Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Abstract

Summary:Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying 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 marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing 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 and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT

Lysosomal storage diseases

“…The first child died within 6 months following the procedure, but another child was followed for 28 months after BMT. This later child demonstrated improvement in the peripheral manifestations of the disease, but neurologic deterioration continued [21].…”

Farber Disease — Disease Description With Case Reports

“…С одной стороны, ТКМ приводит к быстрому разрешению периферических гранулем и улучшению общего состояния ребенка, но, с другой, она не оказы-вает существенного влияния на патологический про-цесс в центральной нервной системе, что ограничивает применение этого метода лечения у тяжелых пациентов с болезнью Фарбера [17,[20][21][22][23][24].…”

“…В последующем зафиксировано умень-шение числа клеток, содержащих донорскую ДНК, до 1% к 21 мес после ТКМ при сохранном уровне активности кислой церамидазы. Однако, несмотря на это, у ребен-ка прогрессировало поражение ценральной нервной системы с развитием тяжелой нейрокогнитивной дис-функции, приведшей к гибели спустя 28 мес после ТКМ, без усиления процесса вне центральной нервной системы [22].…”

Autologous Transplantation of Lentivector/Acid Ceramidase–Transduced Hematopoietic Cells in Nonhuman Primates

“…There is no definitive treatment for Farber disease; palliative care includes corticosteroids, tracheostomies for respiration difficulties, and surgical removal of the granulomas (Haraoka et al, 1997;Levade et al, 2009). Bone marrow (BM) transplantation has resulted in some decrease of peripheral symptoms in the short term, but no neurological benefits (Souillet et al,1989;Yeager et al, 2000;Malatack et al, 2003;Vormoor et al, 2004).…”