Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Infantile ceramidase deficiency (Farber disease) is an uncommon, progressiv e lysosomal storage disease characterized by multiple ceramide-containing n odules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varyin g degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marr ow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-mont h-old female with minimally symptomatic Farber disease who received a pre-t ransplant regimen of busulfan and cyclophosphamide, Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (don or heterozygote level) by 6 weeks after BMT, By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoars eness had resolved. Despite modest gains in cognitive and language developm ent, hypotonia and delayed motor skills persisted. Gradual loss of circulat ing donor cells with autologous hematopoietic recovery occurred; VNTR analy ses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramid ase activity consistently remained in the heterozygous range despite attrit ion of donor cells in peripheral blood. This novel observation indicates on going hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological a nd neurocognitive status progressively declined. She died 28 months after B MT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspir ation pneumonias. Allogeneic BMT improves the peripheral manifestations of infantile ceramidase deficiency, but may not prevent the progressive neurol ogical deterioration, even when carried out in minimally symptomatic patien ts.