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Dear Editor, Fabry disease (FD) is an X-linked lysosomal disorder leading to accumulation of glycosphingolipids.[1] Its severity results from FD vasculopathy in the form of early ischaemic stroke, cardiomyopathy and renal failure. Recognizing skin manifestations is essential in FD, as they usually precede organ involvement, allowing earlier diagnosis and treatment, and are determinant for the prognosis. [Extracted from the article]

Background: Sphingolipidoses are rare inherited metabolic diseases belonging to lysosomal diseases. Early and accurate diagnosis is crucial for effective management and treatment. In this study, we aimed to develop a robust method to accelerate the diagnosis of these sphingolipidoses using dried blood spots and plasma., Method: We employed high-resolution mass spectrometry coupled with liquid chromatography (LC-HRMS) to analyze 6 lysosphingolipids (GlcSph/Psychosine, LysoGb3, LysoSM, LysoSM509, LysoGM1, and LysoGM2) on dried blood spots and plasma samples. The method was used to measure the lysosphingolipid levels in a group of 30 control subjects and 204 samples from patients with sphingolipidoses (61 dB and 143 plasma) including Fabry, Gaucher, GM2 Gangliodosis, Niemann-Pick type A/B, and Niemann-Pick type C., Results: The developed multiplex LC-HRMS method demonstrated linearity, precision, and quantification performances particularly for GlcSph/Psychosine and LysoGb3 on samples including controls and patients with sphingolipidoses. LysoSM showed recovery variability, wherease LysoGM1 and LysoGM2 showed higher matrix effect., Conclusion: Our study presents a high-resolution mass spectrometry method along with the established cutoff values, providing a valuable tool for targeted screening, accurate diagnosis, and monitoring sphingolipidoses. Furthermore, DBS showed reliable results that lay the path to a broader adoption for screening these diseases., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Competing Interests: Conflicts of interest None disclosed.

Background: Acid sphingomyelinase deficiency (ASMD) or Niemann-Pick disease types A, A/B, and B is a progressive, life-limiting, autosomal recessive disorder caused by sphingomyelin phosphodiesterase 1 (SMPD1) gene mutations. There is a need to increase the understanding of morbidity and mortality across children to adults diagnosed with ASMD., Methods: This observational retrospective survey analysed medical records of patients with ASMD with retrievable data from 27 hospitals in France, diagnosed/followed up between 1 st January 1990 and 31 st December 2020. Eligible records were abstracted to collect demographic, medical/developmental history, and mortality data. Survival outcomes were estimated from birth until death using Kaplan-Meier survival analyses; standardised mortality ratio (SMR) was also explored., Results: A total of 118 medical records of patients with ASMD (type B [n = 94], type A [n = 15], and type A/B [n = 9]) were assessed. The majority of patients were males (63.6%); the median [range] age at diagnosis was 8.0 [1.0-18.0] months (type A), 1.0 [0-3] year (type A/B), and 5.5 [0-73] years (type B). Overall, 30 patients were deceased at the study completion date; the median [range] age at death for patients with ASMD type A (n = 14) was 1 [0-3.6] year, type A/B (n = 6) was 8.5 [3.0-30.9] years, and type B (n = 10) was 57.6 [3.4-74.1] years. The median [95% confidence interval (CI)] survival age from birth in patients with ASMD type A and type A/B was 2.0 [1.8-2.7] years and 11.4 [5.5-18.5] years, respectively. Survival analysis in ASMD type B was explored using SMR [95% CI] analysis (3.5 [1.6-5.9]), which showed that age-specific deaths in the ASMD type B population were 3.5 times more frequent than those in the general French population. The causes of death were mostly severe progressive neurodegeneration (type A: 16.7%), cancer (type B: 16.7%), or unspecified (across groups: 33.3%)., Conclusions: This study illustrated a substantial burden of illness with high mortality rates in patients with ASMD, including adults with ASMD type B, in France., (© 2024. The Author(s).)

Fabry disease (FD) is an X-linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti-drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45- and CD45 + CCR7-CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA-CCR7-CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers., (© 2024 SSIEM.)

Objective: Fabry disease is caused by enzymatic defects in alpha-galactosidase A that leads to the accumulation of glycosphingolipids throughout the body, resulting in a multisystemic disorder. The most common neurological manifestations are neuropathic pain, autonomic nervous system dysfunction and strokes, but some rarer neurological manifestations exist. Among these, aseptic meningitis is a possible complication. Our objectives were to measure the prevalence of this complication in a cohort of patients with Fabry disease, and to describe its clinical features., Methods: We conducted a retrospective review of Fabry disease patients followed at our tertiary referral center between 1995 and September 2023 with at least one episode of meningitis, and performed a systematic review to identify similar published cases., Results: Four patients out of 107 (3.7%) had at least one episode of aseptic meningitis. Our systematic review identified 25 other observations. The median age of these 29 patients was 29.0 years, the median cerebrospinal fluid leukocyte count was 24 cells/mm3 with a predominance of lymphocytes in 64.7% of cases. In 82.8% of the patients, the diagnosis of Fabry disease was unknown before the meningitis. Large artery stenosis was present in 17.2% of patients and 57.1% of patients had a recent stroke concomitant with the meningitis. Several differential diagnoses were evoked, such as multiple sclerosis or central nervous system vasculitis., Interpretation: Our study suggests that Fabry disease should be considered as a cause of aseptic meningitis. The pathophysiological mechanisms underlying meningeal inflammation remain largely unknown but may reflect the dysregulation of pro-inflammatory signaling pathways., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Fabry disease (FD) is a lysosomal storage disease responsible for cochleovestibular involvement. Exact prevalence and pathophysiological mechanisms behind ENT affections are still poorly known. Treating FD with enzyme replacement therapy (ERT) does not seem to significantly improve the ENT symptoms, while the impact of migalastat has yet to be determined., Methods: We carried out a retrospective multi-centre study on 47 patients from the FFABRY cohort who had an ENT consultation in the context of their FD. The information collected were as follows: clinical examination, videonystagmoscopy, pure-tone speech audiometry, videonystagmography or VHIT (Video Head Impulse Test). Severe hearing loss was defined as greater than 70 dB., Results: The median age of our cohort was 52 years with a non-negligible proportion of non-classic variants and female carriers. 72.3% of the patients complained of at least one of the following symptoms: hearing loss, tinnitus or vertigo. Pure-tone audiometry was abnormal in 61.7% of the patients (29/47), while speech audiometry was abnormal for 41.7% of the patients. The age of the patients and hypertrophic cardiomyopathy were significantly associated with the existence of an anomaly in pure-tone audiometry results. Severe hearing loss (> 70 dB) was significantly more common in male patients., Discussion: Hearing loss is particularly frequent in FD and is not limited to classic phenotypes. Close ENT follow-up is essential for Fabry patients to detect those who might benefit from hearing aid. Further studies are needed to define the impact of migalastat on cochleovestibular symptoms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6−227.9] vs. 169.4 ng/mL [121.1−203.3], p = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; p < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; p < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; p = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; p = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management.

Acid sphingomyelinase deficiency (ASMD) is a rare inherited lipid storage disorder caused by a deficiency in lysosomal enzyme acid sphingomyelinase which results in the accumulation of sphingomyelin, predominantly within cells of the reticuloendothelial system located in numerous organs, such as the liver, spleen, lungs, and central nervous system. Although all patients with ASMD share the same basic metabolic defect, a wide spectrum of clinical presentations and outcomes are observed, contributing to treatment challenges. While infantile neurovisceral ASMD (also known as Niemann-Pick disease type A) is rapidly progressive and fatal in early childhood, and the more slowly progressive chronic neurovisceral (type A/B) and chronic visceral (type B) forms have varying clinical phenotypes and life expectancy. The prognosis of visceral ASMD is mainly determined by the association of hepatosplenomegaly with secondary thrombocytopenia and lung disease. Early diagnosis and appropriate management are essential to reduce the risk of complications and mortality. The accessibility of the new enzyme replacement therapy olipudase alfa, a recombinant human ASM, has been expedited for clinical use based on positive clinical data in children and adult patients, such as improved respiratory status and reduced spleen volume. The aim of this article is to share the authors experience on monitoring ASMD patients and stratifying the severity of the disease to aid in care decisions.

Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3-55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5-25) vs. 18 cm (17-20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8-43.0) vs. 58.5 % (49.8-69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer ( p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.

Background: Fabry disease (FD) is an X-linked lysosomal disease due to a deficiency in the activity of the lysosomal α-galactosidase A (GalA), a key enzyme in the glycosphingolipid degradation pathway. FD is a complex disease with a poor genotype-phenotype correlation. FD could involve kidney, heart or central nervous system impairment that significantly decreases life expectancy. The advent of omics technologies offers the possibility of a global, integrated and systemic approach well-suited for the exploration of this complex disease., Materials and Methods: Sixty-six plasmas of FD patients from the French Fabry cohort (FFABRY) and 60 control plasmas were analyzed using liquid chromatography and mass spectrometry-based targeted metabolomics (188 metabolites) along with the determination of LysoGb3 concentration and GalA enzymatic activity. Conventional univariate analyses as well as systems biology and machine learning methods were used., Results: The analysis allowed for the identification of discriminating metabolic profiles that unambiguously separate FD patients from control subjects. The analysis identified 86 metabolites that are differentially expressed, including 62 Glycerophospholipids, 8 Acylcarnitines, 6 Sphingomyelins, 5 Aminoacids and 5 Biogenic Amines. Thirteen consensus metabolites were identified through network-based analysis, including 1 biogenic amine, 2 lysophosphatidylcholines and 10 glycerophospholipids. A predictive model using these metabolites showed an AUC-ROC of 0.992 (CI: 0.965-1.000)., Conclusion: These results highlight deep metabolic remodeling in FD and confirm the potential of omics-based approaches in lysosomal diseases to reveal clinical and biological associations to generate pathophysiological hypotheses.

We describe a 79-year-old man with spondylodiscitis and unknown pathogen, treated with cefazolin and rifampicin. He developed a massive digestive hemorrhage. Prothrombin time was prolonged with severe vitamin-K-dependent clotting-factor deficiency. Severe bleeding can occur during cefazolin and rifampicin use. This deficiency should be assessed before prescribing cefazolin-rifampicin and prothrombin time monitored., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2021 Ines Kouki et al.)

Fabry disease is a frequent lysosomal storage disorder secondary to the deficiency of alpha-galactosidase A enzyme. This X-linked genetic disease realizes progressive and systemic manifestations that affect both male and female. Fabry disease may present as "classical", as "late-onset" or "non-classical" forms. Symptoms and organ involvements of classical Fabry disease are acral pain crisis, cornea verticillata, hypertrophic cardiomyopathy, stroke and chronic kidney disease with proteinuria. Other common symptoms are often poorly recognized, such as gastrointestinal or ear involvements. In classical Fabry disease, symptoms first appear during childhood or during teenage years in males, but later in females. Patients with non-classical or late-onset Fabry disease have delayed manifestations or a single-organ involvement. Diagnosis is therefore difficult when classical organ involvements are missing, in paucisymptomatic patients or in late-onset forms. Recognition of Fabry disease is important because effective treatments are available. They have to be prescribed early. In male, diagnosis is made with alpha-galactosidase A enzyme activity dosage in leukocyte, that is very low or null in classical forms and under 30 percent in late-onset forms. Diagnosis is more challenging in females who may express normal residual enzyme activity. Other plasmatic biomarkers, such as lyso-globotriaosylceramide are interesting, especially in females. In this review, we aimed to summarize main clinical manifestations of Fabry disease to know when to evoke Fabry disease and propose a practical diagnosis algorithm to know how to diagnose., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Backgroud: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity., Methods: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients., Results: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI., Conclusion: Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients., Competing Interests: WM received honoraria, congress fees and travel assistance from Shire-Takeda, Amicus and Sanofi- Genzyme. OB, DA, CM declare no conflict of interest. FLam has received travel support from Amicus Therapeutics., Shire and Sanofi-Genzyme. He received lecture fees from Actelion Pharmaceuticals. BD has received honoraria from Amicus (member of the scientific board) and Novartis (lectures) and travel fees from Genzyme-Sanofi. VLS has received travel fees and accommodations from Shire and Sanofi-Genzyme. CC has received consultant honoraria and congress fees from Biomarin and Sanofi-Genzyme and has participated in editorial activity with Takeda-Shire. CD has received travel assistance from Shire, Sanofi-Genzyme, Sobi, Orphan Europe, Nutricia, Lucane Pharma, Amicus, and Ultragenyx and honoraria from Amicus and has participated on boards with Ultragenyx and Sanofi. OB, AD, PDH declare no conflict of interest EN has received travel fees from Shire and Sanofi-Genzyme and an honorarium from Amicus. TZ has received congress fees and travel assistance from Sanofi-Genzyme. MM declare no conflict of interest FM has received honoraria from Shire and travel assistance from Sanofi-Genzyme. KHL declare no conflict of interestGB has received travel assistance from Shire, Genzyme-Sanofi and Amicus. GB has received travel assistance from Shire, Genzyme-Sanofi and Amicus. MW and FLab declare no conflict of interest AM has received travel fees and accommodations from Shire, Sanofi-Genzyme and Amicus. CL has received honoraria from Sanofi-Genzyme and travel assistance from Sanofi-Genzyme and Shire. DL has received honoraria and travel assistance from Sanofi-Genzyme and has participated on boards with Amicus. HM received honoraria and travel assistance from Sanofi-Genzyme and Amicus and has participated on boards with Amicus and Shire. OL has received travel support and lecture fees from Amicus Therapeutics, Shire, and Sanofi- Genzyme. This does not alter our adherence to PLOS ONE policies on sharing data and materials.