Ed Wraith

Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.

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.

Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece

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.

The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK

BackgroundMucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease subdivided into three phenotypes of increasing severity: Scheie, Hurler-Scheie and Hurler. To gauge the effectiveness of treatments and to determine the load likely to fall on health-care systems, it is necessary to understand the prevalence and natural progression of the disease especially with regard to life-expectancy. In general such data on the natural history of lysosomal storage diseases is sparse.MethodsAnalysis of prevalence and patient survival in MPS I disease using a unique longitudinal data set initiated and maintained over a period of more than 20 years by the Society for Mucopolysaccharide Diseases (UK).ResultsThe birth prevalence of MPS I in England and Wales over the period 1981 to 2003 was 1.07/100,000 births and within ± 5% of estimates reported in several studies that examined reasonably large populations. The median survival for MPS I patients (including all phenotypes irrespective of various treatments) was found by Kaplan-Meier analysis to be 11.6 years. This result was driven by the relatively poor survival of patients with the Hurler phenotype who, irrespective of any treatments received, had a median survival of 8.7 years; when censoring for receipt of bone marrow transplant (BMT) was implemented median survival of Hurler patients was diminished to 6.8 years. The difference between these survival curves was statistically significant by log rank test and can be attributed to beneficial effects of BMT and or selection of patients with superior prognosis for intervention with BMT. Survival curves for Hurler patients who received and did not receive BMT were very different. Probability of survival at 2 year after BMT was ~68% and was similar to this after 5 years (66%) and ten years (64%); the mean age of Hurler patients at receipt of BMT was 1.33 years (range 0.1 to 3 years). Follow up was insufficient to determine median survival of the milder phenotypes however, unsurprisingly, this was clearly superior to that for Hurler patients.ConclusionThe birth prevalence of MPS I in England and Wales is 1.07/100,000 and the median survival for MPS I patients is 11.6 years.

Craniovertebral abnormalities in Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome).

INTRODUCTIONThe craniovertebral abnormalities found in patients with Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome) are described, and the indications for and outcomes of surgery in this group are assessed. METHODSThe clinical histories and radiological findings in all patients with Type VI mucopolysaccharidosis treated at Royal Manchester Children’s Hospital during the past 10 years were reviewed. RESULTSThe typical findings in patients with this disease are of canal stenosis at the level of the foramen magnum and upper cervical spine with or without cord compression. The stenosis is secondary to thickening of the posterior longitudinal ligament. Atlantoaxial instability is rare. Of nine patients under regular clinical review, four underwent decompressive surgery for cervical cord compression. Three of the four showed improvement in their neurological symptoms and signs postoperatively. Of the children reviewed, six had radiological evidence of cord compression, although only those with neurological signs or symptoms were treated surgically. DISCUSSIONDespite the often formidable anesthetic challenge, surgery is indicated in those patients who present with progressive neurological deficit due to cervical myelopathy. Surgery can be undertaken safely if the associated medical problems in these children are recognized and managed appropriately.

Laronidase treatment of mucopolysaccharidosis I.

The lysosomal storage disorder (LSD) mucopolysaccharidosis type I (MPS I, McKusick 25280, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome) is caused by a deficiency in the lysosomal enzyme, α-L-iduronidase (EC 3.2.1.76). MPS I patients can present within a diverse clinical spectrum, ranging from classical Hurler syndrome to attenuated Scheie syndrome. Laronidase (Aldurazyme®) enzyme replacement therapy has been developed as a treatment strategy for MPS I patients and has been approved for clinical practice. Here we review the pre-clinical studies and clinical trials that have been used to demonstrate that intravenous laronidase therapy is well tolerated and effective for treating MPS I patients who do not have neuronal pathology. Current challenges for a viable treatment strategy for all MPS I patients include development of an early screening protocol that identifies patients before the onset of irreversible pathology, methods to predict disease severity, appropriate treatment for neuropathology, and an effective patient monitoring regimen.

Anthony H. Futerman, Ari Zimran: Gaucher Disease

Futerman and Zimran deserve praise for this comprehensive book on Gaucher disease. The volume details not only the basic science behind the condition, together with the latest treatment modalities and the direction of new research, but also includes a patient and biotechnology perspective resulting in the Wrst truly comprehensive review of the disorder. The condition is rare but important. It is the best example of an orphan disease in which interest from basic scientists has persuaded the biotechnology industry to invest and develop a highly eVective therapy. The resulting Wnancial success of CeredaseTM and then CerezymeTM (Genzyme Corporation) allowed the company to reinvest and develop other enzyme replacement therapies and also encouraged other biotechnology companies into what is becoming a very competitive market. The scale of revenue generated mainly by enzyme replacement therapy is very large indeed with Genzyme’s reported (unaudited) revenue for 2006 being a staggering

Update on mucopolysaccharidosis type II.

3.2 billion. This is an amazing success story for an organisation which was a small start-up company in 1981, when it Wrst became interested in Gaucher disease, to one which now employs over 9,000 staV worldwide. The editors are at the forefront of research and treatment in Gaucher disease and have attracted an outstanding list of contributors resulting in an authorative and stimulating text which has something to attract anyone who professes an interest in this area. Clinicians, laboratory staV, patient advocates and representatives of the pharmaceutical industry will all beneWt from dipping into this book. The tone is set by Roscoe Brady, a true pioneer in this area, in his introductory chapter which sets the scene. There next follows a series of chapters on the cell biology, cell and molecular pathology and the biochemistry of the disease. Although complex the chapters are written in such a way as to be understandable by even the simplest clinicians! If some of the Wgures in the chapter on “Pathologic anatomy of Gaucher disease” could have been in colour this section might have been more attractive as some of the pictures used do not appear to reproduce well. The matt Wnish of the illustrations in the “Imaging in Gaucher disease” chapter (Chapter 15) is also rather poor and it would have been preferable for the X-Rays to have been reproduced on glossy paper. These are only minor criticisms as many of the other illustrations within the text are of very high quality. The real strength of the book lies in the clinical sections which are superb. All the chapters are well written and uniform in style. There are comprehensive chapters on both neuronopathic and non-neuronopathic Gaucher disease and the treatment of the disorder with both enzyme replacement therapy and substrate reduction therapy is given a thorough airing. Chapters 10 and 11 on type I Gaucher disease and neuronopathic Gaucher disease respectively are especially good. These chapters are up to date with recent references and contain a wealth of information and advice for treating clinicians. This section is completed by an introduction to pharmacological chaperone therapy by Desnick and Fan and after reading all the sections on therapy one is left with a feeling of excitement E. Wraith (&) Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Pendelbury, Manchester, M27 7HA, UK e-mail: ed.wraith@cmmc.nhs.uk

Mucopolysaccharidoses and the Eye

Mucopolysaccharidosis type II (MPS II) is caused by a deficiency of the enzyme iduronate-2-sulphatase (IDS) and is associated with a broad spectrum of clinical phenotypes. Predicting the clinical course of the disease is important so that we can initiate timely and appropriate treatment and monitor progress with realistic expectations. Although, in general, two main forms can be identified (severe and attenuated) there are many intermediate forms and evaluation of severity is complicated by the rarity of the disease, the young age of patients at diagnosis and the lack of a standardized severity scoring index. Our current understanding of the clinical signs and symptoms of MPS II, the effects of therapy and relationship between phenotype and genotype in patients with the disorder were discussed in detail in the session Update on MPS II. As a result of the rare nature of the MPS disorders in humans, the study of animal models of these diseases offers important insights, as is explained by Mark Haskins in a paper reviewing the contribution of such models to this field. Not only do MPS animal models show similar clinical signs to human patients and lesions within the same organ systems, but animals can be bred in considerable numbers within a controlled environment, allowing thorough analyses of these manifestations. Of the existing animal models, larger species, such as the dog and cat, are particularly useful as, like humans, these animals are relatively long-lived, making them suitable for study over a long sample period. In addition to detailed investigation of disease manifestations, such models enable us to evaluate the efficacy and safety of current and novel therapies. This is particularly important for the MPS family of diseases, where the considerable heterogeneity of manifestations makes it likely that a combination of treatment approaches will be required for optimum benefit. One approach to predicting disease severity, illustrated in the paper by Ida Schwartz, Roberto Giugliani and colleagues, is to identify the early clinical differences between patients who go on to develop severe and attenuated forms of the disease. As part of a large observational study of 77 South American patients, these authors report that symptoms typically present earlier in patients with the severe form, leading to poor cognitive development and problematic behaviour during childhood. In addition, some manifestations, such as high levels of urinary glycosaminoglycans and deafness, are more common in patients with severe disease, whereas others, such as delay in motor and language development, may be reported in both forms, indicating that they may not be good indicators of disease severity. As has been shown for other lysosomal storage diseases, irrespective of disease severity, there is a significant delay between the onset of signs and symptoms, and diagnosis. This likely reflects a lack of awareness among physicians of the early manifestations of this rare disease. It has been proposed that it may be possible to correlate genotype – the specific disease-causing mutation – with disease severity in some patients with MPS II. Genotype– phenotype correlations were discussed by Roseline Froissart, Irène Maire and colleagues, who studied alterations of the IDS gene in 155 European patients. In total, 96 different mutations were observed. All patients with large gene alterations presented with the severe form of the disease. The majority of patients had small gene alterations, including small nucleotide deletions or insertions, deletions or insertions leading to frameshift and small in-frame deletions. In these patients, the spectrum of clinical severity was much broader than in those with large gene alterations. Although in many cases, knowledge of both the phenotype and the genotype allowed the authors to speculate about the biochemical processes that influence the severity of phenotype, no specific correlations could be found in this population of patients. The effects of specific mutations are, therefore, difficult to predict. Enzyme replacement therapy (ERT) and other specific treatments for MPS II are now in development, and in many cases, their efficacy relies upon early initiation. Although genotype–phenotype correlations may be difficult to establish, with the advent of these therapies they may be of increasing importance in choosing the most appropriate treatment for individual patients. Together, these papers highlight the importance of the ongoing research into MPS II and other LSDs. They also demonstrate the extreme clinical heterogeneity of MPS II and the need for establishing guidelines for diagnosis, followup and treatment of patients. With ERT for MPS II now approved in the USA and Europe, we are optimistic that there will soon be available an effective treatment for alleviating symptoms and improving quality of life in patients with this debilitating disorder.