Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMD). We examined the outcome of children with IMD received first HCT at Royal Manchester ChildrenÕs hospital from 1985 to 2016, a national metabolic transplant center in the United Kingdom. Cox proportional-hazard models were used to examine the predictors for overall survival. 137 children with IMD were included in this analysis (historical cohort (1985-2006), n = 65; current cohort (2007-2016), n = 72). Primary diagnoses were mucopolysaccharidoses (MPS, n = 112, 81%; MPS IH, n = 103, MPS II, n = 1, MPS III = 2, MPS VI = 6), X-linked adrenoleukodystrophy (XALD, n = 8, 6%), metachromatic leukodystrophy (n = 5, 4%), alpha mannosidosis (n = 4, 3%), Wolman disease (n = 3, 2%) and others (n = 5, 4%). The median age at transplant was 14.4 (range 1.6-220.7) months. Fifty-four children (40%) received relative donor HCT (marrow, n = 43 (78%), apheresis, n = 11 (20%) and cord blood (CB) = 2 (2%)) while 83 (60%) had unrelated donor HCT (marrow, n = 31 (37%), apheresis, n = 9 (11%) and CB, n = 43 (52%)). The estimated 5-year OS improved from 65% (95% CI, 53-76%) in the historical cohort to 91% (95%CI, 81-96%) in the current cohort (P < .001). Male (HR .35, 95%CI, .15-.81, P = .01) and grade III-IV GVHD (HR 5.10, 95%CI, 1.72-15.14, P = .003) were predictors for overall survival. In current cohort, none of the pre-transplant factors, transplant factors and transplant related complications were associated with OS. The estimated 5-year OS in children transplanted in the current cohort was 100% for XALD (n = 5), 98% (95% CI, 83%-98%) for MPS IH (n = 55) and 75% (95% CI, 42-92%) for other IMD. The estimated one-year TRM reduced from 23% (95% CI, 13-40%) in the historical cohort to 7% (95% CI, 3-18%) for current cohort (P = .006). The estimated 5-year engrafted survival (ES) has doubled from 41% (95% CI, 29-53%) in the historical cohort to 86% (95% CI, 75-92%) in the current cohort (P < .001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P < .001). Thirteen out of 18 patients (71%) in the historical cohort and all four patients (100%) in the current cohort receiving a second transplant were alive-and-engrafted. Of 82 survivors followed up at Manchester, 80% had full chimerism (_95% donor chimerism) while 20% had mixed chimerism (20-94% donor chimerism). Despite the limitation of a single centre, our findings reiterated the observation of HCT is a safe and life-long therapy for children with IMD. The outcome of a second transplant is good.

Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype.To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006.All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review.We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease.With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.

We report of a family who has three members affected by medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, one of whom sadly died in the neonatal period prior to diagnosis. Routine sequencing, available on a service basis in the UK, identified only a heterozygous mutation in ACADM gene (c.985A>G, p.Lys329Glu) in this family. Linkage analysis suggested a possible intragenic deletion which was confirmed by the use of array-based comparative genomic hybridization (aCGH). This second mutation was a large intragenic deletion encompassing at least exons 1-6 of the ACADM gene. Now that this deletion has been identified, several family members have come forward for carrier testing which was not possible previously. Larger deletions (20bp or more) have only previously been reported twice, but these may be a more frequent cause of MCAD deficiency than hitherto believed, due to fact that these are not anticipated and, therefore, the routine diagnostic techniques used will not identify them. This finding represents a useful learning point in the management of families with MCAD deficiency, and highlights that we should be routinely looking for larger deletions, when only one of the mutations can be identified on standard sequencing.

We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.

Abstract Abstract 1958 Background: Hurler syndrome (HS), the most severe phenotype in the spectrum of Mucopolysaccharidosis type I, is caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. HS is clinically characterized by a progressive and ultimately fatal multi-system deterioration with involvement of the central nervous system. At present, hematopoietic stem cell transplantation (HSCT) is the only treatment that prevents disease progression in the central nervous system and is therefore considered the treatment of choice in HS. Long-term follow-up of outcomes of HSCT for HS are sparse and risk factors for favorable long-term outcomes are still largely unknown. Therefore, an international multicenter study was initiated to describe the long-term outcomes of successfully transplanted HS patients. Methods: HS-patients transplanted between 1980 and 2007 within the leading transplantation centers in Europe and the United States were include in this study. Patient, donor, and transplantation-related variables which may influence long-term outcome were analyzed. Patients who were ‘alive and engrafted (donor-chimerism >10%)’ with a follow up of at least three years after HSCT were included. The functional outcomes assessed for the various organ systems - orthopedic, cardiac, ophthalmologic, respiratory and audiologic - were analyzed using multivariate Cox proportional hazards and logistic regression models. Results: 197 Hurler patients were included from 8 different transplant centers. This is estimated to be about 70–80% of the successfully transplanted HS patients worldwide during that time period. These patients had a median age of 16 (2–80) months at HSCT with a median follow up of 88 (36–258) months after successful HSCT. Seventy-nine % of the patients received a graft from an unaffected (non-carrier) donor. Seventy-two % of the patients achieved full (>95%)-donor-chimerism and 28% mixed-chimerism. After HSCT, normal enzyme-levels (EL; according to the local reference range) were found in 75% of the patients while 25% had EL below lower limit of normal; either due to mixed-chimerism or carrier-donorship). Multivariate analyses (table 1) showed having a “normal EL” after HSCT and younger (below the median age of 16mths) “age at transplantation” were associated with less serious orthopedic complications requiring surgical interventions; e.g. cord compression, genu-valgum surgery, carpal tunnel surgery. Genotype (double non-sense vs. any other genotype) was associated with a lower probability of requiring hip dysplasia surgery as well as with the occurrence of retinopathy. For other endpoints; e.g progression valve insufficiency, progression corneal clouding and development of retinopathy and the need for hearing aids having a normal EL as well as age at HSCT (<16mths) were predictors for better outcome. Furthermore, growth at the age of 60mths was influenced by EL (−1.93 SDS vs. −1,09 SDS; p=0.042). Conclusion: The long-term outcome of clinical manifestations in HS-patients after successful HSCT is promising although residual disease burden remains. Predictors, favorably influencing the long-term outcomes are suggested to be 1) enzyme level (normal vs. below LLN) after HSCT, 2) genotype and 3) age at HSCT. Achieving normal enzyme levels at an early age might significantly impact the prognosis of Hurler syndrome patients. Newborn screening (resulting in early HSCT), the use of non-carrier donors and achieving full-donor chimerism may be crucial in optimizing long-term outcomes. Disclosures: No relevant conflicts of interest to declare.

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPSIII) is a lysosomal storage disease with predominant neurological manifestations in affected children. It is considered heterogeneous with respect to prevalence, clinical presentation, biochemistry (four biochemical forms of the disease referred to as MPSIIIA, B, C, and D are known), and causative mutations. The perspective of therapeutic options emphasizes the need for better knowledge of MPSIII incidence and natural history. We performed parallel retrospective epidemiological studies of patients diagnosed with MSPIII in France (n = 128), UK (n = 126), and Greece (n = 20) from 1990 to 2006. Incidences ranged from 0.68 per 100,000 live-births in France to 1.21 per 100,000 live-births in UK. MPSIIIA, which predominates in France and UK, was absent in Greece, where most patients have MPSIIIB. The study confirmed the large allelic heterogeneity of MPSIIIA and MPSIIIB and detected several yet undescribed mutations. Analysis of clinical manifestations at diagnosis and over a 6-7 years follow-up indicated that almost all patients, whatever the disease subtype, expressed neurological manifestations before the age of 5 years, including language acquisition delay, cognitive delay, and/or abnormal behavior. In contrast to relatively homogeneous early onset manifestations, disease progression showed significant variation depending on subtype and age at diagnosis. Different severities of disease progressions and different allele distribution between France and UK suggested that mutations are not equally deleterious, although genotype-phenotype correlation could not be established. Notwithstanding the rapidity of further clinical deterioration, all MPSIII patients suffer early onset devastating neurological manifestations that deserve early treatment when available.

Adverse drug interactions due to grapefruit juice are well known prompting warnings even in drug labels. Similar issues have not been reported for clementines and available data is scarce, despite of genetic descent. We observed substantially increased tacrolimus trough concentrations in a renal transplant patient consuming high clementine amounts and, thus, scrutinised the effects of clementine juice on drug metabolism and drug transporters in vitro and compared it to the effects of mandarin and grapefruit juice. All citrus juices profoundly induced several drug transporters and drug metabolising enzymes, whereas the effects of grapefruit juice were most pronounced (e.g. 156-fold and 34-fold induction of cytochrome P450 (CYP) 3A4 mRNA by grapefruit juice and clementine juice, respectively). However, the juices also inhibited e.g. CYP3A4, raising the question which effect prevails in vivo. Using an enzymatic activity assay, we demonstrated that at least in vitro CYP3A4 inhibition prevails for both grapefruit and clementine juice, whereas for CYP1A2 induction appears to predominate. Thus, inhibition of CYP3A4 is presumably the underlying reason for the observed increase in the concentrations of the CYP3A4 substrate tacrolimus in the patient. Taken together, our data indicate that clementine juice as well as grapefruit juice and to a lesser extent also mandarin juice can induce several important drug metabolising enzymes and drug transporters, but also inhibit some of these proteins. Our data indicate that clementine juice similar to grapefruit juice bears the potential for profound interactions with drugs potentially leading to adverse drug effects e.g. through over-exposure to CYP3A4 substrates.

American Journal of Medical Genetics Part AVolume 155, Issue 1 p. fm i-fm iv Table of ContentsFree Access Table of Contents, Volume 155, Number 1, January 2011 First published: 22 February 2011 https://doi.org/10.1002/ajmg.a.33889AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume155, Issue1January 2011Pages fm i-fm iv RelatedInformation

The Niemann–Pick disease group is now divided into two distinct entities: (1) acid sphingomyelinase-deficient Niemann–Pick disease (ASM-deficient NPD) resulting from mutations in the SMPD1 gene and encompassing type A and type B as well as intermediate forms; (2) Niemann–Pick disease type C (NP-C) including also type D, resulting from mutations in either the NPC1 or the NPC2 gene. Both Niemann–Pick diseases have an autosomal recessive inheritance and are lysosomal lipid storage disorders, with visceral (type B) or neurovisceral manifestations. The clinical knowledge is updated taking into account recent surveys in large cohort of patients, particularly for type B and type C. The diagnosis of NP-C is often delayed due to the wide spectrum of clinical phenotypes. Systemic manifestations, if present, always precede onset of neurological manifestations. Most common neurological signs are vertical supranuclear gaze palsy, cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures, and dystonia are other common features of NP-C. For both ASM-deficient NPD and NP-C, strategies for laboratory diagnosis of patients and prenatal diagnosis are discussed. Recent progress towards enzyme replacement therapy in type B patients and management of the neurological disease in type C patients are finally highlighted.