Malattia di Fabry ed ictus ischemico giovanile: frequenza, aspetti clinici e considerazioni terapeutiche

ABSTRACT: Fabry disease (FD) is a rare, inherited, X-linked disorder due to the deficiency of the lysosomal enzyme "α-Galactosidase A", encoded by the GLA gene. The storage of glycosphingolipids leads to a multi-system involvement. Because of the rarity and the clinical heterogeneity of this pathology, the evaluation of the prevalence of FD is challenging. In the general population a frequency ranging from 1:476 000 to 1:117 000 has been documented; nevertheless, screening programs in newborns have found higher prevalence (1:3100), suggesting the need to identify new cases of FD by means of screening of "high risk" adult populations, such as young adults with stroke. The first experimental section of this thesis reports the results of the systematic screening for FD in a consecutive series of young (<60 years old) adults with ischemic stroke, admitted to the University Hospital Careggi (AOUC), Florence, in 2011-2012. Out of 108 patients enrolled, we identified 3 (2.8 %, 95% CI: 0.57 – 8.18) previously undiagnosed Fabry’s patients. Two FD patients carried a new GLA gene mutation, and underwent to a detailed molecular, biochemical, and clinical evaluation. We searched for features potentially useful to identify FD patients in a clinical setting, and we found a significant association for " history of recurrent pain of the extremities", "recurrence of TIA/ischemic stroke", "lacunar infarct " at neuroimaging , and "family history of cardiovascular disease". A brief review of screening studies for FD in stroke populations confirmed that the recurrence of stroke is significantly associated with FD. The second experimental section of this thesis examines the etiology of juvenile ischemic stroke in the consecutive series of 108 patients admitted to the AOUC and previously described. Approximately, 90% of patients had at least 1 vascular risk factor, despite the young age. We documented an age-related increase in the prevalence of classical risk factors (statistically significant for hypertension, dyslipidemia, hyperuricemia), while hereditary coagulopathies, estroprogestinic drugs, and history of alcohol abuse were more represented among younger patients (< 45 years old). The stroke pathogenesis (according to TOAST classification) agreed with other published studies concerning juvenile stroke. We documented that stroke from small vessel disease was absent in younger patients (< 45 years old), where the TOAST subtype “other determined etiology” was more represented. The third experimental section of the thesis describes the cerebrovascular involvement in an Italian cohort of adult FD patients, referred to the Fabry Disease Referral Center of the AOUC, Florence, from 2011 to 2013. We followed 57 patients (male: 38%, mean age: 49 years, mutations associated with classical phenotype: 60%) from 22 different families, coming from Firenze, Pisa, Arezzo, Livorno, Terni, Perugia, Roma, Viterbo, Civitavecchia, Foggia, Catania, Palermo, and Monza. In this population 13 patients had ≥ 1 ischemic stroke (male: 5; median age at first stroke: 47 years), including 7 patients with recurrent cerebral ischemia, for a total of 47 strokes. The occlusion of a cerebral small vessel was the pathogenic mechanism in all but 4 strokes. In 6 patients, stroke occurred before the start of enzyme replacement therapy. With regard to neuroimaging features, standardized data were available only for a subgroup of patients resident in Florence (or in surrounding areas), who performed a standardized MRI protocol at the Neuroradiology Unit of the AOUC (N. 48). In this population we documented a moderate frequency of leukoaraiosis (53 %) and vascular dolichoectasia (31 %), whit an age-related severity. In our experience, no patients had the "pulvinar sign", deemed to be typical for FD. We detected cerebral microbleeds (CMBs) in 6% of patients, so their frequency was lower than other cerebral hereditary microangiopathies (such as CADASIL). CMBs showed a subcortical localization in all patients, and were associated with lacunar stroke, moderate/severe leukoaraiosis on Fazekas scale, angiokeratoma, and the presence of other risk factors, such as hypertension, atrial fibrillation, and antiplatelet therapy.