Renal and urinary tract diseases
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Fabry disease is X-linked with partial manifestation in some females. Cardiac involvement, characteristic skin lesions and painful neuropathy are other predominant features, in addition to nephropathy and also ocular involvement. Diagnosis of the affected hemizygous male can employ enzyme assay (α-galactosidase), but the detection of heterozygous carrier females (whether or not they manifest clinical features of the disorder) is often best achieved by molecular methods. Prenatal diagnosis is also available by molecular diagnostics or by enzyme assay (for a male fetus). Enzyme replacement therapy is available (and useful) for affected males and for females who manifest complications of the condition.
Gene Transfer into Human Hematopoietic Stem Cells
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
Fabry disease is a human lysosomal storage disorder due to an inborn defect of the alpha-galactosidase A gene. Preliminary experiments demonstrated that cord blood or bone marrow CD34+ cells as well as long-term culture derived progenitor cells could be successfully transduced by retroviral vectors carrying the alpha-gal A transgene.117 The efficiency of cord blood CD34+ transduction in this pre-clinical study ranged from 34% to 82%. Furthermore, in vitro experiments established that alpha-gal A transduced cells could secrete alpha-galactosidase A and complement the genetic defect of non-transduced cells derived from patients with Fabry disease.
Metabolic Diseases
Stephan Strobel, Lewis Spitz, Stephen D. Marks in Great Ormond Street Handbook of Paediatrics, 2019
Fabry disease is a lysosomal storage disease and accumulation of α-D-galactosyl moieties, particularly of globotriaosylceramide (Gb3) appears to be the initiation factor of the pathological cascades. While these include features suggestive of a classic vasculopathy, the overall pathological process is still poorly understood. Once significant end-organ damage has occurred, it is largely irreversible. The gene for Fabry disease, GLA, is on the X chromosome. Males tend to have more severe and earlier disease many females are also affected. There is a degree of genotype–phenotype correlation but no particular common mutation.
Recurrent acute coronary syndrome, polymorphic premature ventricular complexes and a son with a (mis)diagnosis of multiple sclerosis
Published in Acta Cardiologica, 2020
Jeremy Nestele, Carst van den Hoven, Emeline M. Van Craenenbroeck, Francois Eyskens, Bernard P. Paelinck, Amélie Dendooven, Steven E. Haine
Fabry disease is a X-linked lysosomal storage disorder that causes excessive accumulation of globotriaosylceramide (GB-3) in various organs. Male patients exhibit classical type Fabry disease, characterised by systemic organ damage. Female subjects can show variable organ involvement. This can be attributed to X-chromosome inactivation. The exact prevalence of Fabry disease is unknown, mainly due to underdiagnosis. As illustrated in our case, even at autopsy the correct diagnosis can be missed. Several family members suffering from undiagnosed Fabry disease, were identified subsequently. In patients with cardiac hypertrophy and multiple organ involvement, Fabry disease should be kept in mind and therefore, alfa galactosidase activity in men and GLA mutation analysis in men and women should be assessed.
Cardiovascular risk in chronic kidney disease: what is new in the pathogenesis and treatment?
Published in Postgraduate Medicine, 2018
Angelika Bazyluk, Jolanta Malyszko, Edyta Zbroch
Over the last years, a process of autophagy was widely examined. Autophagy is an evolutionarily conserved intracellular catabolic process that enables for the degradation of proteins and organelles via the lysosomal pathway [85]. The studies showed that age-related decline in autophagic activity contributed to various aspects of the aging process [86,87]. Age-dependent high basal autophagy is crucial for mitochondrial quality control and genome stability as well as protects against metabolic stress associated with age-related kidney diseases [88]. Several studies revealed that lysosomal injury is associated with proteinuria. Fabry disease, a rare genetic lysosomal storage disease, involves loss of podocytes with subsequent proteinuria [89]. Another study in mice model with depletion of single gene regulating lysosome function resulted in podocyte damage and proteinuria [90]. To confirm if the same mechanism plays a role in the development of proteinuria in diabetic kidney disease the investigators carried out an experiment under diabetic conditions. They revealed that autophagy insufficiency was significant in rodents and patients with massive proteinuria, but not with the other disease stage. They also proved that diabetes alone can cause typical glomerular changes leading to minimal proteinuria, whereas complicated impairment of podocyte autophagy follows with podocyte loss and consequent massive proteinuria [91]. New therapeutic strategy targeting podocytes autophagy could halt progression of proteinuria and subsequent tubulointerstitial fibrosis in patients with diabetic kidney disease.
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
HSC-directed gene therapy is also being investigated by us for treatment of Fabry disease. Fabry disease is caused by a deficiency of α-galactosidase A that leads to the accumulation of globotriaosylceramide – among other glycosphingolipids. This phase I safety trial is being conducted by the Fabry disease clinical research and therapeutics (FACTs) team in Canada (NCT02800070). Pre-clinical mouse modeling of the therapy demonstrated supra-normal levels of circulating enzyme and concomitant reduction in substrate accumulation [47]. Some key differences can be highlighted between Fabry disease and MLD that emphasize the importance of this Fabry trial. Unlike MLD, Fabry is considered an adult-onset disorder where the earliest symptoms are seen when patients are adolescents. The progression of Fabry disease is much slower than MLD, and a wider set of organs seem to be affected, of note those outside the CNS and the hematopoietic system. In fact, brain involvement is thought to be minimal in Fabry disease, though substrate accumulation can occur inside the CNS. As such, HSC-directed gene therapy using lower levels of recipient immuno-ablation may be more suitable to Fabry disease as brain remodeling with transduced cells may not be required. The opening of another phase I/II trial using the same LV-modified HSC method in Australia (NCT03454893) suggests that the first trial has demonstrated a favorable safety profile and promising results thus far.
Related Knowledge Centers
- Biomolecule
- Enzyme
- Mutation
- Sphingolipid
- Integumentary System
- Heart
- Brain
- Kidney
- Genetic Disorder
- Lysosomal Storage Disease