Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4–9 months.

SummaryWe explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first-line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second-line therapy with unrelated donor HSCT post-failed IST (n = 24). The 2-year overall survival in the upfront cohort was 96 AE 4% compared to 91 AE 3% in the MSD controls (P = 0Á30) and 94 AE 3% in the IST controls (P = 0Á68) and 74 AE 9% in the unrelated donor HSCT post-IST failure controls (P = 0Á02).The 2-year event-free survival in the upfront cohort was 92 AE 5% compared to 87 AE 4% in MSD controls (P = 0Á37), 40 AE 7% in IST controls (P = 0Á0001) and 74 AE 9% in the unrelated donor HSCT post-IST failure controls (n = 24) (P = 0Á02). Outcomes for upfront-unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post-IST failure. Front-line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first-line therapy in selected paediatric patients who lack a MSD.

A substantial number of individuals with bone marrow failure (BMF) present with one or more extra-hematopoietic abnormality. This suggests a constitutional or inherited basis, and yet many of them do not fit the diagnostic criteria of the known BMF syndromes. Through exome sequencing, we have now identified a subgroup of these individuals, defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21). They present with global BMF, and one individual developed a hematological cancer (acute myeloid leukemia) in childhood. We show that the encoded protein associates with rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid cells obtained from an affected individual exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced amounts of rRNA. Characterization of mutations revealed impairment in interactions with cofactors (PA2G4, HSPA8, and ZNF622) involved in 60S maturation. DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death. Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.

Little information is currently available regarding the pharmacokinetics of busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of intravenous busulfan in infants and children weighing less than or equal to 12kg, that would achieve targeted exposure with the first dose of busulfan. Population pharmacokinetic modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of busulfan in 149 patients from 8 centers. Busulfan pharmacokinetics were well described by a 1-compartment base model with linear elimination. The important clinical covariates impacting busulfan pharmacokinetics were actual body weight and age. Based on our model, the predicted clearance of busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants less than 5 months of age, the model-predicted doses (mg/kg) required to achieve the therapeutic Css range of 600–900 ng/mL (AUC range = 900–1350 uM·min) were much lower compared to standard busulfan doses of 1.1mg/kg. These results could help guide clinicians and inform better dosing decisions for busulfan in young infants and small children undergoing hematopoietic cell transplantation.

SummaryAllogeneic haemopoietic stem cell transplantation offers a potentially curative treatment option for a wide range of lifethreatening malignant and non-malignant disorders of the bone marrow and immune system in patients of all ages. With rapidly emerging advances in the use of alternative donors, such as mismatched unrelated, cord blood and haploidentical donors, it is now possible to find a potential donor for almost all patients in whom an allograft is indicated. Therefore, for any specific patient, the transplant physician may be faced with a myriad of potential choices, including decisions concerning which donor to prioritize where there is more than one, the optimal selection of specific umbilical cord blood units and which conditioning and graft-versus-host disease prophylactic schedule to use. Donor choice may be further complicated by other important factors, such as urgency of transplant, the presence of alloantibodies, the disease status (homozygosity or heterozygosity) of sibling donors affected by inherited disorders and the cytomegalovirus serostatus of patient and donor. We report UK consensus guidelines on the selection of umbilical cord blood units, the hierarchy of donor selection and the preferred conditioning regimens for umbilical cord blood transplantation, with a summary of rationale supporting these recommendations.Keywords: stem cell transplantation, haematological malignancies, paediatric haematology, umbilical cord blood.Umbilical cord blood (UCB) is an established alternative source of haematopoietic stem cells (HSC) for allogeneic transplantation when suitable human leucocyte antigen (HLA)-matched sibling or well matched unrelated donors are unavailable. Over 35 000 UCB transplants have now been performed worldwide and there are over 630 000 cord blood units (CBU) currently stored in international cord blood blanks. The emerging experience of umbilical cord blood transplantation (UCBT) and, more recently, haploidentical donor transplants have extended access to HSC transplantation (HSCT) in almost all those previously precluded. Consequently, the optimal selection of a donor or specific CBU for an individual patient has become increasingly complex.Here we report new UK consensus recommendations for the method of selection of individual UCB units, the role of cord blood transplantation (CBT) within an overall donor selection strategy and the choice of conditioning regimens for CBT. These recommendations are primarily based on retrospective comparative studies and expert opinion given the lack of randomized trials comparing different donor choices. Cord blood transplantation in the UKThe inclusion of UCBT into routine practice in the UK was initially slow, despite the early establishment of the London Cord Blood Bank in 1996. The reasons for this included lack of a national strategy, lack of clinical trials, concern regarding the safety of UCBT in adults prior to 2004 and well Correspondence: BCSH secretary, British