Comment on the paper: 'novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease'

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Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ

Индекс стабилизации Фабри (FASTEX): инновационный инструмент для оценки клинической стабилизации при болезни Фабри

На сегодняшний день предложены 2 системы количественной оценки бремени гликогеноза с дефицитом α-галактозидазы: индекс оценки степени тяжести Майнца (MSSI) и система балльной оценки тяжести болезни Фабри (DS3). Сделана попытка разработать динамическую математическую модель FASTEX (от англ. FAbry STabilization indEX, индекс стабилизации Фабри) для оценки клинической стабильности состояния. Мультидисциплинарная группа экспертов по болезни Фабри впервые предложила новую шкалу оценки тяжести заболевания по предварительной оценке (от англ. raw score, RS), основанную на 3 доменах (домен нервной системы (боль, цереброваскулярные события), почечный домен (протеинурия, скорость клубочковой фильтрации), сердечный домен (параметры эхокардиографии, электрокардиографии и степень сердечной недостаточности по классификации Нью-Йоркской кардиологической ассоциации)) с небольшим числом пунктов в каждом из них и оценкой клинической стабильности во времени. RS протестирована на 28 пациентах (15 мужчин и 13 женщин) с классической формой болезни Фабри. Получена сильная корреляционная связь предложенной оценки RS и взвешенной оценки (от англ. weighted score, WS) с DS3 и MSSI (r2 = 0,914; 0,949; 0,910 и 0,938 соответственно). Для уточнения RS была рассчитана WS, выражаемая в процентах. WS была основана на относительной клинической значимости каждого пункта в пределах домена, при этом группа экспертов согласовывала присвоение разного веса клинического вреда конкретной системе органов. Для определения динамики тяжести заболевания RS была повторно определена через 1 год. Группа экспертов согласилась с пороговым ограничением в 20 % от исходного уровня в качестве клинической WS для определения клинической стабильности. Модель FASTEX показала хорошую корреляцию с клинической оценкой и клиническим изменением на протяжении времени у всех пациентов. 

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/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/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/1.73m2/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 outcome

Comparison of Total Kidney Volume Quantification Methods in Autosomal Dominant Polycystic Disease for a Comprehensive Disease Assessment

Background: In recent times, the scientific community has been showing increasing interest in the treatments aimed at slowing the progression of the autosomal dominant polycystic kidney disease (ADPKD). Therefore, in this paper, we test and evaluate the performance of several available methods for total kidney volume (TKV) computation in ADPKD patients - from echography to MRI - in order to optimize patient classification. Methods: Two methods based on geometric assumptions (mid-slice [MS], ellipsoid [EL]) and a third one on true contour detection were tested on 40 ADPKD patients at different disease stage using MRI. The EL method was also tested using ultrasound images in a subset of 14 patients. Their performance was compared against TKVs derived from reference manual segmentation of MR images. Patient clinical classification was also performed based on computed volumes. Results: Kidney volumes derived from echography significantly underestimated reference volumes. Geometric-based methods applied to MR images had similar acceptable results. The highly automated method showed better performance. Volume assessment was accurate and reproducible. Importantly, classification resulted in 79, 13, 10, and 2.5% of misclassification using kidney volumes obtained from echo and MRI applying the EL, the MS and the highly automated method respectively. Conclusion: Considering the fact that the image-based technique is the only approach providing a 3D patient-specific kidney model and allowing further analysis including cyst volume computation and monitoring disease progression, we suggest that geometric assumption (e.g., EL method) should be avoided. The contour-detection approach should be used for a reproducible and precise morphologic classification of the renal volume of ADPKD patients

Geometry-independent assessment of renal volume in polycystic kidney disease from magnetic resonance imaging

Total renal volume (TRV) is an important quantitative indicator of the progression of autosomal dominant polycystic kidney disease (ADPKD). The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease proposes a method for TRV computation based on manual tracing and geometric modeling. We developed a fast and nearly-automated technique for kidney segmentation and automatically compute TRV. In this study we aim to compare TRV estimates derived from these two different approaches. The highly-automated technique for the analysis of MR images was tested on 30 ADPKD patients. TRV was computed from both axial and coronal acquisitions, and compared to measurements based on geometric modeling by linear regression and Bland Altman analysis. In addition, to assess reproducibility, intra-observer and inter-observer variabilities were computed. The results of this study provide the feasibility of using a nearly-automated approach for accurate and fast evaluation of TRV also in markedly enlarged ADPKD kidneys