Vision-Related Quality of Life in Danish Patients with Albinism and the Impact of an Updated Optical Rehabilitation.

(1) Background: Albinism is characterized by a lack of pigment in eyes, hair, and skin and developmental changes in the eye such as foveal hypoplasia. Patients require optical rehabilitation due to low vision, refractive errors, and photosensitivity. We aimed to assess vision-related quality of life in patients with albinism and to evaluate how this was affected by optical rehabilitation. (2) Methods: Patients with ocular or oculocutaneous albinism were invited for the study. Free-of-charge optical rehabilitation was provided as needed, including filters, glasses for near or distance, contact lenses, magnifiers or binoculars. Vision-related quality of life was assessed prior to and after optical rehabilitation using the visual function questionnaire (VFQ39) and the effect of optical rehabilitation was evaluated after accounting for age, gender, and visual acuity. (3) Results: Seventy-eight patients filled out the VFQ39 at the initial visit. Fifty patients (64.1%) returned the questionnaire 3-6 months after optical rehabilitation. The mean age of included patients was 35.9 years (standard deviation 16.6), and their best corrected distance visual acuity was 56 ETDRS letters (range 3-81). The VFQ39 composite score improved significantly from a median of 62.5 (range 14.2-77.0) to 76.5 (20.6-99.6). Significant improvements were seen for ocular pain, social functioning, mental health, role difficulties, and dependency, whereas self-assessed distance or near visual functions did not change. (4) Conclusions: Optical rehabilitation improved the self-reported vision-related quality of life in Danish patients with albinism on a number of parameters related to leading an independent and worry-free life, whereas visual improvement for distance and near tasks was likely limited by the nature of the disease and by the fact that most patients already had access to some optical aids prior to the study.

Clinical characterization of patients with PRPF31-related retinitis pigmentosa and asymptomatic carriers: a cross-sectional study.

BACKGROUND/AIM: To describe the clinical phenotype of retinitis pigmentosa (RP) caused by PRPF31-variants and clinical characterization of asymptomatic PRPF31 carriers. MATERIALS AND METHODS: We conducted a descriptive cross-sectional deep phenotyping study. We included subjects with PRPF31 variants predicted to be disease-causing, both individuals with RP and asymptomatic carriers. Participants underwent a comprehensive clinical examination of standard visual function parameters (visual acuity, contrast sensitivity, Goldmann visual field), full-field stimulus threshold (FST), full-field electroretinogram (ff-ERG), and a structural investigation with slit lamp and multimodal imaging. We used Spearman correlation analyses to evaluate associations between quantitative outcomes. RESULTS: We included 21 individuals with disease-causing PRPF31-variants: 16 symptomatic and 5 asymptomatic subjects. The symptomatic subjects demonstrated a typical RP phenotype with constricted visual fields, extinguished ff-ERG, and disrupted outer retinal anatomy. FST was impaired and correlated significantly with other outcome measures in RP subjects. Structure-function correlations with Spearman correlation analysis showed moderate correlation coefficients due to a few outliers in each analysis. The asymptomatic individuals had normal best-corrected visual acuity and visual fields, but showed reduced ff-ERG amplitudes, borderline FST sensitivity, and structural abnormalities on OCT and fundoscopy. CONCLUSIONS: RP11 has a typical RP phenotype but varies in terms of severity. FST measurements correlated well with other functional and structural metrics and may be a reliable outcome measure in future trials as it is sensitive to a broad range of disease severities. Asymptomatic carriers showed sub-clinical disease manifestations, and our findings underline that reported non-penetrance in PRPF31-related RP is not an all-or-none phenomenon.

Genetic Modifiers of Non-Penetrance and RNA Expression Levels in PRPF31-Associated Retinitis Pigmentosa in a Danish Cohort.

(1) Background/aims: To examine potential genetic modifiers of disease penetrance in PRPF31-associated retinitis pigmentosa 11 (RP11). (2) Methods: Blood samples from individuals (n = 37) with PRPF31 variants believed to be disease-causing were used for molecular genetic testing and, in some cases (n = 23), also for mRNA expression analyses. Medical charts were used to establish if individuals were symptomatic (RP) or asymptomatic non-penetrant carriers (NPC). RNA expression levels of PRPF31 and CNOT3 were measured on peripheral whole blood using quantitative real-time PCR normalized to GAPDH. Copy number variation of minisatellite repeat element 1 (MSR1) was performed with DNA fragment analysis. (3) Results: mRNA expression analyses on 22 individuals (17 with RP and 5 non-penetrant carriers) revealed no statistically significant differences in PRPF31 or CNOT3 mRNA expression levels between individuals with RP and non-penetrant carriers. Among 37 individuals, we found that all three carriers of a 4-copy MSR1 sequence on their wild-type (WT) allele were non-penetrant carriers. However, copy number variation of MSR1 is not the sole determinant factor of non-penetrance, as not all non-penetrant carriers carried a 4-copy WT allele. A 4-copy MSR1 mutant allele was not associated with non-penetrance. (4) Conclusions: In this Danish cohort, a 4-copy MSR1 WT allele was associated with non-penetrance of retinitis pigmentosa caused by PRPF31 variants. The level of PRPF31 mRNA expression in peripheral whole blood was not a useful indicator of disease status.

Disease progression of retinitis pigmentosa caused by PRPF31 variants in a Nordic population: a retrospective study with up to 36 years follow-up.

BACKGROUND/AIMS: To investigate the natural history of PRPF31-related retinitis pigmentosa (RP11). MATERIALS AND METHODS: We identified individuals with RP11 and collected retrospective data from disease onset to present date including genetics, demographic data, Goldmann visual field areas, and visual acuity measurements. Visual fields were evaluated as summed squared degrees and best-corrected visual acuity was converted to logMAR. We performed linear mixed model regression analysis to evaluate annual disease progression, and survival analysis to evaluate the age of legal blindness. RESULTS: We included 46 subjects with RP11. Median age of disease onset was 10 years (range 5-65). Follow-up spanned from 0 to 36 years with a median of 8 years. Median Goldmann visual field areas decreased by 10.0% per year (95% CI 7.5%-12.4%) with target IV4e, 7.9% (95% CI 4.5% - 11.2%) with target III4e, and 9.3% (95% CI: 7.0% -11.5%) when combining target sizes. Individuals with RP11 maintained good visual acuity until late stage of disease. Legal blindness was reached at a median age of 57 years (95% CI 50-75 years). CONCLUSIONS: PRPF31 variants cause autosomal dominant retinitis pigmentosa that most commonly manifests in childhood with a variable disease progression. Visual field area deteriorates faster than visual acuity and was the major cause of legal blindness in our study population. This study characterizes disease progression in retinitis pigmentosa caused by PRPF31-variants and demonstrates the importance of differentiation between specific genotypes when counselling patients and conducting natural history studies of RP.

Oliver McFarlane syndrome: two new cases and a review of the literature.

BACKGROUND: Oliver McFarlane syndrome is a rare syndrome. Clinical presentations include trichomegaly, chorioretinal degeneration, pituitary hormone deficits, and neurological manifestations. Genetic analysis has recently placed this syndrome within the group of PNPLA6-related disorders. Here, we describe two new individuals and review the previously published cases. MATERIALS AND METHODS: Clinical investigations were carried out in accordance with local guidelines and clinical information was retrieved from medical records. Genetic studies were carried out using next-generation sequencing based clinical exome sequencing. A PubMed literature search was performed with a review of the published clinical cases of Oliver McFarlane syndrome. RESULTS: Our first individual was a 36-year-old woman with 32 years of follow up and our second individual was a 3-year-old boy. Both individuals were born preterm and presented with prolonged neonatal respiratory distress, trichomegaly, early growth retardation, retinopathy and sparse depigmented hair. So far, none of our cases have demonstrated cognitive impairment or progressive neurological symptoms, but the child revealed persistent abnormal lung structure. Both individuals were compound heterozygous for pathogenic PNPLA6 variants, one of which was novel. We found other 31 clinically documented published cases. CONCLUSIONS: Our two new unrelated cases of Oliver McFarlane Syndrome demonstrate early ophthalmological and systemic findings of this rare syndrome and the progressive nature of the retinopathy with a long follow-up. PNPLA6-related disorders are a phenotypically highly heterogenous group where alterations in the phosphatidylcholine metabolism can lead to manifestations in different tissues with no clear genotype-phenotype correlation.

Interindividual and regional relationship between cerebral blood flow and glucose metabolism in the resting brain.

Studies of the resting brain measurements of cerebral blood flow (CBF) show large interindividual and regional variability, but the metabolic basis of this variability is not fully established. The aim of the present study was to reassess regional and interindividual relationships between cerebral perfusion and glucose metabolism in the resting brain. Regional quantitative measurements of CBF and cerebral metabolic rate of glucose (CMRglc) were obtained in 24 healthy young men using dynamic [15O]H2O and [18F]fluorodeoxyglucose positron emission tomography (PET). Magnetic resonance imaging measurements of global oxygen extraction fraction (gOEF) and metabolic rate of oxygen ([Formula: see text]) were obtained by combined susceptometry-based sagittal sinus oximetry and phase contrast mapping. No significant interindividual associations between global CBF, global CMRglc, and [Formula: see text] were observed. Linear mixed-model analysis showed a highly significant association of CBF with CMRglc regionally. Compared with neocortex significantly higher CBF values than explained by CMRglc were demonstrated in infratentorial structures, thalami, and mesial temporal cortex, and lower values were found in the striatum and cerebral white matter. The present study shows that absolute quantitative global CBF measurements appear not to be a valid surrogate measure of global cerebral glucose or oxygen consumption, and further demonstrates regionally variable relationship between perfusion and glucose metabolism in the resting brain that could suggest regional differences in energy substrate metabolism. NEW & NOTEWORTHY Using method-independent techniques the study cannot confirm direct interindividual correlations of absolute global values of perfusion with oxygen or glucose metabolism in the resting brain, and absolute global perfusion measurements appear not to be valid surrogate measures of cerebral metabolism. The ratio of both perfusion and oxygen delivery to glucose metabolism varies regionally, also when accounting for known methodological regional bias in quantification of glucose metabolism.

Recombinant erythropoietin acutely decreases renal perfusion and decouples the renin-angiotensin-aldosterone system.

The effect of recombinant erythropoietin (rhEPO) on renal and systemic hemodynamics was evaluated in a randomized double-blinded, cross-over study. Sixteen healthy subjects were tested with placebo, or low-dose rhEPO for 2 weeks, or high-dose rhEPO for 3 days. Subjects refrained from excessive salt intake, according to instructions from a dietitian. Renal clearance studies were done for measurements of renal plasma flow, glomerular filtration rate (GFR) and the segmentel tubular handling of sodium and water (lithium clearance). rhEPO increased arterial blood pressure, total peripheral resistance, and renal vascular resistance, and decreased renal plasma flow in the high-dose rhEPO intervention and tended to decrease GFR. In spite of the decrease in renal perfusion, rhEPO tended to decrease reabsorption of sodium and water in the proximal tubule and induced a prompt decrease in circulating levels of renin and aldosterone, independent of changes in red blood cell mass, blood volumes, and blood pressure. We also found changes in biomarkers showing evidence that rhEPO induced a prothrombotic state. Our results suggest that rhEPO causes a direct downregulation in proximal tubular reabsorption that seems to decouple the activity of the renin-angiotensin-aldosterone system from changes in renal hemodynamics. This may serve as a negative feed-back mechanism on endogenous synthesis of EPO when circulating levels of EPO are high. These results demonstrates for the first time in humans a direct effect of rhEPO on renal hemodynamics and a decoupling of the renin-angiotensin-aldosterone system.

No evidence for direct effects of recombinant human erythropoietin on cerebral blood flow and metabolism in healthy humans.

Erythropoietin (EPO) is expressed in human brain tissue, but its exact role is unknown. EPO may improve the efficiency of oxidative metabolism and has neuroprotective properties against hypoxic injuries in animal models. We aimed to investigate the effect of recombinant human EPO (rHuEPO) administration on healthy cerebral metabolism in humans during normoxia and during metabolic stress by inhalation of 10% O2 hypoxic air. Twenty-four healthy men participated in a two-arm double-blind placebo-controlled trial. rHuEPO was administered as a low dose (5,000 IU) over 4 wk ( n = 12) or as a high dose (500 IU·kg body wt-1·day-1) for three consecutive days ( n = 12). Global cerebral blood flow (CBF) and metabolic rate of glucose (CMRglc) were measured with positron emission tomography. CBF, metabolic rate of oxygen ([Formula: see text]), and cerebral lactate concentration were measured by magnetic resonance imaging and spectroscopy. Low-dose treatment increased hemoglobin and was associated with a near-significant decrease in CBF during baseline normoxia. High-dose treatment caused no change in CBF. Neither treatment had an effect on normoxia CMRglc, [Formula: see text], or lactate concentration or an effect on the cerebral metabolic response to inhalation of hypoxic air. In conclusion, the study found no evidence for a direct effect of rHuEPO on cerebral metabolism. NEW & NOTEWORTHY We demonstrate with magnetic resonance imaging and positron emission tomography that administration of erythropoietin does not have a substantial direct effect on healthy human resting cerebral blood flow or effect on cerebral glucose and oxygen metabolism. Also, administration of erythropoietin did not have a direct effect on the metabolic response to acute hypoxic stress in healthy humans, and a suggested neuroprotective effect from erythropoietin is therefore likely not a direct effect of erythropoietin on cerebral metabolism.

Comparison of global cerebral blood flow measured by phase-contrast mapping MRI with 15 O-H2 O positron emission tomography.

PURPOSE: To compare mean global cerebral blood flow (CBF) measured by phase-contrast mapping magnetic resonance imaging (PCM MRI) and by 15 O-H2 O positron emission tomography (PET) in healthy subjects. PCM MRI is increasingly being used to measure mean global CBF, but has not been validated in vivo against an accepted reference technique. MATERIALS AND METHODS: Same-day measurements of CBF by 15 O-H2 O PET and subsequently by PCM MRI were performed on 22 healthy young male volunteers. Global CBF by PET was determined by applying a one-tissue compartment model with measurement of the arterial input function. Flow was measured in the internal carotid and vertebral arteries by a noncardiac triggered PCM MRI sequence at 3T. The measured flow was normalized to total brain weight determined from a volume-segmented 3D T1 -weighted anatomical MR-scan. RESULTS: Mean CBF was 34.9 ± 3.4 mL/100 g/min measured by 15 O-H2 O PET and 57.0 ± 6.8 mL/100 g/min measured by PCM MRI. The measurements were highly correlated (P = 0.0008, R2 = 0.44), although values obtained by PCM MRI were higher compared to 15 O-H2 O PET (absolute and relative differences were 22.0 ± 5.2 mL/100 g/min and 63.4 ± 14.8%, respectively). CONCLUSION: This study confirms the use of PCM MRI for quantification of global CBF, but also that PCM MRI systematically yields higher values relative to 15 O-H2 O PET, probably related to methodological bias. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:692-699.

Acute hypoxia increases the cerebral metabolic rate - a magnetic resonance imaging study.

The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% ([Formula: see text]), glutamate increased by 4.7% ([Formula: see text]) and creatine and phosphocreatine decreased by 15.2% (p[Formula: see text]). The N-acetylaspartate concentration was unchanged (p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia.

Recombinant erythropoietin in humans has a prolonged effect on circulating erythropoietin isoform distribution.

The membrane-assisted isoform immunoassay (MAIIA) quantitates erythropoietin (EPO) isoforms as percentages of migrated isoforms (PMI). We evaluated the effect of recombinant human EPO (rhEPO) on the distribution of EPO isoforms in plasma in a randomized, placebo-controlled, double-blinded, cross-over study. 16 healthy subjects received either low-dose Epoetin beta (5000 IU on days 1, 3, 5, 7, 9, 11 and 13); high-dose Epoetin beta (30.000 IU on days 1, 2 and 3 and placebo on days 5, 7, 9, 11 and 13); or placebo on all days. PMI on days 4, 11 and 25 was determined by interaction of N-acetyl glucosamine with the glycosylation dependent desorption of EPO isoforms. At day 25, plasma-EPO in both rhEPO groups had returned to values not different from the placebo group. PMI with placebo, reflecting the endogenous EPO isoforms, averaged 82.5 (10.3) % (mean (SD)). High-dose Epoetin beta decreased PMI on days 4 and 11 to 31.0 (4.2)% (p<0.00001) and 45.2 (7.3)% (p<0.00001). Low-dose Epoetin beta decreased PMI on days 4 and 11 to 46.0 (12.8)% (p<0.00001) and 46.1 (10.4)% (p<0.00001). In both rhEPO groups, PMI on day 25 was still decreased (high-dose Epoetin beta: 72.9 (19.4)% (p=0.029); low-dose Epoetin beta: 73.1 (17.8)% (p=0.039)). In conclusion, Epoetin beta leaves a footprint in the plasma-EPO isoform pattern. MAIIA can detect changes in EPO isoform distribution up til at least three weeks after administration of Epoetin beta even though the total EPO concentration has returned to normal.