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Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes.
Methods and results Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9–1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = - 0.41 [ - 0.68, - 0.15] mm/year, P\(_{pre–post difference}\)<0.01; IVST: n = 38, slope difference =-0.32 [-0.67, 0.02] mm/year, P\(_{pre–post difference}\) = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m\(^2\)/year, P\(_{pre–post difference}\) = 0.80).
Conclusions Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.
Background
Pain is an early symptom of Fabry disease (FD) and is characterized by a unique phenotype with mainly episodic acral and triggerable burning pain. Recently, we designed and validated the first pain questionnaire for adult FD patients in an interview and a self-administered version in German: the Wurzburg Fabry Pain Questionnaire (FPQ). We now report the validation of the English version of the self-administered FPQ (enFPQ).
Methods
After two forward-backward translations of the FPQ by native German and native English speakers, the enFPQ was applied at The Mark Holland Metabolic Unit, Manchester, UK for validation. Consecutive patients with genetically ascertained FD and current or previous FD pain underwent a face-to-face interview using the enFPQ. Two weeks later, patients filled in the self-administered enFPQ at home. The agreement between entries collected by supervised administration and self-administration of the enFPQ was assessed via Gwet's AC1-statistics (AC1) for nominal-scaled scores and intraclass correlation coefficient (ICC) for interval-scaled elements.
Results
Eighty-three FD patients underwent the face-to-face interview and 54 patients sent back a completed self-administered version of the enFPQ 2 weeks later. We found high agreement with a mean AC1-statistics of 0.725 for 55 items, and very high agreement with a mean ICC of 0.811 for 9 items.
Conclusions
We provide the validated English version of the FPQ for self-administration in adult FD patients. The enFPQ collects detailed information on the individual FD pain phenotype and thus builds a solid basis for better pain classification and treatment in patients with FD.
Background
The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.
Methods
At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.
Results
We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.
Conclusions
Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.
Aims:
Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed.
Methods:
In 2014, experts met to discuss recent advances on this topic and update clinical guidance.
Results:
Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Wurzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs.
Conclusion:
To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications.
Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease
(2017)
Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.
Background
Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system.
Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature.
Objective
To examine hearing loss in patients with FD depending on cardiac and renal function.
Material and methods
Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Würzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA\(_{6}\) (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class.
Results
Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05).
Conclusions
High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used.
Background
Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma.
Methods
To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations.
Results
p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed.
Conclusions
We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.
Background
The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines.
Methods
Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed.
Results
Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels.
Conclusion
The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.
Introduction:
Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD.
Methods:
A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement.
Results:
For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m\(^{2}\)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.
Conclusion:
The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.
Bei Morbus Fabry handelt es sich um eine X-chromosomal rezessiv vererbbare lysosomale Speichererkrankung. Im Vordergrund der kardialen Beteiligung stehen eine progrediente Herzinsuffizienz, bedingt durch eine linksventrikuläre Hypertrophie mit kardialer Fibrosierung, sowie eine Mitbeteiligung des Reizleitungssystems.
Bei 150 Patienten wurden im Zeitraum von 2001-2009 neben einer klinischen Untersuchung ein EKG, eine Echokardiographie, ein Belastungs-EKG und teilweise auch eine Magnetresonanztomographie durchgeführt. Zum Vergleich der Patientenentwicklung wurde jeweils das jüngste Follow-up Ergebnis mit den Baseline-Daten verglichen.
Es konnte eine signifikante Korrelation zwischen der QRS-Dauer und der Wandstärke in der Echokardiographie und der Magnetresonanztomographie eindeutig nachgewiesen werden. Eine myokardiale Fibrose ist bei normalen Ruhe-EKG-Parametern nahezu auszuschließen. In der Untersuchung des Langzeit-EKGs fanden sich bei einigen Patienten höhergradige ventrikuläre Rhythmusstörungen, welche als erhöhtes individuelles Risiko und als bedeutender Faktor der Sterblichkeit bei Morbus Fabry zu werten sind.