Fabryho choroba je na X-chromozóm viazané dedičné metabolické ochorenie, charakterizované defektom odbúravania glykosfingolipidov. Tieto sa v dôsledku ochorenia hromadia v rôznych tkanivách vo forme hustých depozitov. Základnou príčinou ochorenia je mutácia génu lokalizovaného na dlhom ramienku X-chromozómu, kódujúceho lyzozomálny enzým alfa-galaktozidáza A. Fabryho choroba (FCH) je tiež známa ako Andersonova-Fabryho choroba alebo angiokeratoma corporis diffusum. Patrí medzi zriedkavo sa vyskytujúce ochorenia, označované aj ako „orphan diseases“. FCH je progresívne ochorenie a jej prognóza bez liečby je zlá. Pokroky vo farmaceutickom priemysle ponúkajú nové terapeutické možnosti v paliatívnej (symtomatickej) liečbe, vedúce k miernemu zlepšeniu prognózy. Priemerná očakávaná dĺžka života u postihnutých mužov je 50–60 rokov. Postihnuté ženy sa dožívajú 60–70 rokov. Ich prognóza je vo všeobecnosti lepšia ako u mužov, u ktorých sa v neskorších rokoch života prejavujú závažné príznaky ochorenia. Najčastejšou príčinou úmrtia sú kardiovaskulárne príhody a renálne zlyhania. K významnému prelomu došlo v roku 1989, keď Kornreich so spolupracovníkmi rozlúštili genetický kód enzýmu alfa-galaktozidázy, čo umožnilo jeho laboratórnu prípravu. Enzýmová substitučná terapia (EST) prináša zlepšenie kvality života pre pacientov s FCH a niektorých z ďalších zriedkavo sa vyskytujúcich ochorení. Pre substitučnú liečbu sú dostupné dva komerčné prípravky alfa-galaktozidázy A. Oba sú pripravované umelo, z geneticky upravených buniek: z kultivovaných ľudských fibroblastov v prípade agalzidázy-alfa (REPLAGALTM) a z ovariálnych buniek čínskych škrečkov pri agalzidáze-beta (FABRAZYME®).
Fabry disease is an X–linked, hereditary metabolic disorder characterized by a defect in the degradation of glycosphingolipids. It leads to their accumulation as lysosomal dense bodies in various tissues. The underlying cause is mutation in the gene located on the long arm of the X chromosome encoding the lysosomal enzyme, α-galactosidase A. Fabry disease (FD) is also known as Anderson-Fabry disease or angiokeratoma corporis diffusum. It belongs to rare disorders, so-called „orphan diseases“. FD takes a progressive course and the prognosis, if untreated, is bleak. Advances made in the pharmaceutical industry have offered new therapeutic possibilities in palliative (symptomatic) treatment, leading to a slight improvement in prognosis. The average life expectancy of affected males is 50–60 years. Female patients survive to their sixth or seventh decade of life. Their prognosis is generally better than in male patients with more serious manifestations of the disease occurring later in life. The main causes of death are cardiovascular events and renal failure. A major breakthrough came in 1989, when Kornreich and co-workers deciphered the genetic code of α-galactosidase, enabling the enzyme to be produced laboratory. Enzyme replacement therapy (ERT) has brought improving quality of life for the patients with FD and some of the others orphan diseases. Two commercial products of α-galactosidase A are available for ERT. Both are produced artificially from genetically engineered cells: cultured human fibroblasts in case of agasidase-alfa (REPLAGALTM); and Chinese hamster ovary cells in the case of agalsidase-beta (FABRAZYME®)
- Keywords
- Replagal, Fabrazyme,
- MeSH
- European Union MeSH
- Fabry Disease etiology drug therapy therapy MeSH
- Genetic Engineering methods utilization MeSH
- Humans MeSH
- Lysosomal Storage Diseases, Nervous System drug therapy MeSH
- Prognosis MeSH
- Orphan Drug Production economics legislation & jurisprudence MeSH
- Check Tag
- Humans MeSH
- Keywords
- replagal, fabrazyme,
- MeSH
- Ventricular Function, Left MeSH
- Galactosidases administration & dosage deficiency MeSH
- Cardiomyopathy, Hypertrophic MeSH
- Hypertrophy, Left Ventricular MeSH
- Myocardial Ischemia MeSH
- Humans MeSH
- Arrhythmias, Cardiac MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Fabryho nemoc je vzácná dědičná metabolická porucha ze skupiny lysozomálních střádavých onemocnění. Tato nemoc je léčitelná díky enzymové substituční terapii, v České republice dostupné od roku 2004. Vzhledem k dostupnosti terapie je důležité tyto pacienty, skrývající se pod nejrůznějšími diagnózami v mnoha ambulancích, správně a včas diagnostikovat.
Fabry disease is an X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) is available in our country since 2004.The sooner diagnosis is made, the better ERT stabilizes the progression of Fabry disease. The timing of ERT is important in orderto prevent irreversible organ damage.
- Keywords
- fabrazyme, replagal, Galafold,
- MeSH
- Early Diagnosis MeSH
- Stroke MeSH
- Adult MeSH
- Enzyme Replacement Therapy utilization MeSH
- Fabry Disease * diagnosis etiology complications therapy MeSH
- Genetic Diseases, X-Linked MeSH
- Cardiomyopathies MeSH
- Middle Aged MeSH
- Humans MeSH
- Kidney Diseases MeSH
- Aged MeSH
- Tertiary Prevention MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Review MeSH
The function and intracellular delivery of enzyme therapeutics for Fabry disease were studied in cultured fibroblasts and in the biopsied tissues of two male patients to show diversity of affected cells in response to treatment. In the mutant fibroblasts cultures, the final cellular level of endocytosed recombinant alpha-galactosidases A (agalsidases, Fabrazyme, and Replagal) exceeded, by several fold, the amount in control fibroblasts and led to efficient direct intra-lysosomal hydrolysis of ((3)H)Gb3Cer. In contrast, in the samples from the heart and some other tissues biopsied after several months of enzyme replacement therapy (ERT) with Fabrazyme, only the endothelial cells were free of storage. Persistent Gb3Cer storage was found in cardiocytes (accompanied by increase of lipopigment), smooth muscle cells, fibroblasts, sweat glands, and skeletal muscle. Immunohistochemistry of cardiocytes demonstrated, for the first time, the presence of a considerable amount of the active enzyme in intimate contact with the storage compartment. Factors responsible for the limited ERT effectiveness are discussed, namely post-mitotic status of storage cells preventing their replacement by enzyme supplied precursors, modification of the lysosomal system by longstanding storage, and possible relative lack of Sap B. These observations support the strategy of early treatment for prevention of lysosomal storage.
- MeSH
- alpha-Galactosidase metabolism therapeutic use MeSH
- Biopsy MeSH
- Fabry Disease therapy MeSH
- Fibroblasts enzymology MeSH
- Financing, Organized MeSH
- Genetic Therapy methods MeSH
- Microscopy, Confocal MeSH
- Cells, Cultured MeSH
- Middle Aged MeSH
- Humans MeSH
- Myocardium enzymology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Keywords
- Léčivé přípravky Replagal (agalsidáza alfa) a Fabrazyme (alfasidáza beta),
- MeSH
- alpha-Galactosidase genetics MeSH
- Ceramides genetics isolation & purification metabolism MeSH
- X Chromosome genetics MeSH
- Enzyme Replacement Therapy * methods trends utilization MeSH
- Fabry Disease * diagnosis etiology therapy MeSH
- Gastrointestinal Diseases MeSH
- Genetic Techniques utilization MeSH
- Disease Attributes * MeSH
- Skin Manifestations MeSH
- Humans MeSH
- Lysosomes genetics pathology MeSH
- Meta-Analysis as Topic MeSH
- Brain Diseases, Metabolic, Inborn MeSH
- Interdisciplinary Communication MeSH
- Kidney Diseases MeSH
- Heart Diseases diagnosis complications MeSH
- Neurologic Manifestations MeSH
- Statistics as Topic MeSH
- Academic Medical Centers organization & administration trends utilization MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
PURPOSE: Fabry disease, a genetic deficiency of alpha-galactosidase A, is characterized by pathogenic cellular accumulation of globotriaosylceramide. During clinical trials, recombinant human alpha-galactosidase A (agalsidase beta; Fabrazyme, Genzyme Corporation, Cambridge, MA), infused intravenously at 1.0 mg/kg every 2 weeks for 6 months, cleared or reduced globotriaosylceramide in renal, cardiac, and dermal microvascular endothelia and other cells, with results sustained for up to 5 years in most patients evaluated. This study explored whether a lower dose could maintain globotriaosylceramide clearance achieved with 1.0 mg/kg. METHODS: Cellular globotriaosylceramide levels were assessed histologically in kidney and skin biopsies from 21 adult Fabry males treated for 6 months at 1.0 mg/kg/2 weeks followed by 18 months at 0.3 mg/kg/2 weeks. RESULTS: In kidney interstitial capillary endothelium, the primary endpoint, globotriaosylceramide clearance was achieved in 100% of patients with 1.0 mg/kg and maintained in 90% with 0.3 mg/kg. In seven other renal cell types and superficial dermal capillary endothelium, globotriaosylceramide reduction or clearance was maintained with 0.3 mg/kg in approximately 70% of patients. CONCLUSIONS: A lower dose of agalsidase beta may be sufficient in some, but not all, patients with Fabry disease to maintain the cellular globotriaosylceramide clearance achieved with 1.0 mg/kg/2 weeks. Long-term clinical effects of transitioning to the lower dose have not been evaluated.
- MeSH
- alpha-Galactosidase administration & dosage adverse effects therapeutic use MeSH
- Biopsy MeSH
- Adult MeSH
- Endothelial Cells metabolism MeSH
- Fabry Disease drug therapy pathology MeSH
- Fever chemically induced MeSH
- Infusions, Intravenous MeSH
- Isoenzymes administration & dosage adverse effects therapeutic use MeSH
- Skin metabolism pathology MeSH
- Kidney metabolism physiopathology pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Chills chemically induced MeSH
- Follow-Up Studies MeSH
- Diarrhea chemically induced MeSH
- Trihexosylceramides blood metabolism urine MeSH
- Kidney Function Tests MeSH
- Treatment Outcome MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Publication type
- Clinical Trial MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
