Early Biomarkers of Fabry Nephropathy: A Review of the Literature

Riccio, Eleonora; Sabbatini, Massimo; Capuano, Ivana; Pisani, Antonio

doi:10.1159/000502907

Cited by 24 publications

(27 citation statements)

References 68 publications

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“…Early identification of endothelial function or other pathologies can provide insight into when ERT should be initiated in order to slow the advancement of adverse effects [49]. Additional tools and biomarkers for measuring endothelial function and other indicators of future pathologies, such as proteomics, are needed to help prevent the deterioration of vital organs [50][51][52]. Newborn screening for FD has been implemented in several states and will lead to earlier detection.…”

Section: Discussionmentioning

confidence: 99%

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Dutra‐Clarke¹,

Tapia²,

Curtin³

et al. 2021

Molecular Genetics and Metabolism

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A due to mutations in the GLA gene. This leads to an accumulation of globotriaosylceramide (GL-3) in many tissues, which results in progressive damage to the kidneys, heart, and nervous system. We present the molecular and clinical characteristics and long-term outcomes of FD patients from a multidisciplinary clinic at the University of California, Irvine treated with agalsidase beta enzyme replacement therapy (ERT) for 2-20 years. This cohort comprised 24 adults (11 males, 13 females) and two male children (median age 45; range 10-68 years). Of the 26 patients in this cohort, 20 were on ERT (12 males, 8 females). We describe one novel variant not previously reported in the literature in a patient with features of 'classic' FD. The vast majority of patients in this cohort presented with symptoms of 'classic' FD including peripheral neuropathic pain, some form of cardiac involvement, angiokeratomas, corneal verticillata, hypohidrosis, tinnitus, and gastrointestinal symptoms, primarily abdominal pain. The majority of males had clinically evident renal involvement. An annual eGFR reduction of − 1.88 mL/min/1.73 m 2 /yr during the course of ERT was seen in this cohort. The most common renal presentation was proteinuria, and one individual required a renal transplant. Other common findings were pulmonary involvement, lymphedema, hearing loss, and significantly, three patients had strokes. Notably, there was a high prevalence of endocrine dysfunction and low bone mineral density, including several with osteoporosis.While enzyme replacement therapy (ERT) cleared plasma GL-3 in this cohort, there was limited improvement in renal function or health-related quality of life based on the patient-reported SF-36 Health Survey. Physical functioning significantly declined over the course of ERT treatment, which may be, in part, due to the late initiation of ERT in several patients. Further delineation of the phenotypic and genotypic spectrum in patients with FD and the long-term outcome of ERT will help improve management and treatment options for this disease.

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Section: Discussionmentioning

confidence: 99%

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Dutra‐Clarke¹,

Tapia²,

Curtin³

et al. 2021

Molecular Genetics and Metabolism

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“…Although albuminuria is considered a useful marker for FD, many early cases of FD lack significant albuminuria. 27 The study has some method heterogeneity as male DBS was assayed by fluorimetry, while female samples were assayed by tandem mass spectrometry; these methods give comparable but not identical results but most variation is pre-analytical caused by DBS preparation. 28 The cohort we sampled was lower risk than previous studies and included both primary and non-specialist secondary care settings.…”

Section: Discussionmentioning

confidence: 99%

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study

Reynolds

Tylee²,

Booth³

et al. 2020

Int J Clin Pract

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Aims Lysosomal α‐galactosidase A deficiency (Fabry disease (FD)) was considered an X‐linked recessive disorder but is now viewed as a variable penetrance dominant trait. The prevalence of FD is 1 in 40 000‐117 000 but the ascertainment of late‐onset cases and degree of female penetrance makes this unclear. Its prevalence in the general population, especially in patients with abnormal renal function is unclear. This study attempted to identify the prevalence of FD in patients with abnormal renal function results from laboratory databases. Methods Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of reduced estimated glomerular filtration rate categorised by age on one occasion or more over a 3‐year time interval. Patients were recalled and a dried blood spot sample was collected for the determination of α‐galactosidase A activity by fluorimetric enzyme assay in men and mass spectrometry assays of α‐galactosidase A and lyso‐globotriaosylceramide (lyso‐GL‐3) concentrations in women. Results Samples were obtained from 1084 patients identified with reduced renal function. No cases of FD were identified in 505 men. From 579 women, one subject with reduced α‐galactosidase activity (1.5 µmol/L/h) and increased Lyso‐GL‐3 (5.5 ng/mL) was identified and shown to be heterozygous for a likely FD pathogenic variant (GLA c.898C>T; p.L300F; Leu300Phe). It was later confirmed that she was a relative of a known affected patient. Conclusions Pathology databases hold routine information that can be used to identify patients with inherited errors of metabolism. Biochemical screening using reduced eGFR alone has a low yield for unidentified cases of Fabry Disease.

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“…No data on albuminuria or (less relevant) haematuria. Albuminuria is considered a useful marker for FD but many early cases of FD lack significant albuminuria 24 . The cohort sampled was lower risk than previous studies and included both primary and non-specialist secondary care settings.…”

Section: Discussionmentioning

confidence: 99%

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study

Reynolds

Tylee

Booth

et al. 2020

Preprint

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Aims: Lysosomal α-galactosidase A deficiency (Fabry disease (FD)) was considered an X-linked recessive disorder but is now viewed as a variable penetrance dominant trait. The prevalence of FD is 1 in 40000-117,000 but the exact frequency is disputed depending on ascertainment of late-onset cases and degree of female penetrance. Its prevalence in the general population, especially in patients with abnormal renal function is unclear. This study attempted to identify the prevalence of FD in patients with abnormal results identified from laboratory databases. Methods: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of reduced estimated glomerular filtration rate categorised by age on one occasion or more over a 3-year time interval. Patients were recalled and a dried blood spot sample was collected for determination of α-galactosidase A activity by fluorimetric enzyme assay in men and mass spectrometry assays of α-galactosidase A and lyso-globotriaosylceramide (lyso-GL-3) concentrations in women. Results: Samples were obtained from 1084 patients identified with reduced renal function. No cases of FD were identified in 505 men. From 579 women one subject with reduced α-galactosidase activity (1.5 μmol/l/hr) and increased Lyso-GL-3 (5.5 ng/ml) was identified and shown to be heterozygous for a FD mutation (c.898C>T; p.L300F; Leu300Phe). It was later confirmed she was a relative of a known affected patient. Conclusions: Pathology databases hold routine information that can be used to identify patients with inherited errors of metabolism. Biochemical screening using reduced eGFR has a low yield for unidentified cases of Fabry Disease. What is known:• Fabry's Disease is a treatable rare multisystem disorder affecting renal function with complex inheritance. • Its prevalence in the general population is unclear.

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Early Biomarkers of Fabry Nephropathy: A Review of the Literature

Cited by 24 publications

References 68 publications

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study

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