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Association of physical symptom score (PSS) with age and cognitive measures in attenuated mucopolysaccharidosis types I, II and VI
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Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
Results: We collected data from 57 FD patients (44% males, mean age 52,4 ± 16,3 years), 47% with a HL event. The HL didn’t differ according to sex (p = 0,082), but was significantly higher in patients with WML (p = 0,001) and on ERT (p = 0,008). There was a significant correlation, in univariate analysis, between HL and age (R = 0,585; p b 0,001), VM (R = 0,527; p b 0,001) and GFR (R = 0,366; p = 0,006). In the prognostic model of risk to a HL event, age was the only predictor of a HL event (p = 0,046). Given that hearing threshold increases with age, in a logistic regression without age as variable, we found GFR as the sole variable significantly predicting a HL event (p = 0,027). Conclusion: Pure-tone audiometry should be routinely performed in FD, given the great percentage of hearing impairment. However, we should access this variable more frequently in older or with renal impairment patients. doi:10.1016/j.ymgme.2015.12.164
7 Urinary type IV collagen: Better than albuminuria to identify incipient Fabry nephropathy Patricio Aguiara, Rui Pintob, Olga Azevedoc, Jacira Marinod, Rob Bakerd, Carlos Cardosob, Jose Luis Ducla Soaresa, Derralynn Hughesd, aCentro Hospitalar Lisboa Norte, Lisbon, Portugal, bLaboratorio Dr. Joaquim Chaves, Lisbon, Portugal, cCentro Hospitalar do Alto Ave, Guimaraes, Portugal, d Royal Free London NHS Foundation Trust, London, United Kingdom Introduction: Renal involvement in Fabry disease (FD) is a major determinant of overall disease prognosis. Accumulating evidence suggest that early enzyme replacement therapy (ERT) is safe and effective in preventing progression of kidney injury. Gb3 and lyso-Gb3 storage in renal cells may occur with minimal changes on standard renal tests, hence alternative markers of glomerular dysfunction are crucial. In podocytes, lyso-Gb3 induced expression of fibronectin and type IV collagen. Thus, urinary type IV collagen (uColIV) may be an early marker of FD nephropathy. Methods: uColIV, glomerular filtration rate (GFR) and albuminuria were determined in FD patients and controls. FD patients were grouped by nephropathy severity: 1) albuminuria b 30 mg/g and GFR ≥ 60 ml/min/m2; 2) albuminuria 30-299 mg/g; 3) albuminuria N 300 mg/g; 4) GFR b 60 ml/min/m2. Results: 78 FD patients (25, 22, 10 and 21 in the groups 1, 2, 3 and 4, respectively; 43,6% males, mean age 50,1 ± 15,1 years, 69,2% on ERT) and 25 controls (age- and sex-matched with group 1) have been recruited. uColIV was significantly higher in group 1 FD patients compared with controls (130% increase; p = 0,041). There was no difference in uColIV between the several groups of FD patients (p = 0,898), as well as no difference/correlation with age (p = 0,957), sex (p = 0,880), use of ERT (p = 0,508) or use of antiproteinuric agents (p = 0,196). Regarding group 1 of FD patients, there was a significant correlation between uColIV and albuminuria (R = 0,474; p = 0,017) or GFR (R = 0,413; p = 0,040); additionally, 52% of the patients within this group had uColIV above the reference range. Conclusion: Our findings, suggests that uColIV is a better marker of incipient FD nephropathy than albuminuria (we purpose uColIV as new marker, instead of albuminuria, to define the early stage of FD nephropathy), probably reflecting the ongoing alteration of the extracellular matrix turnover induced by lyso-Gb3. Whether increased excretion of uColIV predicts progression to renal failure is being longitudinally evaluated. doi:10.1016/j.ymgme.2015.12.165
8 Association of physical symptom score (PSS) with age and cognitive measures in attenuated mucopolysaccharidosis types I, II and VI Alia Ahmed, Elsa Shapiro, Kyle Rudser, Kelly King, Chester B. Whitley, University of Minnesota, Minneapolis, MN, United States The mucopolysaccharidoses (MPS) are a group of rare genetic lysosomal disease leading to a progressive multi organ diseases. We have designed an MPS-specific physical symptom scale and generated a physical symptom score (PSS) by quantifying the somatic disease burden across MPS I, II and VI. We hypothesize that the physical symptoms of patients with MPS I, II and VI as measured by the PSS will be positively associated with age and inversely associated with cognitive ability. Fifty three patients with attenuated MPS (MPS I = 26, MPS II = 17 and MPS VI = 10) aged 3 to 32 years on enzyme replacement therapy were included who were enrolled in the study “Longitudinal Studies of Brain Structure and Functions in MPS Disorders”. To measure somatic disease burden we used the PSS and for cognitive functions we used the WASI (Wechsler Abbreviated Scale of Intelligence) and TOVA (Test of Variables of Attention) to assess FSIQ and attention. We found a statistically significant positive association of PSS with age in MPS I, MPS II and MPSVI. There was a statistically significant negative association of PSS with FSIQ in MPS I (p b 0.001) and in MPS VI (p b 0.001) but no significant association was found in MPS II. There was also a significant negative association of PSS with attention in MPSVI but no association was found in MPS I and MPS II. In conclusion, physical symptom score increased with age in attenuated MPS I, II and VI. Significant negative association of PSS with FSIQ in attenuated MPS I and MPSVI and significant negative association of PSS with attention in MPS VI, suggesting somatic burden of diseases also affects cognitive ability. In the future, the association between PSS and FSIQ in MPS II and the association between PSS and attention in MPS I and MPS II will be analyzed longitudinally. Support by NIH U54-NS065768 and UL1TR000114, CNBD and CTSI. doi:10.1016/j.ymgme.2015.12.166
9 Mutations in the GBA1 gene in Spanish population with Parkinson disease and plasma miRNA Pilar Alfonsoa,b,c, Javier Gervasa,c, Beatriz Garcia-Rodriguezc,d, Jose-Luis Capabloc,d, Miguel Pocovie, Pilar Giraldoa,b,c, aInstituto de Investigación Sanitaria Aragón (IISAragón), Zaragoza, Spain, bCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain, c Fundación Española para el Estudio y la Terapéutica de la Enfermedad de Gaucher y otras Lisosomales (FEETEG), Zaragoza, Spain, dHospital Unversitario Miguel Servet, Zaragoza, Spain, eUniversidad de Zaragoza, Zaragoza, Spain The link between Parkinson disease (PD) and Gaucher disease (GD) related to mutations in GBA1 gene is established. Nevertheless there is acknowledging about pathogenic relation between the genetic aberrations and the neurodegenerative process. Recently information about additional roles of miRNAs in neurodegenerative processes had been described. The aim of this study is to present the incidence of GBA1 mutations in a cohort of PD patients in our region and compare the profile of some miRNAs in plasma samples among controls and PD patients divided into two groups, depending if they were or not carriers of GBA1 variants. The study included 112 PD and 109 unrelated controls. Complete sequencing of promoter, exons, and intron/exon boundaries of the GBA1 gene was performed and
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
Results: We collected data from 57 FD patients (44% males, mean age 52,4 ± 16,3 years), 47% with a HL event. The HL didn’t differ according to sex (p = 0,082), but was significantly higher in patients with WML (p = 0,001) and on ERT (p = 0,008). There was a significant correlation, in univariate analysis, between HL and age (R = 0,585; p b 0,001), VM (R = 0,527; p b 0,001) and GFR (R = 0,366; p = 0,006). In the prognostic model of risk to a HL event, age was the only predictor of a HL event (p = 0,046). Given that hearing threshold increases with age, in a logistic regression without age as variable, we found GFR as the sole variable significantly predicting a HL event (p = 0,027). Conclusion: Pure-tone audiometry should be routinely performed in FD, given the great percentage of hearing impairment. However, we should access this variable more frequently in older or with renal impairment patients. doi:10.1016/j.ymgme.2015.12.164
7 Urinary type IV collagen: Better than albuminuria to identify incipient Fabry nephropathy Patricio Aguiara, Rui Pintob, Olga Azevedoc, Jacira Marinod, Rob Bakerd, Carlos Cardosob, Jose Luis Ducla Soaresa, Derralynn Hughesd, aCentro Hospitalar Lisboa Norte, Lisbon, Portugal, bLaboratorio Dr. Joaquim Chaves, Lisbon, Portugal, cCentro Hospitalar do Alto Ave, Guimaraes, Portugal, d Royal Free London NHS Foundation Trust, London, United Kingdom Introduction: Renal involvement in Fabry disease (FD) is a major determinant of overall disease prognosis. Accumulating evidence suggest that early enzyme replacement therapy (ERT) is safe and effective in preventing progression of kidney injury. Gb3 and lyso-Gb3 storage in renal cells may occur with minimal changes on standard renal tests, hence alternative markers of glomerular dysfunction are crucial. In podocytes, lyso-Gb3 induced expression of fibronectin and type IV collagen. Thus, urinary type IV collagen (uColIV) may be an early marker of FD nephropathy. Methods: uColIV, glomerular filtration rate (GFR) and albuminuria were determined in FD patients and controls. FD patients were grouped by nephropathy severity: 1) albuminuria b 30 mg/g and GFR ≥ 60 ml/min/m2; 2) albuminuria 30-299 mg/g; 3) albuminuria N 300 mg/g; 4) GFR b 60 ml/min/m2. Results: 78 FD patients (25, 22, 10 and 21 in the groups 1, 2, 3 and 4, respectively; 43,6% males, mean age 50,1 ± 15,1 years, 69,2% on ERT) and 25 controls (age- and sex-matched with group 1) have been recruited. uColIV was significantly higher in group 1 FD patients compared with controls (130% increase; p = 0,041). There was no difference in uColIV between the several groups of FD patients (p = 0,898), as well as no difference/correlation with age (p = 0,957), sex (p = 0,880), use of ERT (p = 0,508) or use of antiproteinuric agents (p = 0,196). Regarding group 1 of FD patients, there was a significant correlation between uColIV and albuminuria (R = 0,474; p = 0,017) or GFR (R = 0,413; p = 0,040); additionally, 52% of the patients within this group had uColIV above the reference range. Conclusion: Our findings, suggests that uColIV is a better marker of incipient FD nephropathy than albuminuria (we purpose uColIV as new marker, instead of albuminuria, to define the early stage of FD nephropathy), probably reflecting the ongoing alteration of the extracellular matrix turnover induced by lyso-Gb3. Whether increased excretion of uColIV predicts progression to renal failure is being longitudinally evaluated. doi:10.1016/j.ymgme.2015.12.165
8 Association of physical symptom score (PSS) with age and cognitive measures in attenuated mucopolysaccharidosis types I, II and VI Alia Ahmed, Elsa Shapiro, Kyle Rudser, Kelly King, Chester B. Whitley, University of Minnesota, Minneapolis, MN, United States The mucopolysaccharidoses (MPS) are a group of rare genetic lysosomal disease leading to a progressive multi organ diseases. We have designed an MPS-specific physical symptom scale and generated a physical symptom score (PSS) by quantifying the somatic disease burden across MPS I, II and VI. We hypothesize that the physical symptoms of patients with MPS I, II and VI as measured by the PSS will be positively associated with age and inversely associated with cognitive ability. Fifty three patients with attenuated MPS (MPS I = 26, MPS II = 17 and MPS VI = 10) aged 3 to 32 years on enzyme replacement therapy were included who were enrolled in the study “Longitudinal Studies of Brain Structure and Functions in MPS Disorders”. To measure somatic disease burden we used the PSS and for cognitive functions we used the WASI (Wechsler Abbreviated Scale of Intelligence) and TOVA (Test of Variables of Attention) to assess FSIQ and attention. We found a statistically significant positive association of PSS with age in MPS I, MPS II and MPSVI. There was a statistically significant negative association of PSS with FSIQ in MPS I (p b 0.001) and in MPS VI (p b 0.001) but no significant association was found in MPS II. There was also a significant negative association of PSS with attention in MPSVI but no association was found in MPS I and MPS II. In conclusion, physical symptom score increased with age in attenuated MPS I, II and VI. Significant negative association of PSS with FSIQ in attenuated MPS I and MPSVI and significant negative association of PSS with attention in MPS VI, suggesting somatic burden of diseases also affects cognitive ability. In the future, the association between PSS and FSIQ in MPS II and the association between PSS and attention in MPS I and MPS II will be analyzed longitudinally. Support by NIH U54-NS065768 and UL1TR000114, CNBD and CTSI. doi:10.1016/j.ymgme.2015.12.166
9 Mutations in the GBA1 gene in Spanish population with Parkinson disease and plasma miRNA Pilar Alfonsoa,b,c, Javier Gervasa,c, Beatriz Garcia-Rodriguezc,d, Jose-Luis Capabloc,d, Miguel Pocovie, Pilar Giraldoa,b,c, aInstituto de Investigación Sanitaria Aragón (IISAragón), Zaragoza, Spain, bCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain, c Fundación Española para el Estudio y la Terapéutica de la Enfermedad de Gaucher y otras Lisosomales (FEETEG), Zaragoza, Spain, dHospital Unversitario Miguel Servet, Zaragoza, Spain, eUniversidad de Zaragoza, Zaragoza, Spain The link between Parkinson disease (PD) and Gaucher disease (GD) related to mutations in GBA1 gene is established. Nevertheless there is acknowledging about pathogenic relation between the genetic aberrations and the neurodegenerative process. Recently information about additional roles of miRNAs in neurodegenerative processes had been described. The aim of this study is to present the incidence of GBA1 mutations in a cohort of PD patients in our region and compare the profile of some miRNAs in plasma samples among controls and PD patients divided into two groups, depending if they were or not carriers of GBA1 variants. The study included 112 PD and 109 unrelated controls. Complete sequencing of promoter, exons, and intron/exon boundaries of the GBA1 gene was performed and