A
Fordøjelsesorganer og stofskifte
Fabrys sygdom
Fabrys sygdom er en X-bunden recessiv arvelig sygdom. Symptomer kan hos mandlige patienter og - i modsætning til andre X-bundne sygdomme - også hos en stor del af de kvindelige bærere, være udtalte fra barnealderen.
Sygdommen forårsages af en manglende eller nedsat aktivitet af det lysosomale enzym α-galactosidase. Dette medfører en ophobning af globotriaosylceramid (Gb3) i lysosomerne i en række organer, specielt i hjertemuskulatur, nyrer, endotel, retikuloendoteliale system, cornea og autonome nervesystem. Det er især aflejringer i det vaskulære system, der er ansvarlig for de kliniske manifestationer.
Symptomerne debuterer ofte i barnealderen med smerter i hænder og fødder, nedsat svedtendens, hudforandringer i form af purpurfarvede angiokeratomer og sjældent proteinuri. Sygdommen er progressiv og fører i voksenalderen til proteinuri, nyresvigt, hjertesvigt og cerebrale komplikationer.
Sygdommen medfører ubehandlet en levetidsreduktion på omkring 20 år.
Diagnostik
Fabrys sygdom diagnosticeres ved bestemmelse af α-galactosidase i leukocytter og/eller ved molekylærgenetiske analyser.
Behandlingsvejledning
Enzymsubstitution med α-galactosidase (agalsidase) kan reducere smerter, stabiliserer nyrefunktionen og reducerer kardielle og cerebrale manifestationer samt øge patienternes livskvalitet, men effekten er afhængig af start på behandlingen, før irreversible manifestationer opstår (se europæiske guidelines, Biegstraaten M) (2726).
Enzymstabilisering med migalastat fører hos patienter med behandlelige varianter i GLA -genet til reduceret lyso-Gb3, stabiliseret nyrefunktion, reduceret masseindeks for venstre ventrikel og forbedring i gastro-intestinale symptomer.
Bemærk: Behandlingen er en specialistopgave og bør forestås af læger med særligt kendskab til Fabrys sygdom.
Referencer
6127. Wallace EL, Goker-Alpan O, Wilcox WR et al. Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study. J Med Genet. 2023, https://pubmed.ncbi.nlm.nih.gov/37940383/ (Lokaliseret 15. april 2024)
6128. Linhart A, Dostálová G, Nicholls K et al. Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study. Orphanet J Rare Dis. 2023; 18(1):332, https://pubmed.ncbi.nlm.nih.gov/37865771/ (Lokaliseret 15. april 2024)
6129. Bichet DG, Hopkin RJ, Aguiar P et al. Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study. Front Med (Lausanne). 2023, https://pubmed.ncbi.nlm.nih.gov/37727761/ (Lokaliseret 15. april 2024)
6130. Hughes D, Gonzalez D, Maegawa G et al. Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease. Genet Med. 2023; 25(12), https://pubmed.ncbi.nlm.nih.gov/37634127/ (Lokaliseret 15. april 2024)
6131. Hughes DA, Bichet DG, Giugliani R et al. Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes. J Med Genet. 2023; 60(7):722-31, https://pubmed.ncbi.nlm.nih.gov/36543533/ (Lokaliseret 15. april 2024)
6132. Germain DP, Altarescu G, Barriales-Villa R et al. An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease. Mol Genet Metab. 2022; 137(1-2):49-61, https://pubmed.ncbi.nlm.nih.gov/35926321/ (Lokaliseret 15. april 2024)
6133. Lenders M, Nordbeck P, Kurschat C et al. Treatment of Fabry Disease management with migalastat-outcome from a prospective 24 months observational multicenter study (FAMOUS). Eur Heart J Cardiovasc Pharmacother. 2022; 8(3):272-81, https://pubmed.ncbi.nlm.nih.gov/35512362/ (Lokaliseret 15. april 2024)
6134. van der Veen SJ, Körver S, Hirsch A et al. Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression. Mol Genet Metab. 2022; 135(2):163-69, https://pubmed.ncbi.nlm.nih.gov/35033446/ (Lokaliseret 15. april 2024)
5378. Ulla Feldt-Rasmussen, Derralynn Hughes, Gere Sunder-Plassmann et al. Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study. Mol Genet Metab. 2020; 131(1):219-28, https://pubmed.ncbi.nlm.nih.gov/33012654/ (Lokaliseret 23. oktober 2023)
4689. Germain DP, Fouilhoux A, Decramer S et al. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin Genet. 2019; 96(2):107-17, https://www.ncbi.nlm.nih.gov/pubmed/30941742 (Lokaliseret 17. oktober 2023)
2947. Germain DP, Hughes DA, Nicholls K et al. Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. N Engl J Med. 2016; 375(6):545-55, http://www.ncbi.nlm.nih.gov/pubmed/27509102 (Lokaliseret 10. maj 2023)
2726. Biegstraaten M, Arngrímsson R, Barbey F et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015; 10:36, http://www.ncbi.nlm.nih.gov/pubmed/25885911 (Lokaliseret 2. maj 2023)
2453. Weidemann F, Krämer J, Duning T et al. Patients with Fabry disease after enzyme replacement therapy dose reduction versus treatment switch. J Am Soc Nephrol. 2014; 25(4):837-49, http://www.ncbi.nlm.nih.gov/pubmed/24556354 (Lokaliseret 27. april 2023)
2454. Sirrs SM, Bichet DG, Casey R et al. Outcomes of patients treated through the Canadian Fabry disease initiative. Mol Genet Metab. 2014; 111(4):499-506, http://www.ncbi.nlm.nih.gov/pubmed/24534763 (Lokaliseret 27. april 2023)
2065. Borgwardt L, Feldt-Rasmussen U, Rasmussen AK et al. Fabry disease in children: agalsidase-beta enzyme replacement therapy. Clin Genet. 2013; 83(5):432-8, http://www.ncbi.nlm.nih.gov/pubmed/22880956 (Lokaliseret 26. april 2023)
1651. Mehta A, Hughes DA, Adam MP et al. Fabry Disease. GeneReviews. 1993 (updated 2024), https://pubmed.ncbi.nlm.nih.gov/20301469/ (Lokaliseret 15. april 2024)
