An unusual presentation of Gaucher's disease: aortic valve fibrosis in a patient homozygous for a rare G377S mutation [Neobična klinička slika Gaucherove bolesti: fibroza aortnog zalistka kod bolesnice homozigotne za rijetku G3775S mutaciju]

Perić, Zinaida and Kardum-Skelin, Ika and Jelić Puškarić, Biljana and Letilović, Tomislav and Vrhovac, Radovan and Jakšić, Branimir (2010) An unusual presentation of Gaucher's disease: aortic valve fibrosis in a patient homozygous for a rare G377S mutation [Neobična klinička slika Gaucherove bolesti: fibroza aortnog zalistka kod bolesnice homozigotne za rijetku G3775S mutaciju]. Collegium Antropologicum, 34 (1). pp. 275-278. ISSN 0350-6134

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Abstract

Gaucher’s disease (GD) has variable presentations, but cardiac involvement is a generally uncommon clinical manifestation of the disease. In the past 25 years, the underlying genetic disorder in GD has been well characterized, with almost 300 mutations identified in the glucocerebrosidase gene (GBA). Nevertheless, clear genotype-phenotype correlations have been confirmed only for the most frequent mutations. We present a female patient, who was known to have aortic valve pathology from the age of 30. Despite medical follow up, at the age of 60 she presented with heart failure (NYHA III). At that time echocardiography showed severe fibrosed aortic valve stenosis. Valvuloplasty was planned, when thrombocytopenia, previously considered to be autoimmune, became severe. Anemia and leukopenia were also noted. Moderate splenomegaly and severe bone marrow infiltration were found on MRI. Bone marrow aspiration revealed typical Gaucher cells and the enzyme activity assay confirmed the diagnosis. DNA investigation showed that the patient is homozygous for the G377S mutation. To our knowledge, of all mutations identified so far, only homozygosity for the D409H mutation has been associated with cardiovascular valvular disease in patients with a rare type 3c GD. G377S, found in our patient, is a rare mutation, previously reported as a 'mild’ mutation, because of the finding that homoallelic patients were essentialy asymptomatic or had mild disease. Our patient, also homozygous for G377S mutation, had a severe form of type 1 GD, with rare cardiac valve involvement, which is a previously unreported clinical presentation for this mutation. This case further proves that patients with the same genotypes can have different phenotypes, emphasizing the influence of other genetic and/or environmental factors.

Abstract in Croatian

Gaucherova se bolest (GB) može prezentirati raznolikom kliničkom slikom, ali rijetko zahvaća kardiovaskularni sustav. U posljednjih je 25 godina genetski poremećaj u podlozi ove metaboličke bolesti dobro istražen, s gotovo 300 identificiranih mutacija u genu za lizosomski enzim glukocerebrozidazu. Ipak, jasne genotipsko-fenotipske korelacije, potvrđene su samo za najčešće mutacije. Kod naše pacijentice, patološke promjene na aortnom srčanom zalistku otkrivene su prvi put u dobi od 30 godina. Usprkos redovitom praćenju, bolesnica se u dobi od 60 godina javlja s kliničkom slikom teškog zatajenja srca (NYHA III). Tada učinjeni UZV srca pokaže tešku aortnu stenozu. Planirani operacijski zahvat zamjene aortne valvule kontraindicira se, zbog progresije trombocitopenije, dotad smatrane autoimunog porijekla. Tada se prvi put zamijete i anemija te leukopenija. MR čitavog tijela pokazuje uvećanu slezenu, te difuznu infiltraciju koštane srži. Citološkom se punkcijom koštane srži otkriju tipične Gaucherove stanice, a nalaz snižene aktivnosti enzima glukocerebrozidaze potvrdi dijagnozu. Genetskom se analizom ustanovi da je pacijentica homozigot za G377S mutaciju. Prema dosadašnjim spoznajama, samo je homozigotnost za D409H mutaciju povezivana s kardiovaskularnim oblikom GB, klinički tipom 3c. G377S mutacija, pronađena kod naše pacijentice, opisivana je dosad kao »blaga« mutacija, zbog nalaza da se kod homozigota javlja asimptomatski ili blagi oblik bolesti. Međutim, naša pacijentica, također homozigot za G377S mutaciju, ima uznapredovali oblik tipa 1 GB, s rijetkim zahvaćanjem aortnog zalistka, što je, prema našim saznanjima, još neopisana klinička slika uz ovu mutaciju. Ovaj slučaj još jednom potvrđuje utjecaj i drugih genetskih i/ili okolišnih faktora na kliničku prezentaciju Gaucherove bolesti.

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