Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino-acids transporter subunit y+LAT1. The disease is characterised by protein-rich food intolerance with secondary urea cycle disorder, but symptoms are heterogeneous ranging from infiltrative lung disease, kidney failure to auto-immune complications. This retrospective study of all cases treated at Necker Hospital (Paris, France) since 1977 describes LPI in both children and adults in order to improve therapeutic management. Sixteen patients diagnosed with LPI (12 males, 4 females, from 9 families) were followed for a mean of 11.4 years (min-max: 0.4-37.0 years). Presenting signs were failure to thrive (n = 9), gastrointestinal disorders (n = 2), cytopenia (n = 6), hyperammonemia (n = 10) with acute encephalopathy (n = 4) or developmental disability (n = 3), and proteinuria (n = 1). During follow-up, 5 patients presented with acute hyperammonemia, and 8 presented with developmental disability. Kidney disease was observed in all patients: tubulopathy (11/11), proteinuria (4/16) and kidney failure (7/16), which was more common in older patients (mean age of onset 17.7 years, standard deviation 5.33 years), with heterogeneous patterns including a lupus nephritis. We noticed a case of myocardial infarction in a 34-year-old adult. Failure to thrive and signs of haemophagocytic-lymphohistiocytosis were almost constant. Recurrent acute pancreatitis occurred in 2 patients. Ten patients developed an early lung disease. Six died at the mean age of 4 years from pulmonary alveolar proteinosis. This pulmonary involvement was significantly associated with death. Age-adjusted plasma lysine concentrations at diagnosis showed a trend toward increased values in patients with a severe disease course and premature death (Wilcoxon p = 0.08; logrank, p = 0.17). Age at diagnosis was a borderline predictor of overall survival (logrank, p = 0.16). As expected, early pulmonary involvement with alveolar proteinosis is frequent and severe, being associated with an increased risk of death. Kidney disease frequently occurs in older patients. Cardiovascular and pancreatic involvement has expanded the scope of complications. A borderline association between increased levels of plasma lysine and poorer outome is suggested. Greater efforts at prevention are warranted to optimise the long-term management in these patients.

Background: Fabry disease (FD) is an X-linked progressive lysosomal disease (LD) due to glycosphingolipid metabolism impairment. Currently, plasmatic globotriaosylsphingosine (LysoGb3) is used for disease diagnosis and monitoring. However, this biomarker is inconstantly increased in mild forms and in some female patients. Materials and Methods: We applied a targeted proteomic approach to explore disease-related biological patterns that might explain the disease pathophysiology. Forty proteins, involved mainly in inflammatory and angiogenesis processes, were assessed in 69 plasma samples retrieved from the French Fabry cohort (FFABRY) and from 83 healthy subjects. For predictive performance assessment, we also included other LD samples (Gaucher, Pompe and Niemann Pick C). Results: The study yielded four discriminant proteins that include three angiogenesis proteins (fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor C (VEGFC)) and one cytokine interleukin 7 (IL-7). A clear elevation of FGF2 and IL-7 concentrations was observed in FD compared to other LD samples. No correlation was observed between these proteins and globotriaosylsphingosine (LysoGb3). A significant correlation exists between IL-7 and residual enzyme activity in a non-classical phenotype. This highlights the orthogonal biological information yielded by these proteins that might help in stratifying Fabry patients. Conclusion: This work highlights the potential of using proteomics approaches in exploring FD and enhancing FD diagnosis and therapeutic monitoring performances.

Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41–12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6–55.6] vs 12.5 [10.1–24.0], p = 0.005). Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.

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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.

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. 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. 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. 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.