Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.

• Klíčová slova
• Farber disease, HSCT, Lysosomal storage disorders, central nervous system, ceramides, spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME),
• MeSH
• ceramidy metabolismus   MeSH
• Farberova nemoc * terapie   genetika   MeSH
• kyselá ceramidasa * genetika   metabolismus   MeSH
• lidé MeSH
• mícha metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myoklonické epilepsie progresivní genetika   terapie   metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Asah1 protein, mouse MeSH Prohlížeč
• ceramidy MeSH
• kyselá ceramidasa * MeSH

Acid ceramidase catalyzes the degradation of ceramide into sphingosine and a free fatty acid. Acid ceramidase deficiency results in lipid accumulation in many tissues and leads to the development of Farber disease (FD). Typical manifestations of classical FD include formation of subcutaneous nodules and joint contractures as well as the development of a hoarse voice. Healthy skin depends on a unique lipid profile to form a barrier that confers protection from pathogens, prevents excessive water loss, and mediates cell-cell communication. Ceramides comprise ~50% of total epidermis lipids and regulate cutaneous homeostasis and inflammation. Abnormal skin development including visual skin lesions has been reported in FD patients, but a detailed study of FD skin has not been performed. We conducted a pathophysiological study of the skin in our mouse model of FD. We observed altered lipid composition in FD skin dominated by accumulation of all studied ceramide species and buildup of abnormal storage structures affecting mainly the dermis. A deficiency of acid ceramidase activity also led to the activation of inflammatory IL-6/JAK/signal transducer and activator of transcription 3 and noncanonical NF-κB signaling pathways. Last, we report reduced proliferation of FD mouse fibroblasts and adipose-derived stem/stromal cells (ASC) along with impaired differentiation of ASCs into mature adipocytes.

• Klíčová slova
• Farber disease, acid ceramidase, adipogenesis, ceramides, macrophages, skin,
• MeSH
• adipogeneze MeSH
• ceramidy metabolismus   MeSH
• Farberova nemoc * MeSH
• kyselá ceramidasa genetika   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ceramidy MeSH
• kyselá ceramidasa MeSH