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1.
Ophthalmology ; 113(6): 1002-9, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16603246

ABSTRACT

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.


Subject(s)
Cysteamine/therapeutic use , Cystinosis/drug therapy , Retina/drug effects , Retinal Diseases/drug therapy , Administration, Oral , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , Electroretinography/drug effects , Female , Humans , Infant , Male , Retina/physiopathology , Retinal Diseases/physiopathology , Visual Acuity/drug effects , Visual Fields/drug effects
2.
Metabolism ; 54(6): 719-28, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15931605

ABSTRACT

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.


Subject(s)
Alkaptonuria/drug therapy , Cyclohexanones/therapeutic use , Nitrobenzoates/therapeutic use , Adult , Aged , Alkaptonuria/metabolism , Cyclohexanones/adverse effects , Cyclohexanones/blood , Dietary Proteins/administration & dosage , Female , Homogentisic Acid/blood , Homogentisic Acid/urine , Humans , Male , Middle Aged , Nitrobenzoates/adverse effects , Nitrobenzoates/blood , Tyrosine/blood
3.
Ophthalmology ; 111(8): 1599-603, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15288994

ABSTRACT

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.


Subject(s)
Carrier Proteins/genetics , Hermanski-Pudlak Syndrome/classification , Iris/pathology , Membrane Proteins/genetics , Retina/pathology , Adolescent , Adult , Aged , Child , Child, Preschool , Cross-Sectional Studies , Hermanski-Pudlak Syndrome/genetics , Humans , Intracellular Signaling Peptides and Proteins , Middle Aged , Phenotype , Photography , Visual Acuity
4.
Traffic ; 5(9): 711-22, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15296495

ABSTRACT

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.


Subject(s)
Carrier Proteins/genetics , Hermanski-Pudlak Syndrome/physiopathology , Adult , Blotting, Northern , Carrier Proteins/metabolism , Child , DNA Mutational Analysis , DNA, Complementary , Female , Hermanski-Pudlak Syndrome/genetics , Humans , Immunohistochemistry , Male , Middle Aged , Mutation , Organ Specificity , Polymerase Chain Reaction
5.
Arch Ophthalmol ; 122(7): 982-4, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15249361

ABSTRACT

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.


Subject(s)
Arginine , Diet, Protein-Restricted , Gyrate Atrophy/diet therapy , Vision Disorders/diet therapy , Adolescent , Adult , Aged , Child , Disease Progression , Electroretinography , Female , Follow-Up Studies , Gyrate Atrophy/blood , Gyrate Atrophy/physiopathology , Humans , Male , Middle Aged , Ornithine/blood , Patient Compliance , Retina/physiology , Vision Disorders/blood , Vision Disorders/physiopathology , Visual Field Tests , Visual Fields
6.
Mayo Clin Proc ; 79(3): 410-2, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15008615

ABSTRACT

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.


Subject(s)
Corneal Diseases/diagnosis , Cystinosis/diagnosis , Multiple Myeloma/diagnosis , Corneal Diseases/complications , Cystinosis/complications , Diagnosis, Differential , Female , Humans , Immunoglobulin G/blood , Middle Aged , Photophobia/etiology
8.
Hum Mutat ; 20(6): 482, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12442288

ABSTRACT

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.


Subject(s)
Hermanski-Pudlak Syndrome/genetics , Membrane Proteins/genetics , Adolescent , Adult , Alternative Splicing/genetics , Base Sequence , Blotting, Northern , Child , Child, Preschool , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Female , Frameshift Mutation , Genes/genetics , Hermanski-Pudlak Syndrome/diagnosis , Humans , Infant , Male , Molecular Sequence Data , Mutagenesis, Insertional , Mutation , Pedigree , Point Mutation , RNA/genetics , RNA/metabolism , Sequence Analysis, DNA , Sequence Deletion
9.
J Pathol ; 198(1): 14-20, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12210058

ABSTRACT

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.


Subject(s)
Genes, Neurofibromatosis 2 , Loss of Heterozygosity , Neurofibromatosis 2/genetics , Optic Nerve Neoplasms/genetics , Retinal Diseases/genetics , Adolescent , Adult , Aged , Chromosomes, Human, Pair 22/genetics , Hamartoma/genetics , Hamartoma/metabolism , Hamartoma/pathology , Humans , Male , Middle Aged , Neoplasm Proteins/metabolism , Neurofibromatosis 2/metabolism , Neurofibromatosis 2/pathology , Neurofibromin 2/metabolism , Optic Nerve Neoplasms/metabolism , Optic Nerve Neoplasms/pathology , Retinal Diseases/metabolism , Retinal Diseases/pathology , Retinal Dysplasia/genetics , Retinal Dysplasia/metabolism , Retinal Dysplasia/pathology
10.
Acta Ophthalmol Scand ; 80(2): 196-201, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11952489

ABSTRACT

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.


Subject(s)
Hearing Loss, Sensorineural/diagnosis , Night Blindness/diagnosis , Retinitis Pigmentosa/diagnosis , Speech Disorders/diagnosis , Vestibular Diseases/diagnosis , Adolescent , Adult , Child , Diagnosis, Differential , Electroretinography , Humans , Middle Aged , Night Blindness/classification , Night Blindness/physiopathology , Retinitis Pigmentosa/classification , Retinitis Pigmentosa/physiopathology , Speech Disorders/classification , Speech Disorders/physiopathology , Syndrome , Vestibular Diseases/classification , Vestibular Diseases/physiopathology , Visual Acuity , Visual Fields
11.
Cornea ; 21(2): 173-6, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11862089

ABSTRACT

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.


Subject(s)
Aging , Conjunctival Diseases/etiology , Cornea/pathology , Corneal Diseases/etiology , Cystinosis/complications , Iris Diseases/etiology , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Conjunctival Diseases/epidemiology , Corneal Diseases/epidemiology , Cross-Sectional Studies , Cystinosis/surgery , Female , Humans , Infant , Iris Diseases/epidemiology , Kidney Transplantation , Male , Prevalence , Regression Analysis
12.
Arch Ophthalmol ; 120(2): 146-53, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11831916

ABSTRACT

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.


Subject(s)
Choroid Diseases/physiopathology , Gyrate Atrophy/physiopathology , Ornithine/blood , Retinal Diseases/physiopathology , Adult , Arginine/administration & dosage , Choroid Diseases/blood , Choroid Diseases/diet therapy , Diet, Protein-Restricted , Disease Progression , Electroretinography , Female , Fundus Oculi , Gyrate Atrophy/blood , Gyrate Atrophy/diet therapy , Humans , Male , Nuclear Family , Pedigree , Photography , Retinal Diseases/blood , Retinal Diseases/diet therapy , Visual Acuity , Visual Fields
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