Additional file 1 of Recurrent, non-traumatic, non-exertional rhabdomyolysis after immunologic stimuli in a healthy adolescent female: a case report

Additional file 1: Appendix. Comprehensive laboratory work-up

Differentially expressed proteins in genetically edited human podocytes: contributing to the understanding of early molecular events in Fabry Disease

Background: Podocyte damage and subsequent proteinuric chronic nephropathy are prominent features of Fabry Disease (FD), a multisystemic X-linked inherited lysosomal storage disorder caused by deficient activity of the alpha-galactosidase A (α-GAL A) enzyme following mutations in the GLA gene. Methods: A proteomic approach based on two-dimensional gel electrophoresis coupled with mass spectrometry was used to explore differentially expressed proteins in podocytes with α-GAL A deficiency. This deficiency was developed through GLA gene deletion using CRISPR/Cas9 genome-editing technology in an immortalized human podocyte culture cell line. To further validate our proteomic findings, we compared the expression of autophagy-specific biomarkers (LC3B and p62) using western blotting, as well as evaluated apoptosis using propidium iodide fluorescence microscopy. Results:  Our results showed that protein levels of ubiquitin carboxyl-terminal esterase L1, alpha-enolase, and heat shock protein 60 were reduced FD podocytes. Functional analysis using gene ontology found these proteins were predominately involved in biological processes, including autophagy regulation and apoptosis. Additionally, we found that autophagy-specific biomarkers LC3B and p62 were overexpressed, confirming impaired autophagy regulation and greater apoptosis in FD podocytes. Conclusions Our findings suggest impaired proteostasis in FD podocytes due to concomitant dysfunction of the ubiquitin–proteasome system and the autophagy pathway; both of which are potentially implicated in the pathogenesis of FD nephropathy

CD77 levels over enzyme replacement treatment in Fabry Disease Family (V269M)

<div><p>ABSTRACT Introduction: Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT). Objective: The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation). Methods: We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types. Results: A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels. Conclusion: The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.</p></div

The Tatton-Brown-Rahman Syndrome:: a clinical study of 55 individuals with de novo constitutive DNMT3A variants

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in &gt;80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS