Background: Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of undegraded substrates within lysosomes, disrupting cellular function across multiple organ systems. While classical phenotypes typically manifest in infancy or early childhood with severe multisystem involvement, a combination of advances in molecular diagnostics [particularly next-generation sequencing (NGS)] and improved understanding of disease heterogeneity have enabled the identification of attenuated forms characterised by residual enzyme activity and later-onset presentations. These milder phenotypes often evade early recognition due to nonspecific or isolated symptoms, resulting in significant diagnostic delays and missed therapeutic opportunities. Objectives/Methods: This study characterises the clinical, biochemical, and molecular profiles of 10 adult patients diagnosed with LSDs, all representing attenuated forms, and discusses them alongside a narrative review. Results: Enzyme activity, molecular data, and phenotypic assessments are described to explore genotype–phenotype correlations and identify diagnostic challenges. Conclusions: These findings highlight the variable expressivity and organ involvement of attenuated LSDs and reinforce the importance of maintaining clinical suspicion in adults presenting with unexplained cardiovascular, neurological, ophthalmological, or musculoskeletal findings. Enhanced recognition of atypical presentations is critical to facilitate earlier diagnosis, guide management, and enable cascade testing for at-risk family members.

Background: Inflammation forms an important part of the human innate immune system and is largely dependent on the activation of the "classical" NF-κB pathway through Toll-like receptors (TLRs). Understanding this has allowed researchers to explore roles of therapeutic targets in managing conditions such as sepsis. Recapitulating an inflammatory response using lipopolysaccharide (LPS), a "sterile" technique, can provide information that is dissimilar to the clinical condition. By examining NF-κB activation (through immunoblotting of the p65 subunit) in two separate cell lines (murine and human) and analyzing two murine models of sepsis (intraperitoneal [IP] LPS and IP stool inoculation), an evaluation of the translational disconnect between experimental and clinical sepsis can be made. Methods: THP-1 (human) cells and RAW 264.7 (murine) cells were dosed with concentrations of LPS (human, 1 pg/mL to 100 ng/mL; murine, 30 pg/mL to 1,000 ng/mL) and nuclear actin and p65 were immunoblotted to measure changes in nuclear density. In vivo, C57BL/6 mice received either IP injection of stool suspension (5 µL/g ) or LPS (25 mg/kg) or saline (1 mL/kg). Animals were culled at 6 hours and tissues were analyzed. Results: An increase in basal p65:actin density in THP-1 cells (mean 0.214, standard error of the mean 0.024) was seen at doses as small as 0.1 ng/mL (0.519±0.064). In contrast to RAW 264.7 cells, basal increases (0.170±0.025) were only seen when a dose of 3 ng/mL (0.387±0.078) was used. Dose–response analysis of p65:actin ratio showed that THP-1 cells respond to lower doses of LPS than RAW 264.7 cells and lower doses produce a greater fold increase in the nuclear p65 density. Both in vivo models showed evidence of neutrophil (NL) recruitment into tissues (which was more intense after LPS treatment). IP stool inoculation resulted in an acute suppurative peritonitis and more substantial evidence of NL recruitment into adipose tissue and skeletal muscle. Conclusion: Our results support previous observations that translation of murine models into the human clinical setting suffers from considerable limitations including species-associated differences in LPS response seen at a molecular level. Furthermore, the histopathological changes during clinical sepsis cannot be adequately reproduced by injection of LPS. Therefore, the so-called translational disconnect that exists between murine LPS models and human sepsis involves NF-κB activation at a molecular level and is further augmented by the use of LPS as a stimulus for infectious responses in vivo.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency, leading to the accumulation of globotriaosylceramide (Gb3) and progressive damage to the cardiovascular, renal, and cerebrovascular systems. This study aimed to assess real-world clinical outcomes in FD patients, focusing on predominantly cardiovascular (CV), but also severe renal, and cerebrovascular outcomes, as well as CV and all-cause mortality. It also explored associations between age at diagnosis, Mainz Severity Score Index (MSSI), genetic mutations, and cardiometabolic risk factors such as smoking, hypertension, and obesity. A retrospective observational cohort study of 405 patients with FD was conducted by reviewing medical records from a National Centre over a 20-year period. Clinical outcomes, predominantly cardiovascular, but also severe renal and cerebrovascular events and mortality were assessed. Age at diagnosis, MSSI, and cardiometabolic risk factors were also evaluated. Statistical comparisons were performed using the Mann-Whitney U test and Chi-square test, with significance set at p < 0.05. Nearly half (48 %) of patients experienced a defined clinical outcome. Higher age at diagnosis and baseline MSSI was observed in patients with poorer outcomes. The c.644 A > G (p.N215S) variant was linked with increased cardiovascular morbidity and mortality. Cardiometabolic risk factors such as smoking, hypertension, and obesity were common in patients with poorer outcomes. A high prevalence of arrhythmia, including paroxysmal atrial fibrillation (AF), was observed. Multi-morbidity was noted in deceased patients. Use of cardiometabolic therapies in at-risk groups (e.g. sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists) was low. This study highlights the clinical burden of FD, particularly among males with the c.644 A > G (p.N215S) variant. The frequent presence of cardiometabolic risk factors in patients with adverse outcomes reinforces the importance of early diagnosis, comprehensive risk evaluation, and individualised management to improve long-term prognosis.

Background: The widely automated method using indirect ion specific electrodes (ISE) potentiometry for determination of sodium concentration is prone to interference from lipaemia. Manufacturer-specified lipaemic (L)-index cut offs may underestimate the effects of endogenous lipaemia. Methods: We assessed the interference on sodium concentration caused by endogenous lipaemia in 32 residual samples (from 13 patients) using indirect ISE (Cobas ^® 8000 modular analyser with c702 module, Roche diagnostics) and direct ISE (GEM 4000 premier, Werfen) potentiometric methods. Regression analysis (linear and non-linear) was used to determine a reliable (L)-index cut off for reporting sodium concentration. Results: There was a poor correlation observed between triglyceride concentration and (L)-index. There was significant negative interference caused by endogenous lipaemia within analysed samples. Non-linear regression demonstrated a negative interference of approximately 5% at an (L)-index of 250. Conclusion: At present, the manufacturer advises not to report sodium concentration by indirect ISE on the Cobas ^® 8000 modular analyser if the (L)-index is >2000. However, this has been determined by the addition of exogenous lipids (Intralipid ^® ) and it is clear that this is not comparable to endogenous lipaemia. To ensure patient safety, clinical laboratories should consider lowering the cut off for (L)-index that they use for reporting sodium concentration.