA4, maps to chromosome 17p13 and is genetically distinct from other forms of LCA. We recently identified the gene associated with LCA4, AIPL1 (aryl-hydrocarbon interacting protein-like 1) and identified three mutations that were the cause of blindness in five families with LCA. In this study, AIPL1 was screened for mutations in 512 unrelated probands with a range of retinal degenerative diseases to determine if AIPL1 mutations cause other forms of inherited retinal degeneration and to determine the relative contribution of AIPL1 mutations to inherited retinal disorders in populations worldwide. We identified 11 LCA families whose retinal disorder is caused by homozygous or compound heterozygous AIPL1 mutations. We also identified affected individuals in two apparently dominant families, diagnosed with juvenile retinitis pigmentosa or dominant cone-rod dystrophy, respectively, who are heterozygous for a 12-bp AIPL1 deletion. Our results suggest that AIPL1 mutations cause approximately 7% of LCA worldwide and may cause dominant retinopathy.
PDF
