Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy.

PURPOSE: Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by the intracellular accumulation of cystine. Treatment involves intracellular cystine depletion with oral cysteamine. A wide spectrum of ocular pathologic features has been associated with nephropathic cystinosis. We used the largest documented cohort of patients in the world to study the posterior segment manifestations associated with infantile nephropathic cystinosis and to determine retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities. DESIGN: Cross-sectional study of a series of patients. PARTICIPANTS: Two hundred eight patients with infantile nephropathic cystinosis were studied at the National Institutes of Health between 1976 and 2004. METHODS: All patients underwent an ophthalmic evaluation. Patients older than 11 years also underwent Humphrey static perimetry, and electrophysiological testing was performed when possible. MAIN OUTCOME MEASURES: Visual acuity, retina findings, visual fields, and electroretinographic (ERG) findings. RESULTS: Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated ERG responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy. CONCLUSIONS: Infantile nephropathic cystinosis has posterior segment complications that can contribute to significant visual handicap. Early initiation of oral cysteamine therapy can reduce the frequency of posterior segment complications in cystinosis patients.

Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy characterized by multiple glistening intraretinal crystals scattered over the fundus, a characteristic degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. The BCD region of chromosome 4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage and haplotype analysis; mutations were found in the novel CYP450 family member CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene, transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid metabolism, consistent with biochemical studies of patients with BCD.

Molecular cloning of ELOVL4 gene from cynomolgus monkey (Macaca fascicularis).

ELOVL4, elongation factor of very long chain fatty acids-4, is known to be responsible for autosomal dominant macular degeneration and Stargardt-like macular degeneration. In this study, we cloned the monkey homologue of ELOVL4 and determined the cellular and tissue distribution of the gene product. Sequence analysis of the monkey ELOVL4 gene revealed a high degree of homology between human and monkey. The cloned full-length cDNA of monkey ELOVL4 encoded 314 amino acids, the same length as human and two amino acids longer than mouse. The monkey ELOVL4 conserved the characteristics typical of the super family of ELO enzymes involved in the metabolism of membrane-bound fatty acid elongation. Real-time quantitative PCR demonstrated that the monkey ELOVL4 gene was highly expressed in restricted tissue-specific fashion, not only in the retina but also in the skin (90% of retina) and thymus (111% of retina). Immunohistochemical analysis detected signals predominantly in the photoreceptor layer of the monkey retina.

Allelic and locus heterogeneity in autosomal recessive gelatinous drop-like corneal dystrophy.

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive disease characterized by the deposition of amyloid beneath the corneal epithelium and by severely impaired visual acuity leading to blindness. Although gelatinous corneal dystrophy has previously been mapped to chromosome 1p and seems to be associated with mutations in the M1S1 gene, molecular genetic studies have been limited to Japanese patients. To investigate the cause of GDLD in patients with diverse ethnic backgrounds, we performed linkage analyses in eight unrelated GDLD families from India, USA, Europe, and Tunisia. In seven of these families, the disease locus mapped to a 16-cM interval on the short arm of chromosome 1 between markers D1S519 and D1S2835, a region including the M1S1 gene. In addition, a 1.2-kb fragment containing the entire coding region of M1S1 gene was sequenced in affected individuals. Seven novel mutations (M1R, 8-bp ins., Q118 E, V194 E, C119 S, 870delC, and 1117delA) were identified in six families and two unrelated individuals. No sequence abnormalities were detected in a single family in which the GDLD locus was also excluded from the M1S1 region by linkage analysis. These findings demonstrate allelic and locus heterogeneity for GDLD.

Usher syndrome clinical types I and II: could ocular symptoms and signs differentiate between the two types?

PURPOSE: Usher syndrome types I and II are clinical syndromes with substantial genetic and clinical heterogeneity. We undertook the current study in order to identify ocular symptoms and signs that could differentiate between the two types. METHODS: Sixty-seven patients with Usher syndrome were evaluated. Based on audiologic and vestibular findings, patients were classified as either Usher type I or II. The severity of the ocular signs and symptoms present in each type were compared. RESULTS: Visual acuity, visual field area, electroretinographic amplitude, incidence of cataract and macular lesions were not significantly different between Usher types I and II. However, the ages when night blindness was perceived and retinitis pigmentosa was diagnosed differed significantly between the two types. CONCLUSIONS: There seems to be some overlap between types I and II of Usher syndrome in regard to the ophthalmologic findings. However, night blindness appears earlier in Usher type I (although the difference in age of appearance appears to be less dramatic than previously assumed). Molecular elucidation of Usher syndrome may serve as a key to understanding these differences and, perhaps, provide a better tool for use in clinical diagnosis, prognosis and genetic counseling.

Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis.

PURPOSE: As a result of successful renal transplantation, patients with nephropathic cystinosis are now living into adulthood. As these patients age, anterior segment ocular complications, other than deposition of corneal crystals, become more evident. With our experience with 172 patients followed up at the National Institutes of Health between 1976 and 2000, the prevalence of anterior segment complications in nephropathic cystinosis was determined. METHODS: A cross-sectional examination of age-specific prevalence was performed with logistic regression analysis of prevalence change with age. RESULTS: Besides the corneal crystals apparent in all age groups, superficial punctate keratopathy, filamentary keratopathy, severe peripheral corneal neovascularization, band keratopathy, and posterior synechiae with iris thickening and transillumination were noted in the older age groups. The prevalence increased with age for each complication. CONCLUSIONS: As patients with cystinosis grow older, more severe ophthalmic manifestations become evident. It remains to be seen how the prevalence of these complications will be altered by early initiation of oral and topical cysteamine therapy.