Hurler Syndrome Research Articles

Whole paternal uniparental disomy of chromosome 4 with a novel homozygous IDUA splicing variant, c.159-9T>A, in a Chinese patient with mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS-I) is a rare autosomal recessive genetic lysosomal storage disorder that is caused by pathogenic variants of the α-L-iduronidase (IDUA) gene. This study aimed to identify the genetic causes of MPS-I in a Chinese patient and construct a minigene of IDUA to analyze its variants upon splicing. Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the potential causative variants. Single-nucleotide polymorphism (SNP) array was subsequently performed to confirm uniparental disomy (UPD). Minigene assay was performed to analyze the effect on splicing of mRNA. We meanwhile explored the conservative analysis and protein homology simulation. A novel homozygous splicing mutation of IDUA, c.159-9T>A, was identified in an individual presenting with overlapping features of MPS-I. Interestingly, only the father and sisters, but not the mother, carried the variant in a heterozygous state. WES and SNP array analyses validated paternal UPD on chromosome 4. Minigene splicing revealed two aberrant splicing events: exon 2 skipping and intron 1 retention. Moreover, the specific structure of the mutant protein obviously changed according to the results of the homologous model. This study describes a rare autosomal recessive disorder with paternal UPD of chromosome 4 leading to the homozygosity of the IDUA splicing variant in patients with MPS-I for the first time. This study expands the variant spectrum of IDUA and provides insights into the splicing system, facilitating its enhanced diagnosis and treatment.

Programmable DNA pyrimidine base editing via engineered uracil-DNA glycosylase

DNA base editing technologies predominantly utilize engineered deaminases, limiting their ability to edit thymine and guanine directly. In this study, we successfully achieve base editing of both cytidine and thymine by leveraging the translesion DNA synthesis pathway through the engineering of uracil-DNA glycosylase (UNG). Employing structure-based rational design, exploration of homologous proteins, and mutation screening, we identify a Deinococcus radiodurans UNG mutant capable of effectively editing thymine. When fused with the nickase Cas9, the engineered DrUNG protein facilitates efficient thymine base editing at endogenous sites, achieving editing efficiencies up to 55% without enrichment and exhibiting minimal cellular toxicity. This thymine base editor (TBE) exhibits high editing specificity and significantly restores IDUA enzyme activity in cells derived from patients with Hurler syndrome. TBEs represent efficient, specific, and low-toxicity approaches to base editing with potential applications in treating relevant diseases.

Ultrasound imaging for assessing aortic phenotypes: A preclinical tool for measuring cardiac disease model progression and therapeutic effect

Cardiac dysfunction is a common feature of numerous diseases, ranging from metabolic disorders like Mucopolysaccharidosis Type 1 (MPS I), a.k.a. Hurler syndrome to neuromuscular disorders such as Myotonic Dystrophy type 1 (DM1). The ability to quantify cardiac abnormalities in animal models of these diseases is a valuable translational tool for preclinical testing of novel therapeutic approaches. In contrast to methods that measure the left ventricle (LV) phenotype, we employed ultrasound imaging to assess the ascending aortic diameter and ascending aortic blood velocity. MethodsWe imaged two disease models - MPS I Hurler mouse model and DM1 mouse model (DMSXL) - using the Vevo2100 platform. Ascending aortic diameter in the proximal thoracic aortic region and ascending aortic blood velocity just before the branching point of the brachiocephalic artery were measured as rapid imaging readouts. In addition, histopathology was performed on relevant tissue samples. ResultsThe two mouse models demonstrate opposing aorta phenotypes. Hurler mice had a dilated aorta and slightly increased blood velocity with disease progression, while the aorta diameter in DMSXL mice narrowed and had a blood velocity decrease as the disease progressed. In the Hurler model, we demonstrated that a single dose of adeno-associated virus (AAV) delivered gene therapy provides aortic phenotype improvement. In the DMSXL model, we established aortic phenotype criteria at baseline. ConclusionUltrasound imaging of aortic diameter and blood velocity can offer objective and longitudinal assessments of disease progression and treatment efficacy in real time. This method might therefore have noninvasive clinical applicability as phenotype indicator of cardiac dysfunction.

Hurler syndrome: Etiology, manifestations, and life complications: A case report

Hurler syndrome: Etiology, manifestations, and life complications: A case report

Anaesthetic Challenge in a Child with Hurler’s Syndrome: Encouraging Experience with Neuraxial Blockade

Mucopolysaccharidoses are uncommon genetic diseases with multisystem involvement. The potential for airway difficulties and varying success rate of neuraxial blockade demands considerable expertise in the anesthetic management in these patients. Airway management has evolved significantly in such syndromic patients with the increasing use of video laryngoscopes and Supraglottic airway devices. However, airway catastrophes are not uncommon. This calls for better utilization of neuraxial and peripheral nerve blocks along with the use of newer agents for sedation having a favorable pharmacological profile. Here, we present a case of child having Hurler disease with an inguinal hernia successfully operated under subarachnoid blockade.

Macroglossia in endocrine and metabolic disorders: current evidence, perspectives and challenges.

Macroglossia is an uncommon condition characterized by chronic, painless and abnormal enlargement of the tongue. A multitude of medical conditions can cause macroglossia. Major endocrine and metabolic disorders associated with macroglossia include genetic, congenital and acquired conditions, such as mucopolysaccharidoses; acquired and congenital hypothyroidism and myxedema; transient neonatal diabetes mellitus; acromegaly and amyloidosis. Macroglossia is often associated (~57-60%) with all types of mucopolysaccharidoses, particularly type I (Hurler syndrome) and type II (Hunter syndrome), being a prominent feature of the disorder. It may also occur in patients with acquired and congenital hypothyroidism and myxedema, being a common sign of congenital hypothyroidism with an approximate prevalence of 12-25% at the time of diagnosis. Macroglossia is a predominant oral finding in subjects with transient neonatal diabetes mellitus (~44%), acromegaly (54-69%) and amyloidosis (10-25%), particularly AL amyloidosis (20-40%) whereas is considered a hallmark of the disease. Secondary to macroglossia various disturbances may occur, such as difficulty in speech or eating, orthodontic anomalies or even more serious conditions including upper airway obstruction or obstructive sleep apnea. Until now, no comprehensive review has been conducted focusing on macroglossia in endocrine and metabolic disorders. The objective of this review is to summarize literature on the etiology and epidemiology of macroglossia in major endocrine and metabolic disorders. It highlights key aspects such as pathophysiology, clinical presentation, diagnostic evaluation, management and prognosis of macroglossia in the context of endocrine and metabolic disorders.

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.

Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here.

A rare Case Report of Hurler syndrome with multisystem involvement including glucose intolerance

Background: Mucopolysaccharidosis type I (Hurler syndrome) is a rare autosomal recessive inborn deficiency in the metabolism of glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, resulting from deficiency of Alpha-L-iduronidase enzyme. An interesting case of a 19 year old male with a combination of skeletal, neurological, ophthalmologic, and radiological findings with MPS I-(Hurler syndrome) has been presented here in this case report.

Ventriculoperitoneal shunt and bilateral herniotomies in mucopolysaccharidosis type I: A surgical challenge

ABSTRACT Mucopolysaccharidosis type I or Hurler syndrome (1 in 100,000) is a rare lysosomal storage disorder caused by a defective IDUA gene which codes for α-L-iduronidase enzyme. Enzyme deficiency results in the accumulation of dermatan and heparan sulfate which leads to characteristic facial features, skeletal abnormalities, hepatosplenomegaly, cardiac and pulmonary disease, and progressive mental retardation. A 1-year-old male child presented with chief complaints of increasing head size and bilateral large inguinoscrotal swellings for 5 months. He had a motor developmental delay with poor speech at 1 year of age. The infant weighed 10 kg with a length of 76.5 cm and large head size with head circumference of 53.5 cm (>97 centiles); the anterior fontanel was wide open. Facial features revealed prominent forehead, bilateral corneal clouding, and coarse facies. Per-abdomen examination revealed hepatosplenomegaly; inguinoscrotal evaluation revealed bilateral large reducible indirect inguinal hernias. Radiographic findings suggested dysostosis multiplex. Serial cranial ultrasonography revealed progressive hydrocephalus. Noncontrast computed tomography brain confirmed communicating type of hydrocephalus with periventricular ooze. Considering the clinical history, clinical examination, and skeletal survey, findings were consistent with mucopolysaccharidoses. Urine spot test for glycosaminoglycans for mucopolysaccharidosis was positive. Enzyme analysis of alpha-L-iduronidase showed deficient levels. A molecular study revealed a homozygous mutation in the IDUA gene confirming the diagnosis of Hurler syndrome. The right ventriculoperitoneal shunt was performed after preoperative optimization. Bilateral inguinal hernia repair was contemplated after a gap of 8 weeks. On 9-month follow-up, there was a gradual reduction in ventricular hemispheric ratio, and the patient is doing well on follow-up. Surgical management of the MPS I patient is challenging, but with timely medical and surgical treatment, the prognosis is improving.

Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome.

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts.

Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10μM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.

Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells.

Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet-based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons.

Programmable RNA pseudouridylation has emerged as a new type of RNA base editor to suppress premature termination codons (PTCs) that can lead to truncated and nonfunctional proteins. However, current methods to correct disease-associated PTCs suffer from low efficiency and limited precision. Here we develop RESTART v3, which uses near-cognate tRNAs to improve the readthrough efficiency of pseudouridine-modified PTCs. We show an average of ~5-fold (range: 2.1- to 9.5-fold) higher editing efficiency than RESTART v2 in cultured cells and achieve functional PTC readthrough in disease cell models of cystic fibrosis and Hurler syndrome. Furthermore, RESTART v3 enables accurate incorporation of the original amino acid for nearly half of the PTC sites, considering the naturally occurring frequencies of sense-to-nonsense codons, without affecting normal termination codons. Although off-target sites were detected, we did not observe changes to the coding information or the expression level of transcripts, and the overall natural tRNA abundance remained constant.

Natural history of craniovertebral abnormalities in a single-center study in 54 patients with Hurler syndrome.

Craniovertebral junction (CVJ) abnormalities are common and well documented in mucopolysaccharidosis type I-Hurler syndrome (MPS IH), often causing severe spinal canal narrowing. However, the requirement for surgical decompression and/or fusion is uncommon. Although hematopoietic cell transplant (HCT) has been shown to prolong the lives of patients with MPS IH, its effect in halting or reversing musculoskeletal abnormalities is less clear. Unfortunately, there are currently no universal guidelines for imaging or indication for surgical interventions in these patients. The goal of this study was to track the progression of the CVJ anatomy in patients with MPS IH following HCT, and to examine radiographic features in patients who needed surgical intervention. Patients with MPS IH treated at the University of Minnesota with allogeneic HCT between 2008 and 2020 were retrospectively reviewed. Patients who underwent CVJ surgery were identified with chart review. All MPS IH cervical scans were examined, and the odontoid retroflexion angle, clivoaxial angle (CXA), canal width, and Grabb-Oakes distance (pB-C2) were measured yearly for up to 7 years after HCT. Longitudinal models based on the measurements were made. An intraclass correlation coefficient was used to measure interrater reliability. Nine children without MPS IH were examined for control CVJ measurements. A total of 253 cervical spine MRI scans were reviewed in 54 patients with MPS IH. Only 4 (7.4%) patients in the study cohort required surgery. Three of them had posterior fossa and C1 decompression, and 1 had a C1-2 fusion. There was no statistically significant difference in the spinal parameters that were examined between surgery and nonsurgery groups. Among the measurements, canal width and CXA varied drastically in patients with different neck positions. Odontoid retroflexion angle and CXA tended to decrease with age. Canal width and pB-C2 tended to increase with age. Based on the data, the authors observed an increase in canal width and pB-C2, whereas the CXA and odontoid retroflexion angle became more acute as the patients aged after HCT. The longitudinal models derived from these data mirrored the development in children without MPS IH. Spinal measurements obtained on MR images alone are not sufficient in identifying patients who require surgical intervention. Symptom monitoring and clinical examination, as well as pathological spinal cord changes on MRI, are more crucial in assessing the need for surgery than is obtaining serial imaging.

Outcomes after Hematopoietic Cell Transplantation for Hurler Syndrome after Implementation Newborn Screening in US and Europe

Outcomes after Hematopoietic Cell Transplantation for Hurler Syndrome after Implementation Newborn Screening in US and Europe

Enzyme replacement is associated with better long-term cognitive outcomes in Hurler syndrome

Enzyme replacement is associated with better long-term cognitive outcomes in Hurler syndrome

Is time growth? The impact of early initiation and duration of enzyme replacement therapy on growth in Hurler syndrome

Is time growth? The impact of early initiation and duration of enzyme replacement therapy on growth in Hurler syndrome

Combination Treatment for Severe Forms of Mucopolysaccharidosis, Type I (Hurler Syndrome): Case Report

Background. Hurler syndrome (mucopolysaccharidosis, type I) is a rare hereditary disease with chronic course. The main methods for Hurler syndrome management are hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). In recent years, combination treatment (ERT administration both before and after HSCT) has shown its efficacy in case of disease progression. Clinical case description. The presented clinical cases demonstrate the efficacy of ERT administration in patients with Hurler syndrome after HSCT: in the first clinical case due to the decrease in alpha-iduronidase activity 2 years after HSCT, in the second clinical case due to the aggravation of the patient's condition (cardiovascular and respiratory systems, hepatomegaly, although the level of enzyme and glycosaminoglycans in the patient's urine remained within normal values). Conclusion. Combination treatment including ERT not only before HSCT, but also in case of clinical state worsening after HSCT, plays significant role in stabilizing the patient's condition, preventing rapid progression of symptoms and development of life-threatening complications (especially cardiovascular ones).

Long-Term Cardiorespiratory, Endocrine, Ophthalmic, and Functional Outcomes in Adult Patients with Mucopolysaccharidosis Type I (Hurler Syndrome) Post Haematopoietic Stem Cell Transplantation: The Irish Experience

Long-Term Cardiorespiratory, Endocrine, Ophthalmic, and Functional Outcomes in Adult Patients with Mucopolysaccharidosis Type I (Hurler Syndrome) Post Haematopoietic Stem Cell Transplantation: The Irish Experience

Long-term outcome of hematopoietic stem cell transplantation in two children with Mucopolysaccharidosis

To explore the long-term efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with Mucopolysaccharidosis (MPS), which has rarely been reported in China. A 18-month-old boy and a 23-month-old girl undergoing alloHSCT for MPS VI and MPS IH Shanghai Children's Medical Center on March 30, 2006 and September 6, 2006 were selected as the study subjects. A busulfan-based myeloablative regimen was used as the conditioning regimen. Peripheral stem cells were respectively collected from a human leucocyte antigen (HLA) matched sibling carrier donor and a HLA 9/10 matched unrelated donor. Both patients were followed up for more than 15 years. The functions of internal organs before and after the transplantation were compared, and child 1 was also compared with his untreated brother and healthy brother. Both children have achieved full donor chimerism after the transplantation, and their enzymatic activities have remained stable. The enzymatic activity of the child 1 was slightly lower than normal but similar to that of his carrier donor, whilst that of the child 2 was normal. Both children have attended schools with good academic performance. Compared with his untreated brother, the respiratory function and hearing of child 1 have significantly improved. However, his orthopedic and cardiac disorders have still remained and required medical intervention. For child 2, her obstructive pulmonary disease was resolved and cognitive development was well preserved after the HSCT. Her heart disease has become stabilized and even improved with time, though her corneal clouding and skeletal malformation still required surgery. MPS patients can sustain long-term and stable enzymatic activities after successful alloHSCT. Compared with untreated patients, their health can be significantly improved, along with considerably prolonged survival, though the long-term efficacy of HSCT for different organs may vary to a certain extent.