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Science Translational Medicine May 2024Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem...
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.
Topics: Humans; Mucopolysaccharidosis I; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Male; Female; Child, Preschool; Infant; Treatment Outcome; Hematopoietic Stem Cells; Child; Bone and Bones; Magnetic Resonance Imaging
PubMed: 38691622
DOI: 10.1126/scitranslmed.adi8214 -
Rhode Island Medical Journal (2013) May 2024Children with Hunter syndrome have a high prevalence of nerve compression syndromes given the buildup of glycosaminoglycans in the tendon sheaths and soft tissue...
BACKGROUND
Children with Hunter syndrome have a high prevalence of nerve compression syndromes given the buildup of glycosaminoglycans in the tendon sheaths and soft tissue structures. These are often comorbid with orthopedic conditions given joint and tendon contractures due to the same pathology. While carpal tunnel syndrome and surgical treatment has been well-reported in this population, the literature on lower extremity nerve compression syndromes and their treatment in Hunter syndrome is sparse.
OBSERVATIONS
We report the case of a 13-year-old male with a history of Hunter syndrome who presented with toe-walking and tenderness over the peroneal and tarsal tunnel areas. He underwent bilateral common peroneal nerve and tarsal tunnel releases, with findings of severe nerve compression and hypertrophied soft tissue structures demonstrating fibromuscular scarring on pathology. Post-operatively, the patient's family reported subjective improvement in lower extremity mobility and plantar flexion.
LESSONS
In this case, peroneal and tarsal nerve compression were diagnosed clinically and treated effectively with surgical release and postoperative ankle casting. Given the wide differential of common comorbid orthopedic conditions in Hunter syndrome and the lack of validated electrodiagnostic normative values in this population, the history and physical examination and consideration of nerve compression syndromes are tantamount for successful workup and treatment of gait abnormalities in the child with Hunter syndrome.
Topics: Humans; Male; Adolescent; Mucopolysaccharidosis II; Tarsal Tunnel Syndrome; Peroneal Neuropathies; Peroneal Nerve; Nerve Compression Syndromes
PubMed: 38687262
DOI: No ID Found -
Orphanet Journal of Rare Diseases Apr 2024Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the... (Review)
Review
Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.
Topics: Humans; Mucopolysaccharidoses; Tandem Mass Spectrometry; Biomarkers; Glycosaminoglycans
PubMed: 38685110
DOI: 10.1186/s13023-024-03195-w -
Cell Death & Disease Apr 2024Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without...
Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/β-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3β inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.
Topics: Induced Pluripotent Stem Cells; Humans; Glycogen Synthase Kinase 3 beta; Neurons; Mucopolysaccharidosis II; Cell Differentiation; Wnt Signaling Pathway; Signal Transduction; Calcium Signaling; Nerve Degeneration; Calcium
PubMed: 38684682
DOI: 10.1038/s41419-024-06692-9 -
Frontiers in Genetics 2024Bibliometrics can trace general research trends in a particular field. Mucopolysaccharidoses (MPS), as a group of rare genetic diseases, seriously affect the quality of...
Bibliometrics can trace general research trends in a particular field. Mucopolysaccharidoses (MPS), as a group of rare genetic diseases, seriously affect the quality of life of patients and their families. Scholars have devoted themselves to studying MPS's pathogenesis and treatment modalities and have published many papers. Therefore, we conducted a bibliometric and visual study of the top 100 most highly cited articles to provide researchers with an indication of the current state of research and potential directions in the field. The Web of Science Core Collection was searched for articles on MPS from 1 January 1900, to 8 November 2023, and the top 100 most cited articles were screened. The title, year of publication, institution, country, and first author of the articles were extracted and statistically analyzed using Microsoft Excel 2007. Keyword co-occurrence and collaborative networks were analyzed using VOSviewer 1.6.16. A total of 9,273 articles were retrieved, and the top 100 most cited articles were filtered out. The articles were cited 18,790 times, with an annual average of 188 citations (122-507). Forty-two journals published these articles, with Molecular Genetics and Metabolism and Proceedings of the National Academy of Sciences of the United States being the most published journal (N = 8), followed by Pediatrics (N = 7), Blood (N = 6). The United States (N = 68), the UK (N = 25), and Germany (N = 20) were the top contributing countries. The Royal Manchester Children's Hospital (N = 20) and the University of North Carolina (N = 18) were the most contributing institutions. Muenzer J was the most prolific author (N = 14). We conducted a bibliometric and visual analysis of the top 100 cited articles in MPS. This study identifies the most influential articles currently available in the field of MPS, which provides a good basis for a better understanding of the disease and informs future research directions.
PubMed: 38680422
DOI: 10.3389/fgene.2024.1377743 -
Pediatric Neurology Jun 2024One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in...
BACKGROUND
One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in adult patients, there is limited experience of this in the pediatric group. We aimed to investigate the results of wrist ultrasonography, which may be a candidate alternative to electrophysiological examination.
METHODS
The participants were evaluated for symptoms, physical examination findings, electrophysiological tests and grayscale US. CTS was diagnosed in accordance with the American Academy of Orthopedic Surgeons Management of Carpal Tunnel Syndrome: Evidence-Based Clinical Practice Guideline.
RESULTS
Included in the study were 27 MPS patients aged 4.5-32 years and 30 healthy control subjects aged 4.3-26 years. Of the 54 wrists in the MPS group, 30 were diagnosed with CTS. The median cross-sectional area (CSA) at the proximal carpal tunnel, the CSA at the forearm, and the wrist-forearm ratio (WFR) were higher in the wrists of the MPS with CTS group than in those without CTS and the healthy control subjects. The WFR cutoff of ≥1.35, 56.6% (95% CI: 437.4-74.5) sensitivity, and 89.8% (95% CI: 81.0-95.5) specificity were consistent with a diagnosis of CTS (receiver operating characteristics analysis, area under the curve = 0.775, 95% CI: 0.673-0.877).
CONCLUSION
Although the US provides results with unsatisfactory specificity and sensitivity, it is a candidate for further investigation for the diagnosis of CTS because it is an innovative, noninvasive, and more accessible method. WFR value may produce more meaningful results than wrist or forearm nerve area measurements.
Topics: Humans; Carpal Tunnel Syndrome; Male; Ultrasonography; Mucopolysaccharidoses; Female; Child; Adolescent; Young Adult; Adult; Child, Preschool; Wrist; Sensitivity and Specificity; Neural Conduction
PubMed: 38669799
DOI: 10.1016/j.pediatrneurol.2024.03.032 -
American Journal of Medical Genetics.... Apr 2024Mucopolysaccharidosis type 10 is caused by biallelic variants in ARSK, which encodes for a lysosomal sulfatase. To date, seven patients with a mild phenotype resembling...
Mucopolysaccharidosis type 10 is caused by biallelic variants in ARSK, which encodes for a lysosomal sulfatase. To date, seven patients with a mild phenotype resembling spondyloepiphyseal dysplasia or multiple epiphyseal dysplasia have been described. In this report, we present two novel ARSK variants and report clinical and radiological findings of three patients. The patients' initial complaints were hip or knee pain and a waddling gait. All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly. While typical dysostosis multiplex findings were not observed, mild platyspondyly with anterior beaking of some vertebral bodies, irregular vertebral endplates, wide ribs, inferior tapering of the ilea with a poorly developed acetabulum, irregularity of the central part of the femoral head, delayed ossification of the carpals were noted. Remarkably, all patients showed metaphyseal striation of the long bones, a crucial diagnostic clue to identify ARSK-related MPS type 10. Interestingly, vertebral involvement regressed during follow-up. On the other hand, hip dysplasia progressed in all patients. In conclusion, this study provides valuable long-term results on a recently discovered form of MPS.
PubMed: 38634625
DOI: 10.1002/ajmg.a.63635 -
Journal of Neurodevelopmental Disorders Apr 2024Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for...
BACKGROUND
Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model.
METHODS
Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging.
RESULTS
We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively.
CONCLUSIONS
Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.
Topics: Humans; Animals; Adult; Child; Mucopolysaccharidosis III; Diffusion Tensor Imaging; Brain; Disease Models, Animal; Treatment Outcome
PubMed: 38632525
DOI: 10.1186/s11689-024-09534-z -
Cell Death & Disease Apr 2024Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in...
Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in iduronate-2-sulfatase (IDS) activity, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remain still underexplored. In this work, we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids mutant larvae display an atypical response to anxiety-inducing stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur with early childhood behavioural abnormalities.
Topics: Animals; Axon Guidance; Brain; Iduronate Sulfatase; Mucopolysaccharidosis II; Nervous System Diseases; Zebrafish
PubMed: 38627369
DOI: 10.1038/s41419-024-06661-2 -
International Ophthalmology Apr 2024This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and... (Review)
Review
PURPOSE
This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and immune liver conditions.
METHODS
Recent data were compiled from PubMed from 2000 to 2020 using keywords that were relevant to the assessed pathologies. Ocular presentations of several liver pathologies were researched and then summarized in a comprehensive form.
RESULTS
Several ocular manifestations of liver disease were related to vitamin A deficiency, as liver disease is associated with impaired vitamin A homeostasis. Alcoholic liver cirrhosis can result in vitamin A deficiency, presenting with Bitot spots, xerosis, and corneal necrosis. Congenital liver diseases such as mucopolysaccharidoses and peroxisomal disorders are also linked with ocular signs. Viral causes of liver disease have associations with conditions like retinal vasculitis, keratoconjunctivitis sicca, retinopathies, Mooren's ulcer, and Sjogren's syndrome. Autoimmune hepatitis has been linked to peripheral ulcerative keratitis and uveitis.
CONCLUSIONS
Building strong associations between ocular and liver pathology will allow for early detection of such conditions, leading to the early implementation of management strategies. While this review outlines several of the existing connections between hepatic and ophthalmic disease, further research is needed in the area in order to strengthen these associations.
Topics: Humans; Vitamin A Deficiency; Keratoconjunctivitis Sicca; Corneal Ulcer; Sjogren's Syndrome; Dry Eye Syndromes; Liver Diseases; Retinal Vasculitis
PubMed: 38622271
DOI: 10.1007/s10792-024-03103-y