Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I Registry

Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler-Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since laronidase became available in 2003 (gap during 2006-2009: Hurler--0.2 year, Hurler-Scheie--0.5 year, Scheie--1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler-Scheie and Scheie patients (gap during 2006-2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with laronidase (42 out of 45 patients by 2009). CONCLUSIONS: Despite the availability of laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler-Scheie and Scheie phenotypes, which can lead to a sub-optimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients.     

Enzyme replacement therapy in mucopolysaccharidosis type I

Mucopolysaccharidosis (MPS) type I is a lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase (IDUA), which presents with a wide spectrum of phenotypes. Recently, enzyme replacement therapy (ERT) became available for patients with MPS I and has been demonstrated to be safe and effective in patients with the milder Hurler-Scheie and Scheie phenotypes. Treatment for 26 weeks with recombinant human IDUA (laronidase) has been shown to significantly increase the percentage of predicted normal forced vital capacity and the distance walked in the 6-minute walk test. There was also a clear reduction in the volume of the liver and the levels of urinary glycosaminoglycan excretion. The drug was generally well tolerated. There were no drug-related severe adverse events, and although the majority of patients developed IgG antibodies, these declined by the end of the study. Conclusion: ERT seems to be a very promising new therapeutic regimen for patients with MPS I, especially for those with the less severe variants. However, as laronidase does not cross the blood-brain barrier it will probably not influence the central nervous manifestations in the most severely affected patients with the Hurler phenotype, although it may improve general lung and heart function, making bone marrow transplantation easier to tolerate.     

Mucopolysaccharidosis type I: identification of alpha-L-iduronidase mutations in Tunisian families]

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease due to mutations in the gene encoding alpha-l-iduronidase (IDUA) leading to variable clinical phenotypes with progressive severe organomegaly, bone and neurological involvement in the most severe forms. The aim of our study was to propose in Tunisia a strategy of molecular and prenatal diagnosis of the MPS I. POPULATION AND METHODS: Our study was carried out on 8 MPS I patients recruited from different Tunisian regions and issued from 5 unrelated families. All the patients were offspring of consanguineous marriages. RESULTS: The clinical and biological study led to diagnose 5 Hurler patients and 3 Hurler-Scheie patients. Three IDUA mutations were identified by molecular analysis within 6 different families: a novel mutation p.F602X and 2 already described mutations p.P533R and p.R628X. DISCUSSION: MPS I is a heterogeneous disease characterized by variability of the phenotypes. The missense mutation p.P533R associated with the intermediate phenotype was the most frequent in the Tunisian but also in the Moroccan population. In Tunisia, the incidence of p.P533R mutation seems to be associated with the high frequency of consanguineous marriages. CONCLUSION: The identification of known MPS I mutations (p.P533R and p.R628X) and of the novel mutation p.F602X permits reliable genetic counselling of at-risk relatives and molecular prenatal diagnosis.     

Enzyme replacement therapy in mucopolysaccharidosis type I

Mucopolysaccharidosis (MPS) type I is a lysosomal storage disorder caused by deficiency of the enzyme α- l -iduronidase (IDUA), which presents with a wide spectrum of phenotypes. Recently, enzyme replacement therapy (ERT) became available for patients with MPS I and has been demonstrated to be safe and effective in patients with the milder Hurler–Scheie and Scheie phenotypes. Treatment for 26 weeks with recombinant human IDUA (laronidase) has been shown to significantly increase the percentage of predicted normal forced vital capacity and the distance walked in the 6-minute walk test. There was also a clear reduction in the volume of the liver and the levels of urinary glycosaminoglycan excretion. The drug was generally well tolerated. There were no drug-related severe adverse events, and although the majority of patients developed IgG antibodies, these declined by the end of the study.
Conclusion: ERT seems to be a very promising new therapeutic regimen for patients with MPS I, especially for those with the less severe variants. However, as laronidase does not cross the blood–brain barrier it will probably not influence the central nervous manifestations in the most severely affected patients with the Hurler phenotype, although it may improve general lung and heart function, making bone marrow transplantation easier to tolerate.     

Mucopolysaccharidosis type I in Morocco: clinical features and genetic profile]

BACKGROUND: Mucopolysaccharidoses (MPS) are inherited metabolic disorders due to lysosomal enzyme deficiencies, leading to glycosaminoglycan accumulation in lysosomes of different tissues. The aim of this study was to characterize MPS types, particularly MPS I, which are difficult to differentiate by clinical features. PATIENTS AND METHODS: Over a period of three years (June 1996-May 1999), 16 Moroccan patients (3-20 years old) with MPS were investigated. Twelve of them came from the Souss region. In subjects with suspected clinical MPS I or II, the diagnosis was confirmed by biochemical investigations, which included the quantification of total glycosaminoglycans (GAGs) released in urine, their identification, and the assay of alpha-L-iduronidase activity in leucocytes. A molecular analysis was performed in parallel, to provide the genetic proof of the diagnosis. RESULTS: These 16 patients belonged to 12 families, nine of which were consanguineous (75%). Twelve patients had Hurler syndrome and three had Hurler/Scheie's syndrome; no case of Scheie's syndrome was observed. Short stature, coarse face, organomegaly, hernia, cardiac disease, mental delay and dysostosis were observed in variable degrees. We report three cases without corneal clouding. Increased total urinary GAGs, identified as dermatan sulfate and heparan sulfate by thin-layer chromatography and total deficiency of alpha-L-iduronidase activity, were noted in studied subjects. At the molecular level the P533R mutation was detected in 24 among 26 alleles studied. CONCLUSION: It is now possible to perform the screening of MPS I and II in Morocco by analysis of clinical, radiologic observations and biological investigation. The predominance of P533R mutation could permit the screening of healthy heterozygotes and genetic counselling for families of Moroccan descent.     

Variable disease progression after successful stem cell transplantation: prospective follow-up investigations in eight patients with Hurler syndrome

We report the results of a prospective, standardized follow-up programme of eight children (median age at SCT 1.2 yr) with mucopolysaccharidosis (MPS1H, M. Hurler) transplanted using a fludarabine-based SCT. SCT resulted in stable engraftment without transplant-related mortality. All patients are alive, engrafted and in ambulatory care. During follow-up (median five yr, 1.9-8 yr), six of eight showed developmental delay (two severe, two mild/no), all eight had spinal deformities and one received hip surgery for acetabular dysplasia. Hand surgery for carpal tunnel release and trigger digits was required in five of the patients. The cranio-cervical junction was narrowed in four patients, one child having already received surgery. CC was present in all patients prior to SCT. It remained unchanged in seven and regressed in one child. Severe cardiac dysfunction was present in two of the eight children before SCT. Cardiac pump function was normal in six patients and ameliorated in two, while valve abnormalities could be detected in six patients. Currently, transplantation seems no longer the major obstacle for MPS1H patients, but the variable musculoskeletal disease progression after successful SCT remains a challenge. Patients with Hurler syndrome need specialized follow-up care because of their manifold health problems. The standardized follow-up presented here is a step to optimize care for MPS children and their families after SCT.     

Idiopathic Hyperammonemia following an Unrelated Cord Blood Transplant for Mucopolysaccharidosis I

Bone marrow transplantation (BMT) has been shown to reverse or stabilize some manifestations of mucopolysaccharidosis I (Hurler syndrome). Idiopathic hyperammonemia (IHA) is a rare complication of solid organ and BMT that is characterized by elevated serum ammonia, normal liver enzymes, and abrupt onset of neurologic deterioration. We present the case of a 14-month-old male patient with Hurler syndrome who developed fatal IHA (ammonia = 2297 mmol/L) 31 days after a cord blood transplant. A complete autopsy was performed, with examination of both frozen and formalin-fixed paraffin-embedded (FFPE) tissues using a variety of special stains and electron microscopy. Hyperammonemia was documented by analysis of antemortem serum and postmortem cerebrospinal and vitreous fluid. Other causes of hyperammonemia, including Reye syndrome, were excluded. Histologic changes included centrilobular microvesicular steatosis of the liver and storage product present in multiple organs. The highly water-soluble mucopolysaccharide (MPS) storage product was best identified by colloidal iron staining of FFPE and unfixed air-dried fresh frozen liver sections. Alcian blue stains failed to convincingly demonstrate MPS in any of the liver sections. This is the first published report, to our knowledge, of IHA in a posttransplant patient younger than 18 years old or following transplantation for Hurler syndrome. Demonstration of the hepatic centrilobular microvesicular steatosis characteristic of IHA was complicated by the diffuse storage of MPS within the liver. MPS storage can be best detected in the liver using colloidal iron staining. Oil-red-O staining may be useful to document microvesicular steatosis in cases with a clinical history of hyperammonemia following solid organ or BMT. Determining if certain subsets of children are at increased risk for IHA requires further study.     

Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome

We report the long-term follow-up of successful treatment of mucopolysaccharidosis type I H (MPS IH, Hurler syndrome) with combined enzyme replacement therapy and haematopoietic progenitor stem cell transplant.     

Rare multivalvular involvement in a family of scheie syndrome

A rare family of mucopolysaccharidoses—Scheie syndrome (MPS I-S) with multivalvular involvement diagnosed by clinical and radiological findings.and confirmed by biochemical features is reported. Two dimensional and doppler echocardiography were of enormous help in not only finding the valvular lesions but also their seventy.     

Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler

Hurler syndrome type 1 (MPS‐1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha‐L‐iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS‐I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease.     

Cardiac functional and histopathologic findings in humans and mice with mucopolysaccharidosis type I: implications for assessment of therapeutic interventions in hurler syndrome

Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a uniformly lethal autosomal recessive storage disease caused by absence of the enzyme alpha-l-iduronidase (IDUA), which is involved in lysosomal degradation of sulfated glycosaminoglycans (GAGs). Cardiomyopathy and valvar insufficiency occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries. Here we report the functional, biochemical, and morphologic cardiac findings in the MPS I mouse. We compare the cardiac functional and histopathological findings in the mouse to human MPS I. In MPS I mice, we have noted aortic insufficiency, increased left ventricular size, and decreased ventricular function. Aortic and mitral valves are thickened and the aortic root is dilated. However, murine MPS I is not identical to human MPS I. Myointimal proliferation of epicardial coronary arteries is unique to human MPS I, whereas dilation of aortic root appears unique to murine MPS I. Despite the differences between murine and human MPS I, the murine model provides reliable in vivo outcome parameters, such as thickened and insufficient aortic valves and depressed cardiac function that can be followed to assess the impact of therapeutic interventions in preclinical studies in Hurler syndrome.     

Challenging symptoms in children with rare life-limiting conditions: findings from a prospective diary and interview study with families

Aim: The aim was to describe the nature, frequency, severity and management challenges of symptoms in children with two rare life‐limiting conditions [Mucopolysaccharide (MPS) and Batten disease]. Methods: This was an embedded mixed‐method study set in the UK between 2009 and 2011. Twenty‐six children from 23 families took part. Seventeen children had an MPS condition [MPS III (Sanfilippo) n = 15; MPS I (Hurler) n = 1; MPS IVA (Morquio); n = 1]. Nine children had Batten disease. Prospective data relating to symptoms were collected over 8 weeks using a symptom diary, and qualitative retrospective interviews with families were conducted. Main outcome measures included frequency, severity rating and identification of most challenging symptoms to manage. Results: The most common and severe symptoms in MPS III were agitation, repetitive behaviours, hyperactivity and disturbed sleep, and in Batten disease were agitation, joint stiffness, secretions, and disturbed sleep. The data highlighted the high prevalence of behavioural symptoms. Distress caused to families by symptoms was not related simply to their occurrence, but to difficulty in management, likelihood of control and extent to which they signalled disease progression and decline. Conclusion: In challenging contrast to the dominant biomedical framing of these rare conditions it was behavioural symptoms, rather than the physical ones, that families documented as most frequent, severe and challenging to manage. The diary developed for this study has potential use in aiding parents and clinicians to document and communicate concerns about symptoms.     

Unrelated CD3/CD19-Depleted Peripheral Stem Cell Transplantation for Hurler Syndrome

For patients with mucopolysaccharidosis type IH (MPS1-H; Hurler syndrome), early allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice. One boy and one girl aged 20.5 and 22 months, respectively, with MPS1-H received a conditioning regimen consisting of thiotepa, fludarabine, treosulfan, and ATG. Grafts were peripheral blood stem cells from unrelated donors (10/12 and 11/11 matched), that were manipulated by CD3/CD19 depletion and contained 20.3 and 28.2 × 10⁶ CD34+ cells/kg body weight, respectively. Both patients achieved stable hematopoietic engraftment and stable donor chimerism. Neither acute or chronic graft-versus-host disease (GVHD) nor other severe transplant-related complications occurred. At a follow-up of 48 and 37 months, both patients are alive and well with normal levels of α-L-iduronidase and have made major neurodevelopmental progress. Treosulfan-based conditioning offers the advantage of reduced toxicity; the use of unrelated CD3/CD19-depleted peripheral stem cell grafts allows transfusion of high CD34+ cell numbers together with a “tailored” number of CD3+ cells as well as engraftment facilitating cells in order to achieve rapid hematopoietic engraftment while reducing the risk of graft rejection and GVHD. This regimen might be an additional option when unrelated donor HSCT is considered for a patient with MPS1-H.     

Narrow trachea in mucopolysaccharidoses

Nine of 56 patients with mucopolysaccharidoses (MPS) showed small tracheal diameters on their frontal chest radiographs. Autopsy of an MPS I-H (Hurler disease) patient demonstrated that the small calibre was secondary to deposition of glycosaminoglycan (mucopolysaccharide). Autopsies of two patients with other storage diseases, one with geleophysic dysplasia and one with mucolipidosis II, also exhibited compromise of their airways because of storage material accumulation. Paper presented at the European Pediatric Radiology Society Meeting in Paris, France, 5 May 1983     

Neurobehavioral phenotypes of neuronopathic mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of lysosomal multisystemic, chronic, and progressive diseases characterized by the storage of glycosaminoglycans (GAGs) that may affect the central nervous system. Neuronopathic MPS such as MPS IH, MPS II, MPS IIIA–D, and MPS VII are characterized by neurocognitive regression. In severe MPS I (MPS IH, or Hurler syndrome) initial developmental trajectory is usually unremarkable but cognitive development shows a plateau by 2 to 4 years of age and then progressively regresses with aging. Patients with neuronopathic MPS II have a plateau of cognitive and adaptive development on average by 4 to 4.5 years of age, although there is significant variability, followed by progressive neurocognitive decline. In patients with classic MPS III, developmental trajectory reaches a plateau around 3 years of age, followed by regression. Sleep disturbances and behavioral problems occur early in MPS II and III with features of externalizing disorders. Acquired autism-like behavior is often observed in children with MPS III after 4–6 years of age. Impaired social and communication abilities do occur, but MPS III children do not have restricted and repetitive interests such as in autism spectrum disorder. MPS type VII is an ultra-rare neuronopathic MPS with a wide clinical spectrum from very severe with early mortality to milder phenotypes with longer survival into adolescence and adulthood. Most patients with MPS VII have intellectual disability and severely delayed speech development, usually associated with hearing impairment. Cognitive regression in neuronopathic MPS runs parallel to a significant decrease in brain tissue volume. Assessment of the developmental profile is challenging because of low cognitive abilities, physical impairment, and behavioral disturbances. Early diagnosis is crucial as different promising treatment approaches have been extensively studied in animal MPS models and are currently being applied in clinical trials.     

Meconium plug obstruction

We reviewed the final diagnosis and incidence of bowel pathology in neonates presenting with large bowel obstruction that was relieved by the passage of meconium plugs. A retrospective case-note review was undertaken of all patients with a discharge diagnosis of meconium plug syndrome (MPS), meconium ileus (MI), Hirschsprungs disease (HD), or small left colon syndrome (SLCS) from January 1996 to April 2002. Of 21 patients with meconium plug obstruction, eight (38%) had HD, nine had MPS, four had SLCS, and none had MI. However, there was considerable clinical and radiological overlap between MPS and SLCS, suggesting that these terms are imprecise. We found a much higher incidence of HD in babies presenting with meconium plug obstruction than has previously been reported. Overlap between MPS and SLCS suggests that these are not specific diagnoses and that current terminology needs to be changed. All babies with meconium plug obstruction should have HD and cystic fibrosis (CF) excluded.     

Mucopolysaccharidosis I presenting with endocardial fibroelastosis of infancy

We describe two female infants with Hurler syndrome (mucopolysaccharidosis I) whose deaths are attributed to cardiac failure with associated, autopsy-confirmed endocardial fibroelastosis. One infant had confirmed alpha-L-iduronidase deficiency in cultured dermal fibroblasts, and the other infant had histologic evidence of tissue mucopolysaccharide accumulation at autopsy and a sibling with confirmed alpha-L-iduronidase deficiency and the Hurler syndrome phenotype. Clear cells ("Hurler" cells) were identified within the myocardium and endocardium of both infants. We propose that the ventricular mural accumulation of mucopolysaccharides induced extensive proliferation of elastic or collagen fibers within the endocardium. Cardiac failure may precede recognition of clinical and roentgenographic features of Hurler syndrome. Our findings and a literature review suggest that certain heritable storage disorders, including mucopolysaccharidosis I, should be considered when infants have clinical electrocardiographic and echocardiographic findings consistent with endocardial fibroelastosis or have autopsy-documented endocardial fibroelastosis.     

Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders – clinical and echocardiographic findings in 64 patients

Cardiovascular abnormalities were evaluated in 64 children aged between 1 year 9 months and 25 years with mucopolysaccharidoses (MPS) and related disorders. A heart murmur was heard in 18 patients, but in only 6 was it characteristic for specific valvular lesions. Echocardiography was performed in 63 children. In one girl cardiac lesions were diagnosed on autopsy. In 46 patients (72%), valvular lesions and/or different types of cardiomyopathy were detected. There were no characteristic changes for different types of MPS. In the majority of children in whom dermatan sulphate accumulated, cardiac involvement was the most frequent (88%) and severe. The most common lesion, regardless of MPS type, was thickening of the mitral valve (66%), with regurgitation or stenosis in 28 (44%). Aortic valve thickening was detected in 17 patients (27%), asymmetric septal hypertrophy or hypertrophic cardiomyopathy in 18, congestive cardiomyopathy in 1 and endocardial thickening in 13 patients. Cardiac involvement was less frequent in children with Sanfilippo disease. Two or more echocardiographic examinations were performed in 23 patients. In 19 of them (83%) cardiac changes were more severe during the second examination. One 7-year-old boy with Hunter disease underwent successful mitral valve replacement. Conclusions Cardiac involvement is present in most patients with MPS although there are few clinical signs and symptoms. The most common and severe changes are in Hurler, Hunter, Maroteaux-Lamy and I-cell disease, rarely in Sanfilippo disease. Mitral valve deformation is most frequent in all patients. The cardiac lesions are progressive. Received: 15 March 1997 / Accepted: 20 January 1998     

Prevalence and diagnostic significance of gliadin antibodies in children with Down syndrome

Malabsorption appears common in patients with Down syndrome. We determined gliadin antibodies (IgG and IgA) in 78 children (aged 1–19 years) with Down syndrome and found increased IgG levels in 23, increased IgA levels in 2 and both increased IgG and IgA levels in 6 patients. Two patients with increased IgG and IgA had coeliac disease, two others had no mucosal abnormalities. There is an increased frequency of gliadin antibodies in patients with Down syndrome. In addition, an increased incidence of coeliac disease in this population cannot be excluded.     

Evaluation of accumulated mucopolysaccharides in the brain of patients with mucopolysaccharidoses by (1)H-magnetic resonance spectroscopy before and after bone marrow transplantation

In seven patients with mucopolysaccharidoses (1 Hurler, 1 Hurler-Scheie, 4 Hunter, 1 Sly), cranial (1)H-magnetic resonance spectroscopy was performed to evaluate the accumulation of mucopolysaccharides and biochemical changes in the CNS in vivo before and after bone marrow transplantation (BMT). In two of seven patients, (1)H-magnetic resonance spectroscopy was performed before and after BMT. Nuclear magnetic resonance spectra of dermatan sulfate and chondroitin sulfate-C and magnetic resonance spectroscopy of chondroitin sulfate-C and urine from patients with mucopolysaccharidoses showed resonance higher than the chemical shift of myoinositol in the brain (3.7 ppm). The resonance was considered to contain signals from mucopolysaccharide molecules. The resonance was measured as presumptive mucopolysaccharides (pMPS). In white matter lesions detected by magnetic resonance imaging, pMPS/creatine ratios and choline/creatine ratios were consistently higher than control ratios. In white matter without lesions, choline/creatine ratios were higher than control ratios. Patients with higher developmental quotient or intelligence quotient tended to show higher N:-acetylaspartate/creatine ratios and lower pMPS/creatine ratios in basal ganglia. After BMT, the pMPS/creatine ratio in white matter lesions of patient 3, with Hunter syndrome, was slightly decreased, but in none of the patients was the ratio ever below the control ratios, even 7 y after BMT. In white matter without lesions, the pMPS/creatine ratio in patient 3 was decreased to the control ratios after BMT, but although the choline/creatine ratios were gradually decreased, they remained higher than the control ratio, 2 y after BMT. These results suggest that evaluation of pMPS, choline, and N:-acetylaspartate by (1)H-magnetic resonance spectroscopy is an important technique that may provide useful biochemical information in vivo on the neurologic process and the efficacy of BMT in patients with mucopolysaccharidoses.