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Background Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by defective enzyme activity involved in the catalysis of glycosaminoglycans. Published data on adult patients with MPS remains scarce. Therefore, the present qualitative survey study was aimed at understanding knowledge of the disease, unmet needs, expectations, care, and overall medical management of adult/adolescent patients with MPS I, II and VI and their caregivers in France. Results A total of 25 patients (MPS I, n p  = 11; MPS II, n p  = 9; MPS VI, n p  = 5) were included and about 36 in-depth interviews (caregivers alone, n c  = 8; patients-caregiver pair, n c+p  = 22; patients alone, n p  = 6) were conducted. Except one (aged 17 years), all patients were adults (median age: 29 years [17–50]) and diagnosed at median age of 4 years [0.4–30], with mainly mothers as caregivers (n c  = 16/19). Patients were classified into three groups: Group A, Patients not able to answer the survey question because of a severe cognitive impairment (n p  = 8); Group B, Patients able to answer the survey question with low or no cognitive impairment and high motor disability (n p  = 10); and Group C, Patients able to answer the survey question with low or no cognitive impairment and low motor disability (n p  = 7). All groups were assessed for impact of disease on their daily lives based on a scale of 0–10. Caregivers in Group A were found to be most negatively affected by the disease, except for professional activity, which was most significantly impacted in Group B (4.7 vs. 5.4). The use of orthopaedic/medical equipments, was more prevalent in Groups A and B, versus Group C. Pain management was one of the global unmet need expressed by all groups. Group A caregivers expected better support from childcare facilities, disability clinics, and smooth transition from paediatric care to adult medicine. Similarly, Group B caregivers expected better specialised schools, whereas Group C caregivers expected better psychological support and greater flexibility in weekly infusion schedules for their patients. Conclusions The survey concluded that more attention must be paid to the psychosocial status of patients and caregivers. The preference for reference centre for follow-up and treatment, hospitalizations and surgeries were evident. The most significant needs expressed by the patients and caregivers include better understanding of the disease, pain management, monitoring of complications, flexibility in enzyme replacement therapy, home infusions especially for attenuated patients, and improved transitional support from paediatric to adult medicine.

Background Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2′-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. Methods Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. Results All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients’ phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. Conclusions The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.

Background Fabry disease (FD) is a rare, X-linked, inherited lysosomal disease caused by absent or reduced α-galactosidase A activity. Due to the heterogeneity of disease presentation and progression, generic patient-reported outcome (PRO) tools do not provide accurate insight into patients’ daily lives and impact of disease specific treatments. Also, the French National Health Authority, (HAS) actively encourages a patient-centric approach to improve the quality of care throughout the patient journey. In response to this initiative, we aimed to develop and validate a specific, self-reported, Patient Needs Questionnaire for people living with Fabry disease to appraise patient needs and expectations towards their treatment (PNQ Fabry). This endeavour was led with the help of French patient associations (APMF & VML) and dedicated expert centres. PNQ Fabry was developed according to the FDA/EMA methodologies and best practices for the development of PRO tools in rare diseases. Our approach comprised of three steps, as follows: concept elicitation and item generation, item reduction, and final validation of the questionnaire through a two-stage survey. Results Intrinsic and extrinsic reliability was established, using a validated benchmark questionnaire. With the invaluable help of patient associations, we recruited a satisfactory population in this rare disease setting, to ensure robust participation to validate our PNQ (final number of questionnaires: 76). At the end of the process, a 26-item patient-reported questionnaire was obtained with excellent psychometric properties, exhibiting very satisfactory measurement outcomes for reliability and validity. The results of this initiative demonstrate that the PNQ Fabry is accurate, suitable and tailored to FD patients, as it addresses themes identified during patient interviews, that were further validated through statistical analyses of quantitative surveys. An ongoing phase IV study is using this tool. Conclusion We believe the PNQ Fabry will be a reliable and insightful tool in clinical practice, to improve patient management in FD.

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.

Background 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. Results 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). Conclusion 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.

Vitamin B12 or cobalamin deficiency occurs frequently (> 20%) among elderly people, but it is often unrecognized because the clinical manifestations are subtle; they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. Causes of the deficiency include, most frequently, food-cobalamin malabsorption syndrome (> 60% of all cases), pernicious anemia (15%-20% of all cases), insufficient dietary intake and malabsorption. Food-cobalamin malabsorption, which has only recently been identified as a significant cause of cobalamin deficiency among elderly people, is characterized by the inability to release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or both. We review the epidemiology and causes of cobalamin deficiency in elderly people, with an emphasis on food-cobalamin malabsorption syndrome. We also review diagnostic and management strategies for cobalamin deficiency.

ABSTRACT 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. Sphingolipidoses is a group of rare inherited lysosomal diseases that require an early and accurate diagnosis for effective treatment and patient management. A high‐resolution mass spectrometry method coupled with liquid chromatography has beendeveloped to analyze lysosphingolipids in plasma and dried blood spots. The study emphasizes the reliability of dried blood spots as a valuable matrix for screening, diagnosis, and monitoring of sphingolipidoses.

IntroductionAcute hepatic porphyria (AHP) comprises a group of rare genetic diseases caused by mutations in genes encoding enzymes involved in heme biosynthesis. AHP is characterized by acute neurovisceral crises including violent abdominal pain, dysautonomia, central and peripheral neurological symptoms. This disease remains underdiagnosed. Identifying AHP is therefore a major challenge for early and appropriate care of patients and their families.The primary objective was to determine the prevalence of patients with AHP from different hospital departments and referred to an internist referent for a suggestive clinical picture with a first negative etiological assessment. The secondary objective was to define and characterize the profile of patients according to their initial symptomatology.Patients et methodsThis was an observational, multicenter, and ambispective study. 160 patients from 13 French hospital centers were included in the study between 09/2021 and 12/2023. The diagnosis of AHP was based on the urinary dosage of the neurotoxic precursors of heme: delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). A patient was diagnosed with AHP (AHP+) if: ALA ≥ 3 µmol/mmol of creatinine and/or PBG ≥ 1 µmol/mmol of creatinine. In all other cases, the patient was considered not to suffer from AHP (AHP-).ResultsAmong the 152 patients included in the analyses, 9 (5.9%) patients were diagnosed AHP+. All were female, mean age was 34.3 years and they were referred by a neurologist (2), an internist (2), an emergency physician (1), a gastroenterologist (1), a gynecologist (1) or another physician (1). One third of AHP+ patients had a family history of AHP. The factors triggering attacks were stress (6), menstrual cycle (4), medications (4), infections (1), alcohol or tobacco consumption (1+1). The mean delay between inclusion and first severe, diffuse and apyretic abdominal pain was 28.4 months. Eight patients had dysautonomia (nausea, vomiting, constipation and/or tachycardia), 5 patients had peripheral neurological symptoms and 6 patients had central neurological symptoms.ConclusionThis study found a 5.9% prevalence of AHP in patients with suggestive clinical picture in France. It confirms the main symptoms of AHP including severe, diffuse abdominal pain over several days, without fever, and possibly associated with neurological symptoms.

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.