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.

Use of nitisinone in patients with alkaptonuria.

Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA). Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria. We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses, 0.35 mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels from an average of 4.0 +/- 1.8 (SD) g/day to 0.2 +/- 0.2 g/day ( P < .001). The average plasma tyrosine concentration, initially 68 +/- 18 mmicro mol/L, rose to 760 +/- 181 micro mol/L ( P < .001). During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 +/- 167 to 603 +/- 114 mu mol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints. Weekly ophthalmologic examinations showed no signs of corneal toxicity. Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels. We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria. Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.

Hermansky-Pudlak syndrome type 1: gene organization, novel mutations, and clinical-molecular review of non-Puerto Rican cases.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder causing oculocutaneous albinism and a platelet storage pool deficiency, reflecting defective biosynthesis and/or processing of melanosomes and platelet dense bodies. Four human genes (HPS1, ADTB3A, HPS3, HPS4) are associated with four subtypes of HPS. The most common is HPS-1. A 16-bp duplication in exon 15 of the HPS1 gene causes HPS-1 in 450 northwest Puerto Rican patients; 13 other HPS1 mutations have been reported in non-Puerto Rican patients. We screened 26 HPS patients, who lacked a molecular diagnosis, for HPS1 defects and identified six patients with six different HPS1 mutations. Four novel mutations were discovered, including the first HPS1 missense mutation, 922T>C, in exon 8. This mutation, along with 624delG in exon 6, preserve RNA transcription, while 561delC in exon 5 and [1581delA;1594C>A] in exon 14 produce no RNA on northern blot. One of six adult patients developed pulmonary fibrosis, and two patients ages 16 and 17 have granulomatous colitis. These complications are common among Puerto Rican HPS-1 patients but have not appeared in HPS-2 or HPS-3 patients. The diagnosis of HPS-1, available only on molecular grounds, has important prognostic and treatment implications.

Keratopathy of multiple myeloma masquerading as corneal crystals of ocular cystinosis.

We describe a 49-year-old woman in whom ocular cystinosis was diagnosed on the basis of a routine eye examination 12 years previously. Conjunctival biopsy was reported to support the diagnosis. The patient described photophobia for the past 5 years and reported a 2-fold increase in her serum IgG level for the past 12 years. On ophthalmic examination, corneal crystals were evident in the epithelium and superficial stromal layers, rather than throughout the corneal epithelium and the entire stroma as in ocular cystinosis. The patient's serum protein level was elevated at 8.7 g/dL; protein electrophoresis showed an elevated gamma-globulin peak, and the IgG level was twice that of normal at 2820 mg/dL. Bone marrow biopsy confirmed the diagnosis of multiple myeloma. This case illustrates that multiple myeloma can mimic corneal findings of cystinosis.

Gyrate atrophy of the choroid and retina: further experience with long-term reduction of ornithine levels in children.

OBJECTIVE: To determine whether the long-term reduction of plasma ornithine levels by way of an arginine-restricted diet in patients with gyrate atrophy will slow the progression of this chorioretinal degeneration. DESIGN: Natural history study of 2 pairs of siblings with gyrate atrophy treated with an arginine-restricted diet. MAIN OUTCOME MEASURES: Fundus photography and electrophysical and psychophysical retinal function tests. RESULTS: After 16 to 17 years of receiving an arginine-restricted diet, the younger sibling in each pair, who was prescribed the diet at an earlier age than the older sibling, demonstrated a slower progression of lesions compared with the older sibling. CONCLUSIONS: If started at an early age, long-term substantial reduction of plasma ornithine levels may appreciably slow the progression of the chorioretinal lesions and, to a lesser extent, the progressive loss of retinal function in patients with gyrate atrophy.

Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy.

OBJECTIVE: To quantify the effect of long-term reduction of plasma ornithine levels through adherence to an arginine-restricted diet on visual function in patients of all ages with gyrate atrophy of the retina and choroid. METHODS: A long-term observational study was conducted on 27 patients with gyrate atrophy, 17 of whom elected to comply with the arginine-restricted diet and 10 who were unable to comply. The mean rates of change in the electroretinogram combined response, electroretinogram flicker response, and kinetic and static perimetry were determined. RESULTS: After mean follow-up of 13.9 years for the patients on the diet and 14.1 years for those not on the diet, the mean rates of change for the diet group compared with those of the no-diet group were statistically significantly slower for all outcome measures (age-adjusted P<.05) except for static perimetry (P =.06). CONCLUSIONS: Adhering to an arginine-restricted diet so as to lower the plasma ornithine level below an average of 5.29 to 6.61 mg/dL (400-500 micromol/L) will slow the loss of function as measured by sequential electroretinography and visual field examinations.

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.

Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2.

Individuals affected with the neurofibromatosis 2 (NF2) cancer predisposition syndrome develop specific ocular lesions. To determine whether these lesions result from altered NF2 gene expression, microdissection and PCR were used to investigate 40 ocular lesions from seven eyes of four NF2 patients for LOH, with markers that flank the NF2 gene on chromosome 22q. NF2 protein (merlin) expression was also evaluated in these lesions, using immunohistochemistry. Retinal hamartoma was observed in all seven eyes, including one with combined pigment epithelial and retinal hamartoma (CPERH). Retinal tufts were present in four eyes (three patients), retinal dysplasia in two eyes (two patients), optic nerve neurofibroma in one eye, iris naevoid hyperplasia in two eyes (two patients) and pseudophakia in all eyes. Markers were informative in three patients (six eyes from three unrelated families). One patient was non-informative due to prolonged decalcification. All retinal and optic nerve, but not iris lesions, demonstrated consistent LOH for the NF2 gene. Merlin was not expressed in the retina, optic nerve, or iris lesions. These results suggest that inactivation of the NF2 gene is associated with the formation of a variety of retinal and optic nerve lesions in NF2 patients.

Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5.

Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelles such as melanosomes and platelet dense granules. Seven genes are now associated with HPS in humans. An accurate diagnosis of each HPS subtype has important prognostic and treatment implications. Here we describe the cellular, molecular, and clinical aspects of the recently identified HPS-5 subtype. We first analyzed the genomic organization and the RNA expression pattern of HPS5, located on chromosome 11p14, and demonstrated tissue-specific expression of at least three alternatively spliced HPS5 mRNA transcripts, coding for HPS5A and HPS5B proteins, that differ at their 5'-ends. Genetic screening of 15 unassigned HPS patients yielded six new HPS5 mutations in four patients. Clinically, our HPS-5 patients exhibited iris transillumination, variable hair and skin pigmentation, and absent platelet dense bodies, but not pulmonary fibrosis or granulomatous colitis. In two patients with homozygous missense mutations, hemizygosity was ruled out by gene-dosage multiplex polymerase chain reaction, and immunocytochemical analyses of their fibroblasts supported the HPS-5 diagnosis. Specifically, LAMP-3 distribution was restricted to the perinuclear region in HPS-5 fibroblasts, in contrast to the normal LAMP-3 distribution, which extended to the periphery. This specific intracellular vesicle distribution in fibroblasts, in combination with the clinical features, will improve the characterization of the HPS-5 subtype.

Milder ocular findings in Hermansky-Pudlak syndrome type 3 compared with Hermansky-Pudlak syndrome type 1.

PURPOSE: To compare clinically 2 different subtypes of Hermansky-Pudlak syndrome (HPS), type 1 (HPS-1) and type 3 (HPS-3). DESIGN: Cross-sectional study of a series of patients. PARTICIPANTS: Sixteen patients with HPS-1 and 14 patients with HPS-3 were studied. METHODS: Complete eye examination, including best-corrected visual acuity and photographs and photographic grading of iris transillumination and macular transparency using a previously established grading system. RESULTS: Snellen visual acuity was 20/160-2 in the HPS-1 group and 20/125+2 in the HPS-3 group (P = 0.017). Iris grading was statistically significant for less translucence in the HPS-3 patients. The HPS-3 patients also tended to have less transparent maculas, but the difference was not statistically significant. CONCLUSIONS: Patients with HPS-3 have less severe ophthalmic manifestations than patients with HPS-1. Ophthalmologists treating patients with albinism should consider HPS in their differential diagnosis even in the case of mild iris and macular hypopigmentation.

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.