2025-08-08 | Farber's Lipogranulomatosis: Multimodal Therapy With Tocilizumab and Consolidative HSCT Improves Assessment, and Long-Term Outcome.
Farber's lipogranulomatosis (FL) is an autosomal recessive lipid storage disorder, arising as a consequence of genetic acid ceramidase deficiency. Clinically, it presents as severe arthritis, voice hoarseness, and widespread, painful subcutaneous nodules (SCN). For those without CNS involvement, haematopoietic stem cell transplant provides a viable option for the improvement of both respiratory and musculoskeletal morbidity. A better understanding of macrophage-driven inflammation in FL has resulted in targeted medical therapies such as Tocilizumab being utilized in FL patients. Since FL is a rare disease, minimal guidance on how treatment modalities should be utilized is available. We describe the case of a girl with FL presenting at 15 months with severe pain, swelling, and deformity of predominantly the small joints secondary to SCNs. Critical airway narrowing from laryngeal nodules necessitated tracheostomy. Regression of motor skills was also apparent. Fortnightly tocilizumab infusions improved pain and irritability, allowing neurological evaluation and tracheostomy decannulation. It did not halt the progression of SCNs. Therefore, we completed a 10/10 matched family donor haematopoietic stem cell transplant. Post-transplant, she is stable neurologically, with resolution of her SCN, and her cognition, performance status, and well-being are considerably improved by transplant.
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2024-11-21 | Endocannabinoid receptor 2 is a potential biomarker and therapeutic target for the lysosomal storage disorders.
Herein, we studied the expression of endocannabinoid receptor 2 (CB2R), a known inflammation mediator, in several lysosomal storage disorder (LSD) animal models and evaluated it as a potential biomarker and therapeutic target for these diseases. CB2R was highly elevated in the plasma of Farber disease and mucopolysaccharidosis (MPS) type IIIA mice, followed by Fabry disease and MPS type I mice. Mice with acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) and rats with MPS type VI exhibited little or no plasma CB2R elevation. High-level expression of CB2R was also observed in tissues of Farber and MPS IIIA mice. Treatment of MPS IIIIA patient cells with CB2R agonists led to a reduction of CB2R and monocyte chemoattractant protein-1 (MCP-1), a chemotactic factor that is elevated in this LSD. Treatment of MPS IIIA mice with one of these agonists (JWH133) led to a reduction of plasma and tissue CB2R and MCP-1, a reduction of glial fibrillary acidic protein (GFAP) in the brain, and an improvement in hanging test performance. JWH133 treatment of Farber disease mice also led to a reduction of MCP-1 in tissues and plasma, and treatment of these mice by enzyme replacement therapy (ERT) led to a reduction of plasma CB2R, indicating its potential to monitor treatment response. Overall, these findings suggest that CB2R should be further examined as a potential therapeutic target for the LSDs and may also be a useful biomarker to monitor the impact of therapies.
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2024-11-18 | [Therapeutic perspectives for lysosomal storage disorders caused by acid ceramidase deficiency].
Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are two ultra-rare lysosomal storage disorders resulting from loss-of-function mutations in the ASAH1 gene encoding for acid ceramidase (ACDase). ACDase deficiency leads to the intracellular accumulation of ceramides with an inflammatory response in tissues. These two diseases manifest differently but are part of a clinical continuum with variable severity affecting the nervous system and/or peripheral tissues, including the neuromuscular system. To date, no specific or curative treatments are available for patients affected by acid ceramidase deficiency. Here, we summarize the clinical features, enzyme function, mouse models and therapeutic perspectives for these allelic diseases.
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