Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.

Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of -0.0401 [p = 0.069] and -0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Phenotypic characterisation of the Mucopolysaccharidosis Type I (MPSI) Idua-W392X mouse model reveals increased anxiety-related traits in female mice.

Mucopolysaccharidosis Type I (MPSI) is a rare inherited lysosomal storage disease that arises due to mutations in the IDUA gene. Defective alpha-L-iduronidase (IDUA) enzyme is unable to break down glucosaminoglycans (GAGs) within the lysosomes and, as a result, there is systemic accumulation of undegraded products in lysosomes throughout the body leading to multi-system disease. Here, we characterised the skeletal/craniofacial, neuromuscular and behavioural outcomes of the MPSI Idua-W392X mouse model. We demonstrate that Idua-W392X mice have gross craniofacial abnormalities, showed signs of kyphosis, and show signs of hypoactivity compared to wild-type mice. X-ray imaging analysis revealed significantly shorter and wider tibias and femurs, significantly wider snouts, increased skull width and significantly thicker zygomatic arch bones in Idua-W392X female mice compared to wild-type mice at 9 and 10.5 months of age. Idua-W392X mice display decreased muscle strength, especially in the forelimbs, which is already apparent from 3 months of age. Female Idua-W392X mice display hypoactivity in the open-field test from 9 months of age and anxiety-like behaviour at 10 months of age. As these behaviours have been identified in Hurler children, the MPSI Idua-W392X mouse model may be important for the investigation of new therapeutic approaches for MPSI-Hurler.

Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function.

BACKGROUND: Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. METHODS: Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. RESULTS: Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. CONCLUSION: Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.

Brain and visceral gene editing of mucopolysaccharidosis I mice by nasal delivery of the CRISPR/Cas9 system.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is an inherited disease caused by deficiency of the enzyme alpha-l-iduronidase (IDUA). MPS I affects several tissues, including the brain, leading to cognitive impairment in the severe form of the disease. Currently available treatments do not reach the brain. Therefore, in this study, we performed nasal administration (NA) of liposomal complexes carrying two plasmids encoding for the CRISPR/Cas9 system and for the IDUA gene targeting the ROSA26 locus, aiming at brain delivery in MPS I mice. METHODS: Liposomes were prepared by microfluidization, and the plasmids were complexed to the formulations by adsorption. Physicochemical characterization of the formulations and complexes, in vitro permeation, and mucoadhesion in porcine nasal mucosa (PNM) were assessed. We performed NA repeatedly for 30 days in young MPS I mice, which were euthanized at 6 months of age after performing behavioral tasks, and biochemical and molecular aspects were evaluated. RESULTS: Monodisperse mucoadhesive complexes around 110 nm, which are able to efficiently permeate the PNM. In animals, the treatment led to a modest increase in IDUA activity in the lung, heart, and brain areas, with reduction of glycosaminoglycan (GAG) levels in serum, urine, tissues, and brain cortex. Furthermore, treated mice showed improvement in behavioral tests, suggesting prevention of the cognitive damage. CONCLUSION: Nonviral gene editing performed through nasal route represents a potential therapeutic alternative for the somatic and neurologic symptoms of MPS I and possibly for other neurological disorders.

A rapid and non-invasive proteomic analysis using DBS and buccal swab for multiplexed second-tier screening of Pompe disease and Mucopolysaccharidosis type I.

PURPOSE: Current newborn screening programs for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) suffer from a high false positive rate and long turnaround time for clinical follow up. This study aimed to develop a novel proteomics-based assay for rapid and accurate second-tier screening of PD and MPS I. A fast turnaround assay would enable the identification of severe cases who need immediate clinical follow up and treatment. METHODS: We developed an immunocapture coupled with mass spectrometry-based proteomics (Immuno-SRM) assay to quantify GAA and IDUA proteins in dried blood spots (DBS) and buccal swabs. Sensitivity, linearity, reproducibility, and protein concentration range in healthy control samples were determined. Clinical performance was evaluated in known PD and MPS I patients as well as pseudodeficiency and carrier cases. RESULTS: Using three 3.2 mm punches (~13.1 µL of blood) of DBS, the assay showed reproducible and sensitive quantification of GAA and IDUA. Both proteins can also be quantified in buccal swabs with high reproducibility and sensitivity. Infantile onset Pompe disease (IOPD) and severe MPS I cases are readily identifiable due to the absence of GAA and IDUA, respectively. In addition, late onset Pompe disease (LOPD) and attenuated MPS I patients showed much reduced levels of the target protein. By contrast, pseudodeficiency and carrier cases exhibited significant higher target protein levels compared to true patients. CONCLUSION: Direct quantification of endogenous GAA and IDUA peptides in DBS by Immuno-SRM can be used for second-tier screening to rapidly identify severe PD and MPS I patients with a turnaround time of <1 week. Such patients could benefit from immediate clinical follow up and possibly earlier treatment.

Quantifying medical manifestations in Hurler syndrome with the infant physical symptom score: associations with long-term physical and adaptive outcomes.

BACKGROUND: A physical symptom score (PSS) for the mucopolysaccharidosis (MPS) disorders has been developed to quantitate the somatic burden of disease across multiple organ systems. Studies have demonstrated the sensitivity and its relationship to age, IQ and adaptive functioning of the PSS in older children. With the onset of newborn screening, there is an increased need to characterize the somatic symptoms in the earliest stages of life, especially for young children under 36 months of age. Consequently, a new scale, Infant Physical Symptom Score (IPSS), was developed to score physical symptoms in infants and toddlers. OBJECTIVE: Part I. To create a measure to quantify somatic burden in patients with MPS disorders under 36 months of age. The IPSS assess outcomes and changes in somatic disease in individuals with MPS disorders diagnosed very early in life. Part II. To determine the relationship between IPSS and other measures to evaluate its validity and utility, a) we evaluated the relationship between the IPSS and PSS in the same patients with MPS I over time to determine if the two scales are measuring the same concepts, and b) we evaluated the association between IPSS and a functional adaptive measure over time with a focus on the age at first treatment (under 36 months) to determine if the IPSS has predictive value. METHODS: Part I. The Infant Physical Symptom Score (IPSS) for the infant population in MPS disorders was established using data from 39 patients enrolled in the Lysosomal Disease Network longitudinal MPS I study (U54NS065768). All of these patients had Hurler syndrome (MPS IH) and underwent hematopoietic stem cell transplant (HSCT) at the University of Minnesota. Items for the IPSS were selected by reviewing CRFs prepared for the MPS I longitudinal study and examining medical records of these patients prior to HSCT based on the knowledge gained from the development of the PSS. Part II. Of those 39 patients, a subset of 19 were all seen 9 to 12 years post HSCT. Having retrospectively calculated their IPSS prior to HSCT, we categorized them by age at HSCT, and examined their most recent PSS along with Composite and Daily Living Skills scores on the Vineland Adaptive Behavior Scales - Second Edition (VABS-II). RESULTS AND CONCLUSION: The total score on the IPSS collected prior to transplant differed by patient's age at transplant, as expected in this progressive condition. Those transplanted at ≤12 months of age had a mean score of 7.4, which was significantly lower, suggesting less somatic disease burden, compared to those transplanted at >12 to ≤24 months (mean 11.8) and > 24 to ≤36 months (mean 13.6). Higher IPSS reflects more evidence of somatic disease burden and lower IPSS reflects less evidence of disease burden. Nine to 12 years later, the severity level as measured by the PSS was comparable to severity on the IPSS suggesting that the two scales are measuring similar concepts. Retrospectively calculated pre-transplant IPSS were negatively associated with higher VABS-II Composite scores 9-12 years later (p value-0.015) and to a lesser extent Daily Living Skills scores (p value-0.081). We conclude that the IPSS appears to be a useful approach to quantifying the somatic disease burden of MPS IH patients under 36 months of age.

Hearing loss in patients with mucopolysaccharidoses-1 and -6 after hematopoietic cell transplantation: A longitudinal analysis.

Hearing loss is frequently seen in mucopolysaccharidoses (MPS) patients. Although hematopoietic cell transplantation (HCT) increases overall survival, disease progression is observed in certain tissues. This study describes the course of hearing loss (HL) over time in transplanted MPS patients. Transplanted MPS patients between 2003 and 2018 were included and received yearly audiological evaluation, including auditory brainstem response (ABR) or pure tone audiometry (PTA). Twenty-eight MPS-1 and four MPS-6 patients were analyzed with a median follow-up of 5 years (range 11 months-16 years). Air conduction threshold improved significantly over time (P < .001) with a PTA 1-year post-HCT of 50 ± 0.7 dB to 23 ± 11 dB 13 years post-HCT. Bone conduction threshold worsened with a PTA 1 year post-HCT of 10 ± 7 dB to 18 ± 9 dB 13 years post-HCT (P = .34). The degree of HL varied from mainly mild-severe early after HCT to normal-mild at longer follow-up. The type of HL consisted of mainly conductive in the first years post-HCT in contrast to mainly sensorineural at longer follow-up. MRIs of the cerebellopontine angle did not show abnormalities. HL is still seen in patients with MPS despite HCT and consists of a conductive type early after HCT in contrast to a sensorineural type at longer follow-up in the majority of cases. Yearly follow-up of HL is necessary to timely intervene, as hearing is important in the speech and language development of children and their academic achievements.

Multimodal imaging of Hurler syndrome-related keratopathy treated with deep anterior lamellar keratoplasty.

BACKGROUND: Hurler syndrome-associated keratopathy is an exceedingly rare corneal disorder that requires corneal transplantation in advanced stages. Precise assessment of the corneal condition is necessary for deciding which type of keratoplasty (i.e., deep anterior lamellar or penetrating) should be proposed. We aimed to confront the results of multimodal imaging with those of histology in a case of Hurler syndrome-associated keratopathy. CASE PRESENTATION: A 16-year-old patient with Hurler's syndrome treated with hematopoietic stem cell transplantation was referred for decreased vision related to advanced keratopathy. The patient was treated with deep anterior lamellar keratoplasty (DALK) in both eyes with uncomplicated outcome. Visual acuity improved from 0.1 (20/200) preoperatively to 0.32 (20/63) and 0.63 (20/32) after transplantation. The corneal endothelial cell density was 2400 cells/mm2 in both eyes 3 years after transplantation. In vivo confocal microscopy (IVCM) and spectral domain optical coherence tomography (SD-OCT) were performed preoperatively. The corneal buttons retrieved during keratoplasty were processed for histology. In SD-OCT scans, corneal opacities appeared as diffuse stromal hyperreflectivity associated with increased corneal thickness. IVCM showed diffuse cytoplasmic granular hyperreflectivity and rounded/ellipsoid aspects of keratocytes, presence of small intracellular vacuoles, and hyperreflective epithelial intercellular spaces. Bowman's layer was thin and irregular. The corneal endothelium was poorly visualized but no endothelial damage was observed. Histology showed irregular orientation and organization of stromal lamellae, with the presence of macrophages whose cytoplasm appeared clear and granular. A perinuclear clear halo was visible within the epithelial basal cells. Bowman's layer featured breaks and irregularities. CONCLUSIONS: The observed corneal multimodal imaging features in mucopolysaccharidosis-related keratopathy were concordant with histology. Compared with standard histology, multimodal imaging allowed additional keratocyte features to be observed. It revealed both morphological and structural changes of all corneal layers but the endothelium. This information is essential for therapeutic management which should include DALK as the first-choice treatment in case of impaired visual acuity.

Lower Exposure to Busulfan Allows for Stable Engraftment of Donor Hematopoietic Stem Cells in Children with Mucopolysaccharidosis Type I: A Case Report of Four Patients.

Busulfan is an alkylating agent routinely used in conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT) for various nonmalignant disorders, including inborn errors of metabolism. The combination of model-based dosing and therapeutic drug monitoring (TDM) of busulfan pharmacokinetics (PK) to a lower exposure target has the potential to reduce the regimen-related toxicity while opening marrow niches sufficient for engraftment in diseases such as mucopolysaccharidosis type I (MPS I). We present four cases of the severe form of MPS I or Hurler syndrome, demonstrating successful and stable CD14/15 donor chimerism following the prospective application of model-based dosing and TDM aimed to achieve lower busulfan exposure. All patients received a busulfan-based conditioning regimen with a median cumulative area-under-the-curve (cAUC) target of 63.7 mg h/L (range, 62.4 to 65.0) in protocol-specific combination of chemotherapeutic regimen. The donor source was unrelated umbilical cord blood for three patients and matched sibling donor bone marrow for one patient. The observed median busulfan cAUC was 66.1 mg h/L (range, 65.2 to 70.6) and was within 10% of the intended target. Stable, full donor myeloid chimerism was achieved for three patients, while one patient achieved a stable mixed chimerism (76% donor CD14/15 at 53 months) without a recurring need for enzyme replacement. The normalization of α-L-iduronidase enzyme levels followed the attainment of successful donor myeloid chimerism in all patients. Regimen-related toxicity remained low with no evidence of acute graft-versus-host disease (GVHD) grades II to IV and chronic GVHD.

Hematopoietic cell transplantation for severe MPS I in the first six months of life: The heart of the matter.

BACKGROUND: Hematopoietic cell transplantation (HCT) is accepted therapy for severe mucopolysaccharidosis type I (MPS IH). With implementation of newborn screening (NBS) for MPS I in the US, HCT may now occur earlier than 1-2 years of age and it might be assumed that cardiac issues will be fewer. To examine this hypothesis, we reviewed our records for any MPS IH infant who underwent HCT at ≤6 months of age. STUDY PATIENTS: Pre- and (most recent) post-HCT cardiac echos and clinical courses were reviewed in all infants with MPS IH undergoing HCT at ≤6 months of age. RESULTS: 7 MPS IH infants (4 M) who were diagnosed at median (range) (MEDRNG) of 14 (3, 22) days of life (DOL) by NBS [2] or because an older sib had MPS IH [5], began enzyme replacement therapy at MEDRNG of 48 (7, 62) DOL. First pre-HCT echo was performed at MEDRNG of 45 (0, 88) DOL. HCT (6 cord blood, 1 related) occurred at MEDRNG of 131 (105, 183) DOL with most recent echo at MEDRNG of 408 (10, 1897) days after HCT. Mitral regurgitation (≥mild) occurred before (2/7) and after (2/7) HCT; LVH (2/7) occurred after HCT; PFO was common before (5/7) and after (3/7) HCT. One infant had severely decreased function at initial echo and required ICU management. Another infant with a patent foramen ovale and indwelling central line required additional neuroimaging to determine the cause of a seizure. A final infant died unexpectedly 69 days post-HCT without evidence of occlusive coronary disease at autopsy. CONCLUSIONS: In addition to the traditional phenotypic features of severe MPS I, newborns presenting for HCT have cardiac and non-cardiac problems unique to their young age. Recognition of these issues is essential for optimal outcomes.

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.

Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome).

Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome-a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose-is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children.

A comprehensive review of Mongolian spots with an update on atypical presentations.

PURPOSE: Mongolian spots (MS) are grayish-blue macules that typically present in the lumbosacral and gluteal regions of newborns. They are mostly benign and tend to resolve with age. This review brings to light recent findings and disorders associated MS. METHODS: In this paper, we review the literature, highlight recent cases and disorders associated with MS, and emphasize how newborns presenting with atypical MS should undergo appropriate screening. RESULTS: Atypical MS on other body parts are more likely to persist and might be an indication for further screening. Recent studies have shown persistent and extensive MS to be associated with various genetic disorders such as lysosomal storage diseases (LSDs) and phakomatosis pigmentovascularis. CONCLUSION: Physicians should be aware of atypical MS and related conditions in order to further assess these patients for risk of any underlying genetic disorders.

Mucopolysaccharidoses: overview of neuroimaging manifestations.

The mucopolysaccharidoses are a heterogeneous group of inherited lysosomal storage disorders, characterized by the accumulation of undegraded glycosaminoglycans in various organs, leading to tissue damage. Mucopolysaccharidoses include eight individual disorders (IS [Scheie syndrome], IH [Hurler syndrome], II, III, IV, VI, VII and IX). They have autosomal-recessive transmission with the exception of mucopolysaccharidosis II, which is X-linked. Each individual disorder has a wide spectrum of phenotypic variation, depending on the specific mutation, from very mild to very severe. The skeletal and central nervous systems are particularly affected. The typical clinical presentation includes organomegaly, dysostosis multiplex with short trunk dwarfism, mental retardation and developmental delay. In this article, we review the neuroimaging manifestations of the different types of mucopolysaccharidoses including the dysostosis multiplex of the skull and spine as well as the various central nervous system complications. These include white matter injury, enlargement of the perivascular spaces, hydrocephalus, brain atrophy, characteristic enlargement of the subarachnoid spaces as well as compressive myelopathy. The correlation between several of the neuroimaging features and disease severity remains controversial, without well-established imaging biomarkers at this time. Imaging has, however, a crucial role in monitoring disease progression, in particular craniocervical junction stenosis, cord compression and hydrocephalus, because this allows for timely intervention before permanent damage occurs.

The Frequency of Carpal Tunnel Syndrome in Hurler Syndrome After Peritransplant Enzyme Replacement Therapy: A Retrospective Comparison.

PURPOSE: Children with Hurler syndrome (HS) develop carpal tunnel syndrome (CTS) owing to glycosaminoglycan deposition secondary to enzyme deficiency. Advancement in the treatment of the underlying enzyme deficiency now commonly includes peritransplant intravenous enzyme replacement therapy (ERT). The primary objective of this study was to determine if the use of limited ERT in addition to hematopoietic stem cell transplantation (HCT) for the treatment of children with HS reduces the incidence of surgical intervention for CTS compared with a cohort of historical controls treated with HCT alone. The secondary objectives were to evaluate the impact of demographic and transplant-related characteristics on the incidence of CTS. Lastly, the results of surgical treatment of CTS in HS are reported. METHODS: Medical records for a historical group of 43 HS patients who underwent HCT alone (group 1) were compared with 31 HS patients who underwent HCT + ERT (group 2). Both groups were compared for genotype, age at transplant, sex, transplant graft source, median/ulnar nerve conduction study parameters as well as the incidence and treatment of CTS. Pre- and postoperative nerve conduction studies were compared for children treated surgically for CTS. RESULTS: The cumulative incidence of CTS at 5 years for HS children treated with HCT + ERT was 51% compared with 47% for HS children treated with HCT alone. The incidence of CTS did not depend upon graft source, age at transplant, or sex. Median nerve conduction velocity for both sensory and motor potentials demonstrated significant improvement after carpal tunnel release. CONCLUSIONS: Although the administration of ERT prior to and for several months after HCT has become routine in our institution, our findings do not suggest this combined therapy is sufficient to decrease the development of CTS. Surgical intervention for median nerve compression remains the treatment of choice for CTS in HS children. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Enzyme replacement therapy prior to haematopoietic stem cell transplantation in Mucopolysaccharidosis Type I: 10 year combined experience of 2 centres.

Haematopoietic stem cell transplantation is the treatment of choice for the severe form of Mucopolysaccharidosis Type I, or Hurler syndrome. In many centres standard practice is to deliver enzyme replacement therapy alongside haematopoietic stem cell transplantation to improve the condition of the patient prior to transplant. We report the combined 10 year experience of this approach in two paediatric metabolic and transplant centres. Of 81 patients who underwent a first transplant procedure for Hurler, 88% (71/81) survived and 81% (66/81) were alive and engrafted at a median follow-up of 46 months (range 3-124 months). The incidence of grade II-IV acute and any chronic graft versus host disease was 17% and 11% respectively. Urinary glycosaminoglycans were significantly reduced after a period of enzyme replacement therapy, and further reductions were seen at 13-24 months and 25+months after transplantation. In several individuals with decreased cardiac contractility, an improvement of their condition during enzyme replacement therapy enabled them to undergo transplantation, with one individual receiving full intensity conditioning.

Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type II.

Mucopolysaccharidoses (MPS), a subgroup of lysosomal storage disorders, are caused due to deficiency of specific lysosomal enzyme involved in catabolism of glycosaminoglycans. To date more than 200 pathogenic variants in the alpha-l-iduronidase (IDUA) for MPS I and ∼500 pathogenic variants in the iduronate-2-sulphatase (IDS) for MPS II have been reported worldwide. The mutation spectrum of MPS type I and MPS type II disorders in Indian population is not characterized yet. In this study, we carried out clinical, biochemical, molecular and in silico analyses to establish the mutation spectrum of MPS I and MPS II in the Indian population. We conducted molecular analysis for 60 MPS-affected patients [MPS I (n = 30) (Hurler syndrome = 17, Hurler-Scheie syndrome = 13), and MPS II (n = 30) (severe = 18, attenuated = 12)] and identified a total of 44 [MPS I (n = 22) and MPS II (n = 22)] different pathogenic variants comprising missense, nonsense, frameshift, gross deletions and splice site variants. A total of 20 [MPS I (n = 14), and MPS II (n = 6)] novel pathogenic sequence variants were identified in our patient cohort. We found that 32% of pathogenic variants detected in IDUA were recurrent and 25% in MPS II. This is the first study revealing the mutation spectrum of MPS I and MPS II patients in the Indian population.

A novel explanation of corneal clouding in a bone marrow transplant-treated patient with Hurler syndrome.

One common complication of mucopolysaccharidosis I-Hurler (MPS1-H) is corneal clouding, which occurs despite current treatments, including bone marrow transplantation. Human corneas were obtained from a 14 year old subject with MPS1-H and visual disability from progressive corneal clouding despite a prior bone marrow transplant at age 2. This was compared to a cornea from a 17 year old donated to our eye bank after his accidental death. The corneas were analyzed microscopically after staining with Alcian blue, antibodies to collagen I, IV, VI, and α-smooth muscle actin. Differences in levels of expression of the indicated molecules were assessed. Corneas from Hurler and control mice were examined similarly to determine potential mechanistic overlap. The MPS1-H subject cornea showed elevations in mucopolysaccharide deposition. The MPS1-H and Hurler mice corneas showed increased and disorganized expression of collagen I and IV relative to the control corneas. The MPS1-H corneas also showed increased and disordered expression of collagen VI. Positive expression of α-smooth muscle actin indicated myofibroblast conversion within the MPS1-H cornea in both the patient and mutant mouse material compared to normal human and control mouse cornea. Increased deposition of collagens and smooth muscle actin correlate with corneal clouding, providing a potential mechanism for corneal clouding despite bone marrow transplantation in MPS1-H patients. It might be possible to prevent or slow the onset of corneal clouding by treating the cornea with drugs known to prevent myofibroblast conversion.

[Mucopolysaccharidosis: clinical features, diagnosis and management]. / Mucopolisacaridosis: características clínicas, diagnóstico y de manejo.

The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at lysosomal level. When there is a deficiency of a particular enzyme there is an accumulation of GAGs in the cells resulting in progressive cellular damage, which can affect multiple organ systems and lead to organ failure. Diagnosis is based on knowledge of the clinical manifestations, performing biochemical analyses to identify the type of GAG that is accumulating, and confirm the type of disorder with the corresponding enzymatic determination. Their identification is essential to initiate early treatment, taking into account that multidisciplinary management and enzyme replacement therapy is available for MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome. In this review, an analysis is made of each of these syndromes, as well as their diagnosis and treatment.

Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines.

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure-targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety.