Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort
Abstract
:1. Introduction
2. Materials and Methods
2.1. Lyso-Gb3 and GLA Screening
2.2. Patient Enrollment
2.3. Sample Collection
2.4. Measurement of Plasma Lyso-Gb3
2.5. Measurement of Plasma GLA Activity
2.6. Genetic Counseling
2.7. Gene Analysis
2.8. Defining FD
2.9. Statistical Analyses
3. Results
3.1. Study Population
3.2. Plasma Lyso-Gb3 Levels
3.3. Plasma GLA Activity
3.4. Classification of FD Probands with Class 1 Variants
3.5. Frequency of Positive Lyso-Gb3 Screens and FD Diagnosis by Clinical Department
3.6. Prosaposin (PSAP) Analysis for Probands with Late-Onset Biopsy-Proven FD
3.7. Comparison of Lyso-Gb3 Screening and GLA Analysis between Cohorts
3.8. Differences in Plasma Lyso-Gb3 Levels and GLA Activity between Cohorts
3.9. ROC Curve Analysis for Plasma Lyso-Gb3 Levels, GLA Activity, and GLA/lyso-Gb3 Ratio
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cardiology | Nephrology | Neurology | Pediatrics | Total | |
---|---|---|---|---|---|
Males | (n = 1006) | (n = 1771) | (n = 624) | (n = 38) | (n = 3439) |
Median (IQR) age (years) | 64 (51–71) | 66 (56–74) | 54 (47–71) | 11 (9–13) | 64 (51–73) |
Clinics (n) | 59 | 47 | 43 | 13 | 162 |
Females | (n = 451) | (n = 1249) | (n = 492) | (n = 60) | (n = 2252) |
Median (IQR) age (years) | 67 (53–75) | 69 (61–77) | 66 (47–81) | 12 (9–14) | 68 (54–77) |
Clinics (n) | 74 | 57 | 57 | 26 | 214 |
Patient No. | Lyso-Gb3 Levels (ng/mL) | GLA Activity (nmol/h/mL) | GLA Variants | Age (Years) | Early-Onset Classic Manifestations | Manifestations | ||||
---|---|---|---|---|---|---|---|---|---|---|
DNA | Protein | Heart | Kidneys | CNS | ||||||
Males; Classic type | ||||||||||
Pediatrics | 1 1 | 190.2 | 0.4 | c.(202C>T) | p.Leu68Phe | 13 | Acroparesthesia Hypohidrosis | None | None | None |
2 1 | 172.2 | 0.3 | c.(254G>T) | p.Gly85Val | 9 | Acroparesthesia Hypohidrosis | None | None | None | |
3 | 230.1 | 0.3 | c.(658C>T) | p.Arg220* | 9 | Acroparesthesia Hypohidrosis | None | None | None | |
4 | 177.4 | 0.3 | c.1133G>T | p.Cys378Phe | 9 | Acroparesthesia Hypohidrosis | None | None | None | |
Males; Late-onset type | ||||||||||
Cardiology | 5 1 | 3.6 | 2.7 | c.(335G>A) | p.Arg112His | 61 | None | LVH | G5DA1 | None |
6 | 14.2 | 1.5 | c.547+4A>G r.486_547del | p.Gly163Leufs*2 | 74 | None | Arrhythmia LVH | G3a | None | |
7 1 | 15.6 | 1.1 | c.(902G>A) | p.Arg301Gln | 55 | None | LVH | None | None | |
8 1 | 14.5 | 1.0 | c.(935A>G) | p.Gln312Arg | 77 | None | LVH | None | None | |
Nephrology | 9 | 14.7 | 1.9 | c.44C>G | p.(Ala15Gly) | 66 | None | Arrhythmia LVH | G3A2 | None |
10 1 | 4.1 | 0.6 | c.(335G>A) | p.Arg112His | 42 | None | None | G2A3 | None | |
11 1 | 4.0 | 1.3 | c.1171A>G | p.(Lys391Glu) | 75 | None | None | G5DA2 | Stroke | |
Females; Classic type | ||||||||||
Cardiology | 12 | 29.5 | 1.9 | c.(281G>A) | p.Cys94Tyr | 71 | None | Arrhythmia LVH | G3a | Stroke |
13 1 | 21.8 | 3.2 | c.559_560del | p.(Met187Valfs*6) | 65 | Acroparesthesia Gastrointestinal symptoms | LVH | None | Stroke | |
14 1 | 24.2 | 1.6 | c.(659G>C) | p.Arg220Pro | 65 | Angiokeratoma Cornea verticillata | LVH | G3bA1 | Stroke | |
15 1 | 4.0 | 8.0 | c.691G>A | p.Asp231Asn | 63 | None | Arrhythmia Heart failure | None | None | |
Nephrology | 16 | 19.9 | 1.9 | c.334C>T | p.(Arg112Cys) | 44 | None | LVH | G2A3 | None |
17 1 | 15.0 | 2.6 | c.1244T>C | p.(Leu415Pro) | 32 | Acroparesthesia | LVH | G1A3 | None | |
Neurology | 18 1 | 135.0 | 0.8 | c.[788A>G];[0] | p.(Asn263Ser) | 27 | Acroparesthesia Hypohidrosis Angiokeratoma | Arrhythmia | G1A3 | None |
Females; Late-onset type | ||||||||||
Nephrology | 19 | 15.8 | 2.2 | c.1163T>A | p.(Leu388His) | 59 | None | LVH | G3aA3 | None |
20 1 | 3.3 | 2.6 | c.1208T>C | p.(Leu403Ser) | 53 | None | LVH | G5A3 | None |
Cardiology | Nephrology | Neurology | Pediatrics | Total | ||
---|---|---|---|---|---|---|
Males | Lyso-Gb3-positive patients, n/N (%) | 4/1006 (0.4) | 6/1771 (0.3) | 0/624 (0) | 4/38 (10.5) | 14/3439 (0.4) |
GLA variant, n/N (%) | 4/1006 (0.4) | 3/1771 (0.2) | 0/624 (0) | 4/38 (10.5) | 11/3439 (0.3) | |
Classic type, n | 0 | 0 | 0 | 4 | 4 | |
Late-onset type, n | 4 | 3 | 0 | 0 | 7 | |
Females | Lyso-Gb3-positive patients, n/N (%) | 10/451 (2.2) | 8/1249 (0.6) | 1/492 (0.2) | 0/60 (0) | 19/2252 (0.8) |
GLA variant, n/N (%) | 4/451 (0.9) | 4/1249 (0.3) | 1/492 (0.2) | 0/60 (0) | 9/2252 (0.4) | |
Classic type, n | 4 | 2 | 1 | 0 | 7 | |
Late-onset type, n | 0 | 2 | 0 | 0 | 2 |
Department | Patient No. | Lyso-Gb3 Levels (ng/mL) | GLA Activity (nmol/h/mL) | GLA Class 1 Variants | Age (years) | Early-Onset Classic Manifestations | Manifestations | ||
---|---|---|---|---|---|---|---|---|---|
Heart | Kidneys | CNS | |||||||
Male | |||||||||
Nephrology | 1 | 3.2 | 8.4 | None | 75 | None | None | G2A1 Lamellar body | None |
Females | |||||||||
Cardiology | 2 1 | 8.4 | 8.5 | None | 59 | None | Arrhythmia LVH Lamellar body | G5A3 Lamellar body | None |
3 1 | 18.5 | 10.9 | None | 67 | None | Arrhythmia LVH Lamellar body | None | None | |
Nephrology | 4 1 | 7.8 | 4.7 | None | 69 | None | Arrhythmia | G3aA3 Lamellar body | None |
5 | 5.6 | 5.9 | None | 66 | None | None | G3aA3 Lamellar body | None |
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Maruyama, H.; Taguchi, A.; Mikame, M.; Izawa, A.; Morito, N.; Izaki, K.; Seto, T.; Onishi, A.; Sugiyama, H.; Sakai, N.; et al. Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort. Curr. Issues Mol. Biol. 2021, 43, 389-404. https://doi.org/10.3390/cimb43010032
Maruyama H, Taguchi A, Mikame M, Izawa A, Morito N, Izaki K, Seto T, Onishi A, Sugiyama H, Sakai N, et al. Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort. Current Issues in Molecular Biology. 2021; 43(1):389-404. https://doi.org/10.3390/cimb43010032
Chicago/Turabian StyleMaruyama, Hiroki, Atsumi Taguchi, Mariko Mikame, Atsushi Izawa, Naoki Morito, Kazufumi Izaki, Toshiyuki Seto, Akifumi Onishi, Hitoshi Sugiyama, Norio Sakai, and et al. 2021. "Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort" Current Issues in Molecular Biology 43, no. 1: 389-404. https://doi.org/10.3390/cimb43010032