ライソゾーム病

Gaucher disease is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of acid beta-glucocerebrosidase (Enzyme Commission 3.2.1.45). Its clinical presentation is polymorphic, dominated by hepatosplenomegaly and cytopenias, and may mimic a malignant hematologic disorder or a chronic infection. This is a clinical case report compiled in the pediatrics department of the Yalgado Ouédraogo University Hospital Center. The patient was a four-year-old boy with a history of chronic malnutrition and multiple hospitalizations in various hospitals across the country. He was admitted for abdominal distension that had been present for two years, associated with recurrent epistaxis and severe bicytopenia. Clinical signs on admission included good general condition, pallor of the skin and mucous membranes, and hepatosplenomegaly. Laboratory findings revealed bicytopenia on the complete blood count and hyperproteinemia. The progression to pancytopenia led to the performance of a myelogram, which revealed numerous foam cells resembling Gaucher cells, raising suspicion of a constitutional lysosomal storage disorder. Enzyme assay confirmed a glucocerebrosidase deficiency, leading to a diagnosis of Gaucher disease type 1. Treatment was symptomatic, and the patient died the day before the enzyme assay results were received, eighty-four days after his initial admission to our hospital. This case illustrates the difficulties and consequences of delayed diagnosis in countries with limited resources and technical capabilities.

INTRODUCTION: Enzyme replacement therapy (ERT) is the standard treatment for patients with Pompe disease, a hereditary metabolic myopathy. While ERT in the home situation is increasingly common in adults with Pompe disease, experience in children remains limited due to higher dosing requirements and increased risk of infusion-associated reactions (IARs). We analysed the results of the in-hospital and home-based infusion programme applied in the Netherlands to children since 1999 to provide guidance. METHODS: We studied hospital and home-based infusions administered to children with Pompe disease (i.e., classic infantile, atypical infantile, and childhood onset phenotypes) who started ERT between 1999 and 2022 and analysed the characteristics of patients and IARs. The IARs were graded by healthcare providers. RESULTS: A total of 11,898 infusions with recombinant human α -glucosidase (rhGAA) were administered in 52 Pompe patients (27 classic infantile, two atypical infantile and 23 childhood onset phenotypes). Of these, 5278 infusions (44.4%) were given in hospital and 6620 (55.6%) were administered at home. IARs occurred in 458 hospital infusions (8.7%) and 110 home infusions (1.7%). The majority of IARs (87.1%) occurred in patients with the classic infantile phenotype. Most IARs were mild; only 21 severe IARs were reported, two of which occurred at home. All IARs could be managed adequately. CONCLUSION: Recombinant human α-glucosidase can be safely administered at home using our protocol in children with Pompe disease, including those with classic infantile Pompe disease who are more likely to develop IAR, provided that in-hospital treatment has been shown to be safe, and the appropriate infrastructure and clinical support are in place.

Lucerastat is an iminosugar with the potential to provide substrate reduction therapy for the treatment of Fabry disease (FD), an inherited X-linked lysosomal storage disorder. The aims of this study were to develop a population pharmacokinetic (PK) model describing lucerastat plasma concentration over time, to investigate the relationships between subject-specific characteristics and model parameters, and to assess the influence of these differences between subjects on lucerastat exposure via model-based simulations. Longitudinal nonlinear mixed effects modeling was applied to develop a model based on data from 250 participants in six Phase 1 and two Phase 3 studies. Lucerastat pharmacokinetics were described by a two-compartment model with linear first-order absorption and elimination, including allometric scaling of body weight on clearance and volume parameters. Lucerastat clearance was reduced in subjects with lower estimated glomerular filtration rate (eGFR). Disease status (with/without FD) was found to impact clearance and volumes of distribution to a limited extent. The model described the data well across the dose range from 100 to 4000 mg. Body weight, disease status, and renal function were shown to influence exposure, with dose adaptation only required in patients with renal function impairment, as body weight and disease status had limited impact. Dose adaptation as applied in Phase 3 (i.e., eGFR [mL/min/1.73 m2] ≥60: 1000 mg; ≥45 and <60: 750 mg; ≥30 and <45: 500 mg; ≥15 and <30: 250 mg b.i.d.) resulted in achieving similar exposure in study participants with FD with different levels of renal function impairment.

Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca2+/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.

BACKGROUND: Leukodystrophies are inherited disorders that primarily affect the central nervous system white matter and often present with nonspecific symptoms, making early diagnosis difficult. Magnetic resonance imaging (MRI) is the key initial imaging test because it reveals characteristic myelin patterns that can guide biochemical and genetic workups. OBJECTIVE: To review clinically useful MRI and MR spectroscopy (MRS) patterns in major leukodystrophies and emphasize their diagnostic relevance using a practical, pattern-recognition approach. METHODS: Narrative review of the literature integrating conventional MRI, including T1/T2 fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI), as well as advanced techniques (MRS), with a pictorial, case-based approach. RESULTS: The pivotal imaging distinction is between hypomyelination-diffuse, persistent T2/FLAIR hyperintensity with relative temporal stability and absent enhancement-and demyelination, characterized by confluent, progressive lesions with disorder-specific topographic predilection. Recognizable signatures include U-fiber sparing and a tigroid pattern in metachromatic leukodystrophy (MLD); parieto-occipital predominance with trizonal enhancement and restricted diffusion in X-linked adrenoleukodystrophy (X-ALD); frontal predominance and the "tadpole sign" in Alexander's disease; optic pathway and thalamic involvement in Krabbe's disease; markedly elevated N-acetylaspartate (NAA) on MRS in Canavan's disease; and tract-selective leukoencephalopathy brainstem/spinal cord involvement with a lactate peak (LBSL). These imaging clues refine differential diagnosis, guide targeted genetic testing, and support longitudinal monitoring. CONCLUSION: The use of MRI-especially when complemented by DWI and MRS-remains central for early recognition and classification of leukodystrophies. A structured, pattern-based approach integrating clinical context with imaging topography can reduce diagnostic delay and support timely management.