Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Fabry's disease is an X-linked lysosomal enzyme disorder of α-galactosidase, resulting in accumulation of glycosphingolipids with α-galactosyl moieties. The inability to process these glycosphingolipids results in their buildup in multiple organs. Most of the early, prominent symptoms are the result of accumulation in the blood vessels and the peripheral and central autonomic nervous system, although all tissues are affected. As the disease progresses, accumulation in kidneys and heart will lead to organ failure. Progressive arterial accumulations result in infarction. Fabry's disease usually affects males (1:60,000), but many heterozygous females have disease symptoms including strokes. Furthermore, some heterozygous females have symptoms as severe as the classic male phenotype due to nonrandom X-inactivation, where the unaffected X-chromosome is inactivated in more than 50% of cells, leading to more pronounced deficiency of α-galactosidase. Onset is late childhood (usual) into middle age.
Inborn errors of metabolism
Martin Andrew Crook in Clinical Biochemistry & Metabolic Medicine, 2013
Here a deficiency of a lysosomal hydrolase is inherited, resulting in the accumulation of sphingolipid. The following are some examples: GM1 gangliosidosis defect of β-galactosidase,GM2 gangliosidosis such as Tay–Sachs disease, due to hexosaminidase deficiency,Gaucher’s disease, due to a deficiency of β-glucosidase (glucocerebrosidase),Niemann–Pick disease, resulting from sphingomyelinase deficiency,Fabry’s disease, resulting from α-galactosidase A deficiency,metachromic leucodystrophy, resulting from arylsulphatase deficiency.
Biocatalytic Nanoreactors for Medical Purposes
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Fabry disease is a disorder linked to glycosphingolipid metabolism caused by α-galactosidase A (α-Gal) deficiency. The successful use of ERT for Fabry disease has been reported (Alfadhel and Sirrs, 2011). Recombinant agalsidase alfa and agalsidase beta have been compared for Fabry disease treatment (Arends et al., 2018). The authors found no difference between patients treated with either agalsidase, and a more pronounced reduction of storage materials was found with agalsidase beta.
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.
Fabry disease – a multisystemic disease with gastrointestinal manifestations
Published in Gut Microbes, 2022
Treatment with either agalsidase-alfa (0.2 mg/kg b.w. e.o.w. intravenously; Replagal, Takeda) or agalsidase-beta (1.0 mg/kg b.w. e.o.w. intravenously; Fabrazyme, Sanofi Genzyme) was repeatedly reported to decrease frequencies of abdominal pain in affected adult and adolescent patients.20,21,23,32,59–63 Within the same studies, improvement of diarrhea,21,23,32,59,62 nausea and vomiting,21,60,62 and constipation21,62 were observed. In addition, the dose or compound might affect the outcome for GI symptoms. In this respect, patients who received a reduced dose of agalsidase-beta (0.3 to 0.5 mg/kg b.w. e.o.w. intravenously) or those who were switched from agalsidase-beta (1.0 mg/kg b.w.) to agalsidase-alfa (0.2 mg/kg b.w.) during the worldwide shortage of agalsidase-beta reported an increase of gastrointestinal pain.64 However, not all patients benefit from ERT, and GI symptoms are sometimes quite pronounced and relevant to daily life in ERT-treated patients, significantly reducing quality of life.
Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies
Published in Expert Opinion on Drug Safety, 2021
Mina Tsurumi, Shinya Suzuki, Jiro Hokugo, Kazuo Ueda
The Special Drug Use Investigation of agalsidase beta analyzed the safety and efficacy of long-term agalsidase beta use in Japanese patients with Fabry disease. The Drug Use Investigation of agalsidase beta was conducted using an all-case surveillance method and analyzed the safety profile in all Japanese patients with Fabry disease who were not included in the Special Drug Use Investigation of agalsidase beta.
Related Knowledge Centers
- Angiokeratoma
- Ceramide
- Enzyme
- Fabry Disease
- Hypohidrosis
- Recombinant DNA
- Sphingolipidoses
- Glycoside Hydrolase
- Melibiose
- Lysosomal Storage Disease