Use of a rare disease registry for establishing phenotypic classification of previously unassigned GLA variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup.

BACKGROUND: Fabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic GLA variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified GLA variants from the GLA-specific fabry-database.org database. METHODS: A Fabry disease genotype-phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan-Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes. RESULTS: Final consensus on classifications of 'pathogenic' was achieved for 32 of 33 GLA variants (26 'classic' phenotype, 171 males; 6 'later-onset' phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between 'classic' and 'later-onset' phenotypes. CONCLUSION: The iterative system implemented by a Fabry disease genotype-phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular GLA variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants.

Risk factors for severe clinical events in male and female patients with Fabry disease treated with agalsidase beta enzyme replacement therapy: Data from the Fabry Registry.

BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death. METHODS: This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death. RESULTS: The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free. CONCLUSIONS: Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies.

Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.

BACKGROUND: Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. METHODS: The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. RESULTS: 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were -1.89 mL/min/1.73 m(2)/year and -6.82 mL/min/1.73 m(2)/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥ 40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. CONCLUSIONS: This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation.

BACKGROUND: The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. METHODS: Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. RESULTS: Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). CONCLUSIONS: Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.

Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry.

PURPOSE: To evaluate life expectancy and cause of death among patients with Fabry disease, an X-linked lysosomal storage disorder. METHODS: Data from 2848 patients in the Fabry Registry were summarized using descriptive statistics. Life expectancy at birth was compared with that of the United States general population. RESULTS: As of August 2008, 75 of 1422 males and 12 of 1426 females in the Fabry Registry were reported to have died. The 87 deceased patients were diagnosed at a much older age than other patients in the Fabry Registry: median age at diagnosis was 40 vs. 24 years in males and 55 vs. 33 years in females. The life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease. Most (57%) patients who died of cardiovascular disease had previously received renal replacement therapy. CONCLUSIONS: Most deceased Fabry Registry patients exhibited serious cardiac and renal dysfunction. Late diagnosis may have contributed to the early deaths of these patients.

Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A deficiency. The Fabry Registry is a global clinical effort to collect longitudinal data on FD. In the past, most "carrier" females were usually thought to be clinically unaffected. A systematic effort has been made to enroll all FD females, regardless of symptomology. Of the 1077 enrolled females in the Registry, 69.4% had symptoms and signs of FD. The median age at symptom onset among females was 13 years, and even though 84.1% had a positive family history, the diagnosis was not made until a median age of 31 years. Twenty percent experienced major cerebrovascular, cardiac, or renal events, at a median age of 46 years. Among adult females with estimated glomerular filtration rate (eGFR) data (N=638), 62.5% had an eGFR <90 ml/min/1.73 m2 and 19.0% had eGFR <60 ml/min/1.73 m2. Proteinuria 300 mg/day was present in 39.0% of females, and 22.2% had >1 gram/day. Quality of life (QoL), as measured by the SF-36((R)) survey, was impaired at a later age than in males, but both genders experience significantly impaired QoL from the third decade of life onward. Thus, females with FD have a significant risk for major organ involvement and decreased QoL. Females should be regularly monitored for signs and symptoms of FD, and considered for enzyme replacement therapy.

Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry.

Fabry disease is an X-linked lysosomal disease caused by deficiency of alpha-galactosidase A. Signs and symptoms of Fabry disease occurring during childhood and adolescence were characterized in 352 Fabry Registry patients. At enrollment (median age 12 year), 77% of males and 51% of females reported symptoms. The median age of symptom onset was 6 year in males and 9 year in females. The most frequent symptom, neuropathic pain, was reported by 59% of males (median age 7 year) and 41% of females (median age 9 year). Gastrointestinal symptoms were reported by 18% of children (median age 5 year in males and 9.5 year in females). Males exhibited height and weight values below the US 50th percentile. Females had weight values above the US 50th percentile. A few patients had serious renal and cardiac manifestations, stage 2 or 3 chronic kidney disease (n = 3), arrhythmia (n = 9), and left ventricular hypertrophy (n = 3). Thus, many pediatric Fabry patients report early symptoms, particularly pain, gastrointestinal symptoms, and impaired quality of life. Some children experience major complications during the pediatric years.

Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta: Data from the Fabry Registry.

Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with agalsidase beta on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received agalsidase beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal symptoms (abdominal pain, diarrhea). Outcomes at baseline and last follow-up, and their change from baseline to last follow-up, were assessed. Relevant data were available for 168 female patients. Mean age at the start of ERT was 43 years and mean treatment duration 5.7 years. Baseline pre-treatment abdominal pain was reported by 45% of females and diarrhea by 39%. At last follow-up, 31% reported abdominal pain (p < 0.01) and 27% diarrhea (p < 0.01). The results of this Fabry Registry analysis suggest that while on sustained treatment with agalsidase beta (1.0 mg/kg every 2 weeks), both abdominal pain and diarrhea improved in many female patients with Fabry disease.

Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry.

BACKGROUND AND OBJECTIVES: These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included. RESULTS: Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > -1 ml/min per 1.73 m(2) per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P < 0.0001). Patients were grouped into quartiles based on averaged UP/Cr; renal function in men declined more rapidly with higher UP/Cr, with the steepest declines observed in men with UP/Cr > 1.5 (mean eGFR slope, -5.6 ml/min per 1.73 m(2) per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, -1.3 ml/min per 1.73 m(2) per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function. CONCLUSIONS: Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease.