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Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder characterized by deficient alpha‐l‐iduronidase activity, leading to abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a strong clinical need for improved treatment approaches that specifically target joint tissues; however, their development is hampered by poor understanding of underlying disease pathophysiology, including how pathological changes to component tissues contribute to overall joint dysfunction. Ligaments and tendons, in particular, have received very little attention, despite the critical roles of these tissues in joint stability and biomechanical function. The goal of this study was to leverage the naturally canine model to undertake functional and structural assessments of the anterior (cranial) cruciate ligament (CCL) and Achilles tendon in MPS I. Tissues were obtained postmortem from 12‐month‐old MPS I and control dogs and tested to failure in uniaxial tension. Both CCLs and Achilles tendons from MPS I animals exhibited significantly lower stiffness and failure properties compared to those from healthy controls. Histological examination revealed multiple pathological abnormalities, including collagen fiber disorganization, increased cellularity and vascularity, and elevated GAG content in both tissues. Clinically, animals exhibited mobility deficits, including abnormal gait, which was associated with hyperextensibility of the stifle and hock joints. These findings demonstrate that pathological changes to both ligaments and tendons contribute to abnormal joint function in MPS I, and suggest that effective clinical management of joint disease in patients should incorporate treatments targeting these tissues. [ABSTRACT FROM AUTHOR]

Key Clinical Message: In Hurler syndrome, corneal opacification is a common finding but rarely manifests as hypertrophic scars. A 6‐year‐old boy with Hurler syndrome had a hypertrophic scar on his left eye, which was successfully treated with superficial keratectomy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease with progressive central nervous system involvement. This study examined the lipid, cholesterol, and myelin basic protein composition of white matter in the corpus callosum of MPS I mice. We studied 50 week‐old, male MPS I mice and littermate, heterozygote controls (n = 12 per group). Male MPS I mice showed lower phosphatidylcholine and ether‐linked phosphatidylcholine quantities than controls (p < 0.05). Twenty‐two phospholipid or ceramide species showed significant differences in percent of total. Regarding specific lipid species, MPS I mice exhibited lower quantities of sphingomyelin 18:1, phosphatidylserine 38:3, and hexosylceramide d18:1(22:1) mH2O than controls. Principal components analyses of polar, ceramide, and hexosylceramide lipids, respectively, showed some separation of MPS I and control mice. We found no significant differences in myelin gene expression, myelin basic protein, or total cholesterol in the MPS I mice versus heterozygous controls. There was a trend toward lower proteolipid protein‐1 levels in MPS I mice (p = 0.06). MPS I mice show subtle changes in white matter composition, with an unknown impact on pathogenesis in this model. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We report a retrospective analysis of 53 haematopoietic stem cell transplants for inherited metabolic disorders performed at ANZCHOG transplant centres between 1992 and 2008. Indications for transplant included Hurler syndrome, ALD, and MLD. The majority of transplants utilized unrelated donor stem cells (66%) with 65% of those being unrelated cord blood. Conditioning therapy was largely myeloablative, with Bu plus another cytotoxic agent used in 89% of recipients. Primary graft failure was rare, occurring in three patients, all of whom remain long-term survivors following the second transplant. The CI of grade II- IV and grade III- IV acute GVHD at day +100 was 39% and 14%, respectively. Chronic GVHD occurred in 17% of recipients. TRM was 12% at day +100 and 19% at one yr post-transplant. OS at five yr was 78% for the cohort, 73% for patients with ALD and 83% for patients with Hurler syndrome. There was no statistically significant difference in overall survival between unrelated marrow and unrelated cord blood donor groups. The development of interstitial pneumonitis was an independent variable shown to significantly impact on TRM and OS. In summary, we report a large cohort of patients with inherited metabolic disorders with excellent survival post-allogeneic transplant. [ABSTRACT FROM AUTHOR]

Aim: To assess the effect of bone marrow transplantation (BMT), enzyme replacement therapy (ERT), and a fiberoptic endotracheal intubation technique in patients with mucopolysaccharidosis type I (MPS I, Hurler syndrome). Background: The mucopolysaccharidoses are inherited metabolic conditions with a well-documented association with difficult airway management. We present the largest series to date of patients with Hurler syndrome (MPS I) and look at the impact of new treatments, such as BMT and ERT, on anesthesia and airway management. Methods/Materials: We carried out a retrospective chart review of patients with MPSI undergoing anesthesia over 9 years at the Royal Manchester Children's Hospital. Data were collected on incidence of difficult and failed intubation and airway difficulties under anesthesia. Results: There were 39 patients identified, of which 20 had the attenuated form of MPS I and received ERT, 18 were treated by BMT and one patient received neither treatment. These patients had a total of 114 general anesthetics for 141 procedures. The incidence of airway complications overall is lower than previously reported at 31%. Patients with the attenuated form of the disease on ERT still have a high incidence of airway problems at 57% and a failed intubation rate of 3%. BMT patients on the other hand have a much lower incidence of airway complications at 14%, and there were no failed intubations in this group. Conclusions: Managing the MPS1 patient continues to be a challenge but with treatment and newer forms of airway management it is improving. [ABSTRACT FROM AUTHOR]

Hurler syndrome is a rare autosomal recessive disorder of mucopolysaccharide metabolism. It results from a deficiency in lysosomal enzymes responsible for the breakdown of glycosaminoglycans. Affected individuals may show progressive physical and mental deterioration as glycosaminoglycans are deposited in the organs of the body. Bone marrow transplantation (BMT) is effective in improving some of the clinical manifestations of Hurler syndrome. Death is caused by cardiorespiratory failure and usually occurs before the second decade of life. In this case report, the course of dental development was followed over 5 years, from the primary dentition into the permanent dentition, of a child who was successfully treated with a bone marrow transplant in infancy. The timing of bone marrow therapy has significant and variable effect on the stages of tooth development with implications for the long-term maintenance of the dentition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I (MPS I) results from a deficiency in the enzyme α-l-iduronidase (IDUA), and is characterized by skeletal abnormalities, hepatosplenomegaly and neurological dysfunction. In this study, we used a late generation lentiviral vector to evaluate the utility of this vector system for the transfer and expression of the human IDUA cDNA in MPS I fibroblasts. We observed that the level of enzyme expression in transduced cells was 1.5-fold the level found in normal cells; the expression persisted for at least two months. In addition, transduced MPS I fibroblasts were capable of clearing intracellular radiolabeled glycosaminoglycan (GAG). Pulse-chase experiments on transduced fibroblasts showed that the recombinant enzyme was synthesized as a 76-kDa precursor form and processed to a 66-kDa mature form; it was released from transduced cells and was endocytosed into a second population of untreated MPS I fibroblasts via a mannose 6-phosphate receptor. These results suggest that the lentiviral vector may be used for the delivery and expression of the IDUA gene to cells in vivo for treatment of MPS I. [ABSTRACT FROM AUTHOR]

The article presents information on the early presentation in the mucopolysaccharide disorders. The mucopolysaccharidoses are a group of inherited lysosomal storage disorders with distinctive phenotypes and a progressive course. In the single largest attempt to study the natural history of the mucopolysaccharidoses, a comprehensive questionnaire covering details of initial presentation, timing of diagnosis, development, health and behaviour problems was sent out to the families of 258 affected children, worldwide.