SanRomnMonserrat I GimenoBlanes JR RodrguezGonzlezHerrero - PDF document

San-Román-Monserrat I, Gimeno-Blanes JR, Rodríguez-González-Herrero ME, Sodi A, Mecocci A. Page 64 of 69 FMNry diseMse: ProPoPype of IysosomMl SPorMge Gisorder RiPO sysPemic Hrene SMn-Román-MonserrMP*, JuMn-RMmón Gimeno-BlMnes Article InfoArticle Notes Fabry disease is a rare inherited metabolic disorder with systemic involvement. Heart, kidney, brain, skin and eye are the main involved systems, but virtually every tissue may be affected. The disease is due to mutations in GLA gene, located in X chromosome (Xq22.1). GLA mutations result in a mutant α-Galactosidase-A enzyme (α-AGA) with deficient activity. α-AGA deficient activity leads to deposition of not-catabolised Commentary Journal of Rare Diseases Research & Treatment San-Román-Monserrat I, Gimeno-Blanes JR, Rodríguez-González-Herrero ME, Sodi A, Mecocci A. J 2016 1(2): 64-69 (male I69, female I61-), to underline main clinical clues for early diagnosis and to recall the novel features we exposed Particularly novel was that systemic involvement and clinical severity were approached from a quantitative point of view, by means of -ainz 3everity 3core Index (-33I) calculation in its classical and FC3 versions(9). -33I evaluates severity and systemic involvement using 4 subscores: general (maximum 18/76 or 13’5/64’5 points for classical and FC3 versions respectively), cardiovascular (2-/76 or 18/64’5 points), renal (18/76 or 18/64’5) and neurological (2-/76 or 18/64’5 points). For every subscore severe involvement was considered if more than half of maximum points were obtained (>1-/2- points for cardiac subscore, for example).Another important feature exposed in our 2-14 work was the description of novel mutation p.-1872/g72194>G located in exon-4 of G,A gene. It is a missense mutation that affects methionine in position 187. Its absence in 1-- healthy-population chromosomes was checked. Predictive in-silico analysis confirmed high probability of pathogenicity with elevated scores. Clinical co-segregation was concordant. 4here are 3 other reported missense mutations related to classic phenotype in this position (-1876, -187I, -1874), suggesting that this is a ‘‘hot spot’’ in G,A gene. In 2--5 -atsuzawa et al built a structural mutated α-AGA model, in which 161 GLA gene mutations were analysed. Those mutations that involved three or more atoms, particularly if located in the main chain of α-AGA, tended to associate classical Fabry phenotype. 4his is the case of -1876 and -1872 mutations. 4his fact may at least partially explain in molecular terms why -1872 mutation associates a severe phenotype. 2egarding systemic involvement 66% of individuals had 2 or more affected systems. 53% of individuals had cardiovascular disease, 53% had neurological involvement, 32% had renal involvement, 84% had other not-organ-specific involvement and 1--% of individuals had ophthalmological manifestations (4able 1). 4hese data clearly show the systemic nature of Fabry disease4he heart was the main organ involved. 53% of individuals displayed Fabry cardiomyopathy, including young females. Cardiac involvement was early and severe and heart failure (HF) was the most frequent mode of death. 3 sudden deaths were reported. 2 females and 1 male died suddenly being 64, 63 and 57 years (yrs) respectively. Cardiac subscore of Fabry Cutcome 3urvey--33I was severe for both males and females over 4-yrs (16’3/18 in males vs. 13’6/18 in females). Cardiac involvement in female carriers was even more severe than in males in particular cases. 7e remark the case of female III4. Being only 59yr and 4yrs older than her brother (male III1 -33Icardiac:12/2-, diagnosis age 49yrs, α-AGA activity:9%, table 3), she has even more severe cardiac findings. Both siblings had arterial hypertension (secondary to Fabry disease) and the proband was a light smoker in his youth. Female III4 Figure 1: Family tree (updated 2016) Square means male, Circle means female, diagonal line means deceased + means carrier of p.M187R. Females (n=15)Males + Females CardiovascularNeurologicalRenalOphthalmological*Other not organ speci�cOnly 2 males and 10 females were alive and willing to par�cipate in our study about Fabry ophthalmopathy in the famil

yTable 1. Systemic involvement in p.M187R carriers. San-Román-Monserrat I, Gimeno-Blanes JR, Rodríguez-González-Herrero ME, Sodi A, Mecocci A. J . 2016 1(2): 64-69 displayed stage III HF secondary to severe BEHA III not-obstructive hypertrophic cardiomyopathy, with severe systolic impairment (,eft 6entricle Ejection Fraction [,6EF]:3-%-46%, severe ventricular asynchrony) and received cardiac resynchronization therapy plus implated cardiac defibrillator being 55yrs (-33Icardiac:2-/2-, diagnosis age:53yrs, α-AGA activity:9% table 3). 4his case exemplifies how lyonizaion may explain severe phenotype in Fabry females. It supports, together with the 3 above mentioned sudden deaths, the association of novel mutation with severe phenotype in both male and female Cur study was the first to report short P2-interval associated to delta wave, suggestive of accessory pathway. In this context, the occurrence of syncope deserves careful attention: 4he combination of conduction disease, “Fabry-cardioneuropathy”, functional ischaemia and fibrosis secondary to advanced hypertrophic cardiomyopathy may trigger ventricular arrhythmia and sudden death The storage of not catabolised ceramides in endocardial and myocardial cells partially explains the physiopathology of Fabry hypertrophic cardiomyopathy. 3everal recent works propose a more dynamic hypothesis for hypertrophy. Instead of simple passive endothelial storage of glycosphingolipids, a complex interaction of storage molecules (like ,yso-GB3), cytokines, inflammatory Total MaleFemaleCommentsGastrointes�nalColickyabdpainCons�pa�on-HemorroidsMissdiagnosis of irritable bowels yndrome in F II2ENT area**4/19 (21%)1/4 (33%)3/15(20%)Occasional/Episodic �nnitusVer�go3/19 (16%)1/4 (33’3%)2/15 (13%)Occasional Rotatory ver�goHypoacusia/Audiometry 5/19 (26%) 3/4 (75%)2/15 (13%)M1Aud: RE: severe mixed hearing loss, LE: mod sensorineural hearing loss. Bilat osteoma aud ch.F2 Aud: Both ears hearing impairment at 4 KHzPneumologicalBronchospasm4/19 (21%)3/4 (75%)1/15 (6%)With lower respiratory tract infs mainly during second to fourth decade.RheumatologicalArthralgia(large joints)7/19 (37%)3/4 (75%)4/15 (26%)ankles, knees, wrists, shouldersOsteoporo�c fracturesRaynaudNo osteoporo�c fractures/Raynaud iden��ed un�l the date.Endocrinological2º HyperPTH CKDcon�rmed2º HyperPTH CKDprobableNo PTH available data of M II3, M II5, F I2 and F II2)(deceased).Thyroid1/19 (5%)0/4 (0%)1/15 (6%)Thyroid nodule excised to F III9 (third decade, no AP available).1/19 (5%)1/4 (25%)0/15 (0%)On oral an�diabe�cs M II5 (deceased)Fas�ngimpairedglycaemia2/19 (10%)1/4 25%)1/15 (6%)On diet, F II8Neoplas�c diseaseBreast carcinoma2/19 (10%)0/4 (0%)2/15 (13%)F II8: Ductal SLQ R breast ca (surgery+RTAug‘05). Remission.F III9:Breast ca+MTS deceased 38yInfec�ous diseaseLowerrespiratorytrac�nfs.3/4 (75%)1/15 (6%)With bronchospasm, mainlyduring third to fourth decade.Community adquired pneumoniae M2 (35y)B-Hepa��s1/19 (5%)1/4 (25%)0/15 (0%)M II3 (aged 51y). Acute Pielonephri�s1/19 (5%)0/4 (0%)1/15 (6%)F II2 (aged 61 y)Recurrent tonsilli�s1/19 (5%)0/4 (0%)1/15 (6%)F II2 (infance)Costal Zoster-Herpes (P)1/19 (5%)0/4 (33.3%)1/15 (6%)F III4 (aged 48y)Mumps1/19 (6.6%)1/4 (33.3%)0/15 (0%)M II5 (aged 21y). Table 2: Other organs and systems involvement. MaleIII1MaleIV9FemII8FemIII4FemIII6FemIII11FemIV6FemIV8Age (yrs)3633α-AGA %5951MSSINov’14 50/7611/7655/7641/7613/7614/769/764/76Table 3. α-AGA ac�vity and MSSI data from M187R carriers. San-Román-Monserrat I, Gimeno-Blanes JR, Rodríguez-González-Herrero ME, Sodi A, Mecocci A. J 2016 1(2): 64-69 mediators implicated in fibrosis, apoptosis and in the proliferation of smooth-muscle fibers within vessel walls would happen. Aerts et al found that, as opposed to GB3, left ventricular mass correlated with plasma ,yso-GB3 concentration in Fabry heterozygote females. 4hey also obtained a trend to correlation between ,yso-GB3 increasing levels and higher -33I punctuation, also onl

y for heterozygote femalesCardiac--2I was performed in those individuals with ECG or echocardiogram abnormalities/unclear findings (43%, 6/14 individuals that were alive at family diagnosis). ,ate gadolinium enhancement on cardiac--2I was found in every tested individual, including a female with normal echocardiogram. 4his remarks the importance of cardiac--2I for prognostic stratification of Fabry cardiomyopathy. Cardiac disease was the most frequent mode of death in Fabry males and femalesdirectly attributable to Fabry disease in p.-1872 carriers was 21% (4/19, 2males, 2females). In 1--% of the deceased cases Fabry cardiomyopathy was present, with 3/4 sudden deaths. Finally, Fabry cardiomyopathy represents 1%of all unclear-origin genetic cardiomyopathies. 4herefore, cardiologists dealing with hereditary cardiac disease should be aware of Fabry disease signs and symptoms.2enal disease was the second cause of death in males after cardiac causes. 32% developed renal disease and 2 males required hemodyalisis at 48 and 45yrs. Bilateral parapyelic cysts were identified in proband, being an important diagnostic clue. -icroalbuminuria with normal glomerular filtration rate (GF2) was detected in one female in the fourth decade, which together with subtle ECG abnormalities set up the indication for enzymatic replacement therapy (E24) starting. Heart and kidney transplant were performed to one male being 57yrs due to stage-I6 cardiac failure and end stage renal disease. 2enal disease was less severe in females. Bevertheless, 2-% of females had chronic kidney disease (CKD). Fabry disease is a poorly recognized cause of CKD and should be screened out in every proteinuric nephropathy of unknown origin, particularly when it associates parapyelic renal cystsCerebrovascular disease affected 53% of individuals. Peripheral neuropathy was common, with 1--% of those with neurological disease displaying peripheral neuropathy. Ear-Bose-4hroat area was involved in 16% of individuals. 3troke happened in 16% of individuals (2males, 1female). It represented the debut of overt organic disease in all of them, being 49, 45 and 61yrs respectivelyIn male cases posterior cerebral artery territory was the main area of cerebrovascular disease. Fabry disease causes approximately 1’2% of strokes previously considered as cryptogenetic. Therefore, Fabry disease should be considered in differential diagnosis of young-onset cerebrovascular ictal disease, particularly when it involves posterior territory and assocites systemic disease in renal or cardiovascular sites, as it happened in our proband. 2egarding psychological involvement 2/19 individuals (1%, females III4 and I68) displayed chronic anxious symptoms exacerbated by Fabry disease. A recent reviewsuggested a high prevalence of psychological disorders such as depression in Fabry patients. 4hey obtained that 8%–17% of Fabry males scored within the mild-to-moderate ranges of Depression, Anxiety and 3tress 3cale as compared with 11% of male-controls. 4here were no differences observed between Fabry and control females. Cognitive impairment in Fabry patients is also a poorly addressed subject. In the above mentioned review Fabry males demonstrated slower speed of information processing, reduced performance on measures of executive functions and were more likely to show significant reductions. Conversely, Fabry females performed similarly to controls. Another reviewcorrelational analyses suggesting a link between cognitive impairment and clinical measures of disease severity.Cphthalmological involvement deserved particular attention in this family. Eye involvement was detected in every individual from this large family regardless gender. Corneal disease was particularly severe, with 1--% of individuals displaying cornea verticillata. 3lit-lamp exam cornea verticillata images were particularly striking, with bizarre and early forms (Figure 2). 4hese bizarre images were detected not only in older than 40yrs individuals with Figure 2: Cornea ver�cillata. 26yr old asymptoma�c p.M187R carrier cornea ver�cillata. San-Román-Monserrat I, Gimeno-Blanes JR, Rodríguez-González-Herrero ME, Sodi A, Mecocci A. J 2016 1(2): 64-69 organic overt disease but also i

n younger paucisymptomatic/asymptomatic individuals, regardless their gender. In fact, the youngest individual in whom cornea verticillata was detected was a 7yr old female. This remarks the utmost importance of ophthalmological examination for early diagnosis of Fabry disease. Furthermore, in our present research line we have explored the potential implications of ophthalmological exam in terms of prognostic stratification of Fabry patients. 7e have obtained interesting results that have been accepted for publication in 2etina, the *ournal of 2etinal and 6itreous DiseasesCther organs and systems are frequently involved in Fabry disease, such as skin (angiokeratomata), gastrointestinal, pneumological or rheumatological system. 7e summarize these sites involvement in table 2. Cnce more, this fact remarks the systemic character of the disease4hree family members are on E24 with biweekly iv infusion of agalsidase beta, 2 males (III1, proband, and I69) and 1 female (III11) (Figure 1). Cther 2 females with clear indication of E24 (III4 and III6) have been repeatedly offered but have refused until the date. All the individuals under E24 attend regularly the infusion sessions. 7hen indicated, they are receiving secondary prevention therapy for renal, cardiovascular and/or cerebrovascular disease (angiotensin-converter-enzyme blockers, betablockers, antiagregants/anticoagulants and statins) as stated in current guidelines. E24 was started in proband soon after Fabry diagnosis in 2--9, being 49yrs. He had just suffered right hemibulbar cerebral infarction, was diagnosed of stage III chronic kidney disease and BEHA III not-obstructive hypertrophic cardiomyopathy. As we described in our 2-14 article, he suffers severe classic Fabry phenotype. After 7 years on E24 renal function seems to be stable with -D2D-4 GF2 of 37ml/min as well as stable ,6EF, on 52%. Bo other cerebrovascular events have occurred. Achroparestesia and arthralgia are controlled with symptomatic treatment and ophthalmological signs remain unchanged. -ale I69 (21yrs) was diagnosed with paucisymptomatic classical Fabry without overt organic disease and subtle ECG repolarization abnormalities. He started on E24 only 1 year ago, and no cardiac, renal or cerebrovascular events have been observed to date. His mother is female III11 (49yrs). -icroalbuminuria with normal GF2 was detected together with subtle electrocardiographic abnormalities setting up the indication for E24 starting, also approximately 6 months ago. GF2 remains under normal range, no changes in microalbuminuria have been observed and no cardiovascular or cerebrovascular events have happenedTo conclude, with our 2014 work we intended to remark Fabry disease systemic nature with a real clinical family-case. 4he main “red-flags” that should trigger Fabry disease diagnostic work-up were exemplified. 7e also remarked the high severity that novel p.-1872 mutation seems to associate. A quantitative approach to systemic severity and systemic involvement was intended by means of -33I calculation. 3everity was particularly high for cardiac features and corneal disease was evident for both male and female carriers. Finally with this family we described the first 3cases in literature in which short-P2 interval associated delta wave in electrocardiogram in Faby disease, suggesting the existence of accessory intracardiac conduction pathways.AbbreviationsAP: anatomopathological; Aud: Audiometry; aud ch: auditory channels; bilat: bilateral; Ca: carcinoma D--2: type 2 diabetes mellitus; HyperP4H CKD*: secondary to Chronic Kidney Disease Hyperparathyroidism* out of 4 cases of CKD; infs: infections; 28 KHz: kilohertz; ,E: left ear; mod: moderate; -43: metastases; P: probable; 2E: right ear; 24: radiotherapy; 3,1: superolateral quadrant; yrs: years. **: EB4 symptoms evaluable only in 12/15 individuals; Audiometry feasible only in -ale III1 and female II8.References -, Pagliardini 3, Easuda -, 4ukel 4, 4hiagarajan G, 3akuraba H, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am * Hum Genet. 2--6 *ul; 79(1):31-4-. *, Easuda -, Benson 3D, Desnick 2*. Fabry disease: identification of 5- novel alpha-galactosidase A mutations causing the classic phenotype and three-di

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