Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues

Tøndel, Camilla; Thurberg, Beth L.; DasMahapatra, Pronabesh; Lyn, Nicole; Maski, Manish; Batista, Julie L.; George, Kelly; Patel, Hiren

doi:10.1016/j.ymgme.2022.10.005

Cited by 15 publications

(7 citation statements)

References 104 publications

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“…Fabry’s disease (FD) is a genetic X-linked systemic and progressive rare disease characterized by the deficiency or loss-of-function of α-galactosidase with accumulation of globotriaosylceramide (GB3) into the lysosomes of many tissues ( 1 ). GB3 accumulation is responsible for the damaging effects observed in heart, CNS, skin, kidney, endothelium, etc.…”

Section: Introductionmentioning

confidence: 99%

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Sansone,

Barreca,

Belli

et al. 2024

Front. Endocrinol.

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IntroductionFabry’s disease (FD) is a genetic X-linked systemic and progressive rare disease characterized by the accumulation of globotriaosylceramide (GB3) into the lysosomes of many tissues. FD is due to loss-of-function mutations of α-galactosidase, a key-enzyme for lysosomal catabolism of glycosphingolipids, which accumulate as glycolipid bodies (GB). In homozygous males the progressive deposition of GB3 into the cells leads to clinical symptoms in CNS, skin, kidney, etc. In testis GB accumulation causes infertility and alterations of spermatogenesis. However, the precise damaging mechanism is still unknown. Our hypothesis is that GB accumulation reduces blood vessel lumen and increases the distance of vessels from both stromal cells and seminiferous parenchyma; this, in turn, impairs oxygen and nutrients diffusion leading to subcellular degradation of seminiferous epithelium and sterility.MethodsTo test this hypothesis, we have studied a 42-year-old patient presenting a severe FD and infertility, with reduced number of spermatozoa, but preserved sexual activity. Testicular biopsies were analyzed by optical (OM) and transmission electron microscopy (TEM). Activation and cellular localization of HIF-1α and NFκB was analyzed by immunofluorescence (IF) and RT-PCR on homogeneous tissue fractions after laser capture microdissection (LCMD).ResultsOM and TEM showed that GB were abundant in vessel wall cells and in interstitial cells. By contrast, GB were absent in seminiferous epithelium, Sertoli’s and Leydig’s cells. However, seminiferous tubular epithelium and Sertoli’s cells showed reduced diameter, thickening of basement membrane and tunica propria, and swollen or degenerated spermatogonia. IF showed an accumulation of HIF-1α in stromal cells but not in seminiferous tubules. On the contrary, NFκB fluorescence was evident in tubules, but very low in interstitial cells. Finally, RT-PCR analysis on LCMD fractions showed the expression of pro-inflammatory genes connected to the HIF-1α/NFκB inflammatory-like pathway.ConclusionOur study demonstrates that infertility in FD may be caused by reduced oxygen and nutrients due to GB accumulation in blood vessels cells. Reduced oxygen and nutrients alter HIF-1α/NFκB expression and localization while activating HIF-1α/NFκB driven-inflammation-like response damaging seminiferous tubular epithelium and Sertoli’s cells.

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Section: Introductionmentioning

confidence: 99%

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Sansone,

Barreca,

Belli

et al. 2024

Front. Endocrinol.

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“…Patients with FD and CKD have a high risk of cardiovascular events, similar to patients with CKD of any cause [4][5][6]. ERT with recombinant human agalsidase and pharmacological chaperones are specific therapies for FD nephropathy [8,9], but pharmacological and non-pharmacological nephroprotective interventions are also necessary to prevent the progression of FD kidney damage [3][4][5][6]. Blockade of the Renin-Angiotensin-Aldosterone System (RAAS) has been the first-line pharmacological strategy to eGFR slow decline in CKD of various causes, including FD [10].…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Dapagliflozin Effect on Proteinuria in a Female Patient with Classic Fabry Disease First Literatura Report

Jaurretche,

Daminato

2023

austinjnephrolhypertens

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A 75-year-old female patient, with “classic” Fabry disease (DEL 3&4 EXON, GLA gene) and severe multi-organic compromise (cardiac, brain, renal and peripheral nervous system) is presented. Patient presented treatment initiation criteria, and was a “classic” Fabry phenotype, for this reason, agalsidase-β was indicated. In addition, enalapril, were indicated. After the treatment start and to date, the patient presented: i) LVH stabilization; ii) brain damage stabilization; iii) stable eGFR and sustained improvement in proteinuria and; iv) pain improvement. In September 2022, due to the results of DAPA-CKD study, it was decided to start treatment with dapagliflozin to extend the renal protective effect; patient presented good tolerance to drug and no adverse effects were recorded. A slight decrease in eGFR was observed, but suspension was decided after 8 weeks due to increased proteinuria. Kidney disease is a major Fabry disease complication; it is more severe in the “classic” phenotype and males, although the “non-classic” Fabry phenotype and affected females may also present severe renal disease. Patients with Fabry disease and chronic kidney disease have a high risk of cardiovascular events, SGLT-2 inhibitor drugs have shown favorable effects on cardiovascular events in chronic kidney disease patients, both DBT and non-DBT. Multiple pathophysiological mechanisms have been described in Fabry nephropathy, none of them could explain, the reason why SGLT-2 blockade produced an increase in proteinuria in presented case.

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“…The correlation between GL-3 accumulation and pathogenic mechanism for renal damage has been documented in FD [20,22]. Renal biopsies of Fabry patients often show signs of histological damage before proteinuria or elevated serum creatinine is detected.…”

Section: Kidney Failure and Bone Healthmentioning

confidence: 99%

Assessing Osteopenia and Osteoporosis with Dual-energy X-ray Absorptiometry Studies in Fabry Disease

Shmara,

Lee,

Mgdsyan

et al. 2024

Preprint

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Background Fabry disease is a rare multi-systemic lysosomal storage disease that affects the heart and kidneys most significantly. An underappreciated manifestation of FD is reduced bone mineral density. Currently, there are no specific guidelines for routine bone density assessments, and treatment of osteoporosis and osteopenia in Fabry disease. Materials and methods To ascertain the frequency of low bone mineral density in FD we studied dual-energy x-ray absorptiometry (DXA) scans obtained as part of routine care from a cohort of 25 individuals followed at the University of California - Irvine Medical Center. The most recent DXA scan results were analyzed from 12 males and 13 females to examine the prevalence of low bone mineral density. In our cohort the mean age was 51 years (median 56 years, range 18-77 years). The Z-scores for all participants and T-scores from postmenopausal women and men ≥ 50-year-old were analyzed and correlated with various measures including disease duration, BMI, renal function (measured by eGFR), plasma GL3, Lyso-GL3, calcium, vitamin D, and alkaline phosphatase levels. Results The average Z-score for all the participants was -1.2±1.3 (range -4.6 to 1.6). Twenty-four percent of all participants (n=6) had significantly low Z-scores below ≤ -2.0. To identify the frequency of subjects with osteopenia, defined as T-score between -1.0 and -2.5and osteoporosis defined as T-score < -2.5, T-scores were analyzed in postmenopausal women (n=8) and men 50 years and older (n=7). Of these 15 individuals, average T-score was -2.2±1.3 (range -5.4 to – 0.3), and 86.7% (n=13) had abnormal results (osteopenia and osteoporosis), 53.3% (n=8) had osteoporosis and 33.3% (n=5) had osteoporosis. We found a significant difference in Z-scores between male (-1.98 ±1.33) and female patients (-0.45 ±0.82) t (23) = 3.487 (p = < 0.001). We did not find any differences in z-scores between different ethnic backgrounds. There was a strong negative correlation between Z-scores and Lyso-GL3 levels [r (23) = -.72, p=.001] and a moderate positive correlation between Z-scores and body mass index (BMI) [r (23) = .43, p=.033]. No correlation was found between Z-scores and calcium levels. There is a strong negative correlation between T-scores and Lyso-GL3 levels [r (8) = -.86, p=.001] and a strong negative correlation between T-scores and participants’ ages at the time of DXA [r (13) = -.57, p=0.028]. There is a strong positive correlation between T- scores and calcium levels [r (12) = .58, p=0.030]. No significant correlation was observed between T-scores and BMI. There was no correlation between Z or T- scores and disease duration, duration of ERT use, renal function (measured by eGFR), GL3, creatinine, vitamin D, or alkaline phosphatase levels. We did not find a significant difference in Z- or T- scores between the individuals based on their use of vitamin D or concomitant antiepileptic medications. Conclusion The findings of this cohort highlight the high prevalence of low bone mineral density in Fabry disease and correlations of low Z and T- scores with elevated levels of Lyso-GL3, and low calcium levels. We did not find correlations with renal function, and vitamin D levels. We discuss etiology, prevention, and treatment strategies for osteopenia/osteoporosis in Fabry disease.

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Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues

Cited by 15 publications

References 104 publications

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Infertility in Fabry’s Disease: role of hypoxia and inflammation in determining testicular damage

Paradoxical Dapagliflozin Effect on Proteinuria in a Female Patient with Classic Fabry Disease First Literatura Report

Assessing Osteopenia and Osteoporosis with Dual-energy X-ray Absorptiometry Studies in Fabry Disease

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