Assessment of corneal topographic, tomographic, densitometric, and biomechanical properties of Fabry patients with ocular manifestations.

PURPOSE: To investigate whether cornea verticillata affects corneal topography, tomography, densitometry, or biomechanics of Fabry patients with ocular manifestations and to compare these results with those obtained from healthy subjects. METHODS: This prospective, cross-sectional study included 23 Fabry patients (Fabry group) with cornea verticillata and the 37 age- and sex-matched healthy subjects (control group). After comprehensive ophthalmological examinations, corneal topography, tomography, and densitometry measurements were taken using Pentacam HR and corneal biomechanics were captured via Corvis ST for all participants. RESULTS: All the investigated topographic and tomographic values were similar in the eyes with Fabry disease (FD) and the controls (P > 0.05). The corneal densitometry values of patients with FD were statistically significantly higher in all the concentric zones and layers, except posterior 0-2 mm and posterior 2-6 mm zones, compared to the controls (P < 0.05). The mean values of A1 velocity, A2 velocity, deformation amplitude ratio, Corvis biomechanical index, tomographic and biomechanical index, and Stiffness parameter at the first applanation in the Fabry group were statistically significantly different compared to control group (P < 0.05). However, the mean values of A1 length, A2 length, and the biomechanically corrected intraocular pressure were similar between the groups (P = 0.317, P = 0.819, and P = 0.468; respectively). CONCLUSION: Although cornea verticillata associated with FD is not considered to affect vision, it is associated with increased light backscattering and reduced corneal transparency as well as altered corneal biomechanical properties.

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography.

Purpose: Fabry disease (FD) is a multiorgan X-linked condition characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in a progressive intralysosomal deposit of globotriaosylceramide. The aim of this study was to evaluate the macular ultrastructure of the vascular network using optical coherence tomography angiography (OCTA) and to evaluate macular function using focal electroretinography (fERG) in Fabry patients (FPs). Methods: A total of 20 FPs (38 eyes, mean age 57 ± 2.12 SD, range of 27-80 years) and 17 healthy controls (27 eyes, mean age 45 years ± 20.50 SD, range of 24-65 years) were enrolled in the study. Color fundus photography, swept-source optical coherence tomography (SS-OCT), OCTA and fERG were performed in all subjects. The OCTA foveal avascular zone (FAZ), vasculature structure, superficial and deep retinal plexus densities (images of 4.5 × 4.5 mm) and fERG amplitudes were measured. Group differences were statistically assessed by Student's t-test and ANOVA. Results: In the FP group, the FAZ areas of the superficial and deep plexuses were enlarged (P = 0.036, t = 2.138; P < 0.001, t = -3.889, respectively), the vessel density was increased in the superficial plexus, and the fERG amplitude was reduced (P < 0.001, t = -10.647) compared with those in healthy controls. No significant correlations were found between the structural and functional data. Conclusions: OCTA vascular abnormalities and reduced fERG amplitudes indicate subclinical signs of microangiopathy with early retinal dysfunction in FPs. This study highlights the relevance of OCTA imaging analysis in the identification of abnormal macular vasculature as an ocular hallmark of FD.

Cardiopulmonary fitness assessment on maximal and submaximal exercise testing in patients with Fabry disease.

The cardiopulmonary exercise test (CPET) is a valuable tool to assess a patient's aerobic fitness and cardiac function, including the response to stress. There have been few studies using CPET to evaluate cardiopulmonary exercise capacity in patients with Fabry disease. We performed a retrospective chart review of patients with Fabry disease from 2001 to 2016, compared to age, gender, and size-matched normal controls. A total of 18 patients were evaluated using the Bruce protocol (treadmill) and 11 patients were evaluated with the ramp protocol (cycle ergometer). The Fabry group demonstrated significantly lower heart rate at peak exercise (151.2 ± 22.5 vs. 178.6 ± 16.2, p < .05), max indexed VO2 (23.7 ± 7 vs. 33.9 ± 8.4, p < .05), and peak index oxygen pulse (12.1 ± 3 vs. 15.2 ± 4.2, p < .05). When the groups were further separated into treadmill or cycle ergometry testing only, there remained statistically significant differences in peak indexed oxygen pulse, heart rate at peak exercise, and max indexed VO2 . There was a statistically significant difference between the Fabry patients evaluated by treadmill testing for systolic blood pressure at peak exercise that was not seen in the cycle ergometry group. Additionally, when looking at the patients who had concurrent cardiac MRI (cMRI) with their CPET, there was a positive correlation with max indexed VO2 and right ventricular end-diastolic volume (r = .55, p = .007) and end-systolic volume (r = .59, p = .007). Patients with Fabry disease have impaired cardiopulmonary exercise capacity as measured by CPET. Additionally, in patients with Fabry disease there is a positive correlation with functional capacity and right ventricular volumes on cMRI.

Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study.

Quality of life (QoL) is decreased in patients with Fabry disease (FD). To improve QoL, it is important to understand the influence of FD related characteristics, symptoms, and complications. In this retrospective cohort study we explored the effect of pain (measured by the Brief Pain Inventory), phenotype, treatment, and FD-related complications on QoL. QoL data of Fabry patients as assessed by the EuroQol five dimension questionnaire (EQ-5D) from two international centers of excellence were collected. The aim of this study was to evaluate the effect of sex, phenotype, age, different states of disease severity, pain, and ERT on EQ-5D utilities. For 286 adult FD patients (mean age 42.5 years, 40% men, 60% classical phenotype) 2240 EQ-5Ds were available. QoL is decreased in men as well as women with FD, especially in older men with a classical phenotype. At age 50, utility was lower in men with classical FD compared to those with non-classical disease (ß = -0.12, 95% CI: -0.23 - 0.01, p = 0.037) with further difference in the years thereafter. Cardiovascular complications, stroke or transient ischemic attacks, multiple FD-related complications and pain were also associated with decreased utilities. Overall, no change in utility was seen in patients on ERT over a mean follow-up of 6.1 years. FD leads to a decreased QoL compared to the general population. Disease complications and pain both negatively influence QoL. Adequate assessment and treatment of pain as well as improved strategies to prevent disease complications are needed to improve QoL in the FD population.

Cognitive testing in Fabry disease: pilot using a brief computerized assessment tool.

BACKGROUND: Recently, cognitive assessments of patients with Fabry disease highlighted neurocognitive impairment using test batteries that are time and labor intensive. OBJECTIVES: To introduce a user-friendly self-administered tool for cognitive testing in patients with Fabry disease. METHODS: We used a computerized system requiring about 1 hour for patient follow-up. All patients with enzymatic and/ or molecular diagnosis of Fabry disease seen in our clinic underwent assessment with the Fabry-specific Mainz Severity Score Index (MSSI) with subscores (neurological, renal, cardiac, and general) and a Mindstreams neurocognitive battery for mild impairment, evaluating memory, executive function, attention, information processing, visual spatial processing, verbal function, and motor skills. A Global Cognitive Score (GCS) was also computed. RESULTS: Ten patients (3 males, 7 females) were tested (mean age 41.5, range 25-56 years). Males were younger, had moderate nephropathy and no cerebrovascular accident (CVA); their Mindstreams GCS was 85.6-107 points. Three females had mild-moderate (8,10,15 points) neurological MSSI subscores (two CVA); all females had Mindstreams GCS of 59-107.7 points. Below-average performance was prevalent, particularly in information processing and motor skills consistent with mild impairment. Average GCS in females (90.3 points) was lowerthan in males (98.2 points). For individual patients, performance was poorest in information processing (n = 4), attention (n = 2), motor skills (n = 2), verbal function (n = 1), and visual spatial processing (n = 1). CONCLUSIONS: MindStreams may simplify cognitive assessment monitoring in Fabry disease.

The value of estimated GFR in comparison to measured GFR for the assessment of renal function in adult patients with Fabry disease.

BACKGROUND: Renal disease is one of the major complications in Fabry disease, an X-linked lysosomal storage disease due to deficiency of the enzyme alpha-galactosidase A. The aim of our study was to determine the value of creatinine-, cystatin C- and beta-trace-based formulas for the estimation of glomerular filtration rate (eGFR) in Fabry patients. For comparison, the gold standard method (125)I-labelled iothalamate/(131)I-labelled hippuran [measured GFR (mGFR)] was used. METHODS: GFR was estimated by using 11 different formulas based on creatinine, cystatin C and beta-trace protein. Accuracy and precision, detection of early decline of renal function and follow-up of renal function by eGFR was compared to mGFR. RESULTS: One hundred and thirty-six GFR measurements and plasma samples were available from 36 (20 male) Fabry patients, treated with agalsidase alpha or beta with a median follow-up of 3.1 (range 1.5-5.2) years. Median mGFR was 97.3 (15.5-148.6) ml/min/1.73 m(2) in males and 84.4 (23.0-131.0) ml/min/1.73 m(2) in females at the start of follow-up. CONCLUSIONS: Although none of the investigated endogenous markers proved to be an equivalent substitute for mGFR in Fabry patients, the Stevens equation, a creatinine- and cystatin C-based formula, most closely approximated the mGFR. When a creatinine-based formula is preferred, considering that there is no standardized method available for cystatin C, the abbreviated Modification of Diet in Renal Disease (aMDRD) and the recently developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas had the best performance. In male Fabry patients, the aMDRD may overestimate GFR, especially in the higher ranges. In these cases, CKD-EPI may perform better.

Assessment of renal pathology and dysfunction in children with Fabry disease.

Overt renal disease often first presents in male individuals with Fabry disease in early to middle adulthood, but proteinuria and reduced GFR may occur in adolescents and in young children. More recently, kidney biopsy data have shown early renal histologic changes in pediatric patients, and kidney dysfunction, primarily proteinuria, seems to be more common in girls. Renal investigations and their timing in children remain poorly defined. A consensus on renal investigations is necessary to understand the natural progression of the disease and to evaluate the efficacy of treatments such as enzyme replacement therapies. This article addresses three main categories: Use of GFRs, measuring albuminuria, and renal biopsies in children.

A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). DATA SOURCES: Electronic databases from inception up to mid-2004. Contact with clinical experts. REVIEW METHODS: Relevant studies were identified and assessed using recommended quality criteria. RESULTS: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. CONCLUSIONS: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.

Functional assessment of A delta and C fibers in patients with Fabry's disease.

The pathophysiology of neuropathic pain in Fabry's disease (FD) is still largely unknown. Seven FD patients were studied by laser evoked potentials (LEPs) to assess the function of the A delta and C fibers. Laser pulses were delivered on the skin of the hand and perioral region at painful intensity to record LEPs related to A delta-fiber inputs and at nonpainful intensity to obtain LEPs related to C-fiber inputs. When the perioral region was stimulated, a vertex positive component was recorded with a mean latency of 260.3 ms and 376 ms after A delta- and C-fiber stimulation, respectively. The mean A delta-LEP amplitude was significantly lower in FD patients (N1/P1 mean values were 2.8 microV and 4.5 microV after hand and face stimulation, respectively, compared to 4 microV and 8.9 microV for controls; N2/P2 mean values were 8.2 microV and 11.1 microV after hand and face stimulation, respectively, and 16.7 microV and 22.3 microV in controls). Unlike the healthy subjects, 6 FD patients, suffering from neuropathic pain, showed a late positive potential related to C-fiber function (mean latency, 377.1 ms) also after facial stimulation at painful intensity, suggesting a relative overflow of C-fiber input, which may be relevant in the pathophysiology of pain in this disease.

Assessment of health-related quality-of-life in males with Anderson Fabry Disease before therapeutic intervention.

Anderson Fabry Disease (AFD) is an extremely painful and debilitating multi-system X-linked disorder due to alpha-galactosidase enzyme deficiency. To date, no baseline data on health-related quality-of-life (HR-QoL) have been reported in males affected with this condition. In this study, 38 males with AFD completed Medical Outcomes Study Short Form, EuroQoL questionnaires and an AFD-specific questionnaire prior to the start of a trial involving replacement therapy with alpha-galactosidase. Results from these questionnaires were compared to the results from a similar HR-QoL study in males with severe haemophilia (factor VIII/IX deficiency) that used the same questionnaires and to the results of two large normative studies. The results on both questionnaires showed that in most instances males with AFD recorded significantly lower HR-QoL compared with males in the general population and individuals with severe haemophilia after adjusting for differences in age. These findings suggest therefore, that the scope for improvement in HR-QoL as a result of treatment with an appropriate agent is extremely large.

Pathophysiology and assessment of neuropathic pain in Fabry disease.

UNLABELLED: Severe neuropathic pain and hypohidrosis are important symptoms of Fabry disease, particularly in the first three decades of life. The pain is associated with a length-dependent small-fibre neuropathy that also causes a selective deficiency of cold perception. Cold exposure often accentuates the pain and worsens thermal perception. The hypohidrosis leads to poor exercise and heat tolerance. The mechanisms by which alpha-galactosidase A deficiency causes these physiological abnormalities are poorly understood. The stored glycolipid (globotriaosylceramide) may interfere with the function of cellular membrane proteins, such as ion channels, or may lead to cytotoxicity. The characteristic neuropathic pain can be symptomatically treated with various types of anticonvulsant drugs, such as carbamazepine. Improvement in neuropathic pain as a primary outcome measure has been useful in demonstrating that enzyme replacement therapy is effective in improving pain-related quality of life in Fabry disease. CONCLUSIONS: The dysfunction of the peripheral nervous system is easily assessable and more readily reversible with specific therapy than the destructive processes that occur in organs such as the kidney. In future, therefore, it is likely that neuropathic pain, quantitative sensory testing and hypohidrosis will serve as clinical outcome measures for studies of specific and effective therapies for Fabry disease.