The relationship of central foveal thickness to urinary iodine concentration in retinitis pigmentosa with or without cystoid macular edema.

IMPORTANCE: Current treatments for cystoid macular edema (CME) in retinitis pigmentosa (RP) are not always effective, may lead to adverse effects, and may not restore visual acuity. The present research lays the rationale for evaluating whether an iodine supplement could reduce CME in RP. OBJECTIVE: To determine whether central foveal thickness (CFT) in the presence of CME is related to dietary iodine intake inferred from urinary iodine concentration (UIC) in nonsmoking adults with RP. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional observational study of 212 nonsmoking patients aged 18 to 69 years referred to our institution for RP with visual acuity of no worse than 20/200 in at least 1 eye. EXPOSURE: Retinitis pigmentosa with or without CME. MAIN OUTCOMES AND MEASURES: With the eye as the unit of analysis, the relationship of log CFT measured by optical coherence tomography to UIC measured from multiple spot samples and represented as a 3-level classification variable (<100, 100-199, and ≥200 µg/L), assigning greater weight to patients with more reliable UIC estimates. RESULTS: Analyses were limited to 199 patients after excluding 11 who failed to return urine samples for measuring UIC and 2 outliers for UIC. Of the 199 patients, 36.2% had CME in 1 or both eyes. Although log CFT was inversely related to UIC based on findings from all eyes (P = .02), regression of log CFT on UIC separately for eyes with and without CME showed a strong inverse significant relationship for the former group (P < .001) and no significant relationship for the latter group (P = .66) as tested. For the eyes with CME, CFT ranged from a geometric mean of 267 µm for a median UIC of less than 100 µg/L to a geometric mean of 172 µm for a median UIC of 200 µg/L or greater. In contrast, we found no significant association between CME prevalence and UIC based on the entire sample as tested (odds ratio, 1.01 [95% CI, 0.38-2.67]; P = .99). CONCLUSIONS AND RELEVANCE: A higher UIC in nonsmoking adults with RP was significantly associated with less central foveal swelling in eyes with CME. Additional study is required to determine whether an iodine supplement can limit or reduce the extent of CME in patients with RP.

Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis.

We observed a characteristic shortening of plasma and urinary dolichols in retinitis pigmentosa (RP) patients carrying K42E and T206A mutations in the dehydrodolichol diphosphate synthase (DHDDS) gene, using liquid chromatography-mass spectrometry. Dolichol-18 (D18) became the dominant dolichol species in patients instead of dolichol-19 (D19) in normal individuals. The D18/D19 ratio was calculated and used as an index of dolichol length distribution. K42E/K42E and K42E/T206A patients have significantly higher plasma and urinary D18/D19 ratios than K42E and T206A carriers. The ratios of carriers are significantly higher than normal individuals. Receiver operating characteristic (ROC) analysis shows that plasma and urinary D18/D19 ratios can unambiguously discriminate patients from carriers, and carriers from normal individuals. Dolichol analysis also provides evidence that the T206A mutation is RP-causative. The methodologies and procedures used for dolichol profiling are reliable, high throughput, and cost effective. Dolichol profiling, complementary to genotyping, can be readily adapted as a test in the clinic not only for the diagnosis of patients but also for identification of carriers with DHDDS or other genetic mutations that may impair dolichol biosynthesis.

Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa.

OBJECTIVE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness and peripheral vision loss, and in many cases leads to blindness. Despite extensive knowledge about genes involved in the pathogenesis of RP, the genetic cause remains elusive in many patients. In this study, we aimed to identify novel genes that are involved in the cause of RP. DESIGN: We present a case series with mutations in the mevalonate kinase (MVK) gene. PARTICIPANTS: A total of 769 patients with nonsyndromic RP and 174 Dutch control individuals participated in this study. METHODS: Exome sequencing analysis was performed in a proband of Dutch origin who was initially diagnosed with nonsyndromic autosomal recessive RP. Mutations in MVK were identified and subsequently tested for segregation within the patient's family and screened in a large cohort of patients with genetically unsolved RP. Patients with mutations underwent extensive clinical reexamination. MAIN OUTCOME MEASURES: Digital fundus photography, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence analysis were performed in patients with MVK mutations. Mevalonate kinase (MK) enzyme activity was analyzed in cultured lymphoblastoid cells, and mevalonic acid levels were measured in urine samples. RESULTS: Exome variant filtering and prioritization led to the identification of compound heterozygous mutations in MVK (p.I268T and p.A334T) in the proband and her affected brother. Screening of our nonsyndromic RP patient cohort revealed an additional individual who was homozygous for the p.A334T alteration. Clinical reevaluation of all 3 patients showed a classic form of RP with variable extraocular symptoms, such as history of recurrent childhood febrile crises in 2 patients, mild ataxia in 1, and renal failure in 1. All 3 affected individuals showed a significantly decreased MK activity and highly elevated levels of urinary mevalonic acid. CONCLUSIONS: Although the MK activity in cells and mevalonic acid concentrations in urine are strongly aberrant and comparable to that in patients with systemic mevalonate kinase deficiency (MKD), only mild clinical symptoms related to this syndrome were observed in our patients. In the current article, we add another phenotype to the spectrum of diverging disorders associated with mutations in MVK.

Specific combination of compound heterozygous mutations in 17ß-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency.

BACKGROUND: D-bifunctional protein (DBP) deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old) with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa. METHODS AND RESULTS: Biochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS) platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of the 17ß-hydroxysteroid dehydrogenase type 4 gene (HSD17B4). These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP hydratase and dehydrogenase activity were markedly decreased but detectable. CONCLUSIONS: We propose that the DBP phenotype seen in this family represents a distinct and novel subtype of DBP deficiency, which we have termed type IV based on the presence of a missense mutation in each of the domains of DBP resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP. Given that the biochemical testing in plasma was normal in these patients, this is likely an underdiagnosed form of DBP deficiency.

Ocular findings in glutaric aciduria type 1.

PURPOSE: To determine the nature and course of ocular abnormalities in glutaric aciduria (acidemia) type 1 (GA1). METHODS: Fifteen children with GA1 have been studied in the Republic of Ireland. A retrospective review of the records of the 6 children who died during their illness and prospective clinical examination of 9 survivors were performed. RESULTS: Seven of the 15 children had abnormal eye findings. Ocular complications included intraretinal hemorrhages, cataract, gaze palsy, strabismus, ametropia, and pigmentary retinopathy. CONCLUSION: Ocular involvement is common in glutaric aciduria. Complete ophthalmologic evaluation is recommended in all patients suspected to have this rare disease. Intraretinal hemorrhages due to GA1 could be misinterpreted as resulting from child abuse, and it is important to include this disorder with the differential diagnosis of child abuse.

Mesangioproliferative glomerulonephritis associated with retinitis pigmentosa.

Two patients with retinitis pigmentosa and glomerulonephritis are described. The patients were unrelated and had identical renal lesions, mesangioproliferative glomerulonephritis. This may not be a chance association, and simple dip-stick urine analysis in patients with primary retinal degenerations may lead to earlier identification of renal disease.

Chemical definition of the mucopolysaccharidoses.

Glycosaminoglycans were isolated from the urines of 46 patients with mucopolysaccharidosis; 11 with Type I (Hurler), 8 with Type II (Hunter), 16 with Type III (Sanfilippo A and B), 9 with Type V (Scheie), one with Type VI (Marateaux-Lamy), and one unclassified. All 46 patients excreted in their urine excessive amounts of dermatan sulfate, heparan sulfate or both. In addition, patients of certain types excreted excessive amounts of chondroitin sulfates A and/or C. There is a trend in each type of the disease towards the same carbazole/orcinol ratio, glucosamine/galactosamine ratio and glycosaminoglycan composition. Molecular weight distribution of the urinary glycosaminoglycans by gel filtration from Sephadex G-200 is characteristic for each different type of mucopolysaccharidosis and is distinguished from normal controls and patients without mucopolysaccharidosis. Preparation of elution diagrams from Sephadex G-200 allows an estimation of the composition of the glycosamino-glycans. Practically all heparan sulfate and a sizable part of dermatan sulfate from the urinary glycosaminoglycans of all these patients have been highly degraded. In all the patients in which the specific enzyme defect was demonstrated, the assignment of the type of mucopolysaccharidosis, on the basis of the elution diagrams, was correct. Patients with mucopolysaccharidosis Type V displayed two conspicuously different types of elution patterns, suggesting heterogeneity. Indeed, only a portion of these patients showed alpha-L- iduronidase deficiency. Carriers had normal urinary glycosaminoglycan output and composition and exhibited normal elution diagrams.