Patients have a homozygous missense mutation in the ACER3 gene that encodes the enzyme, alkaline ceramidase 3 that catalyzes the hydrolysis of specific ceramide species (C18:1/C18:1 and C18:1/C18:0) into sphingosine and free fatty acids (oleic acid and stearic acid). The mutation inactivates the catalytically function of ACER3, thus increasing the levels of ceramides (the substrates of ACER3) in cells, such as neurons and other brain cells. Ceramides not only act as bioactive lipids to mediate cell death but also serve as precursors of complex sphingolipids, important components of the myelin sheath. Increased ceramides may cause death of neurons and impair myelination, thereby leading to neurodegeneration and leukodystrophy. Diagnostic testing can be done by measuring enzymatic activity of ACER3 in peripheral blood mononuclear cells (PBMC).
ACER3