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Mucopolysaccharidosis type IIID (MPS IIID; Sanfilippo D) is caused by biallelic pathogenic variants in N-acetylglucosamine-6-sulfatase (GNS), which participates in catabolism of heparan sulfate (HS) glycosaminoglycans. Characterization of MPS IIID disease at a cellular level has not been robustly achieved. We used unbiased quantitative proteomics to establish a cellular phenotype for MPS IIID mice. Recombinant human GNS (rhGNS), a variant of which previously demonstrated single dose efficacy in MPS IIID human fibroblasts and in MPS IIID neonatal mice, was used to establish a repeat dosing schedule to treat MPS IIID mice. Adult Gns KO mice or heterozygous carriers were treated via intracerebroventricular (ICV) injections and received 3, 30, or 200 μg rhGNS in 4 doses over 2 weeks or vehicle. Twenty-four hours after the final dose, HS in brain and CSF showed dose-dependent reductions, reaching carrier levels in the higher dose groups. Furthermore, the proteomic perturbations that we described were corrected by rhGNS treatment. Next, Gns KO or carrier adult mice were treated via ICV and received 3, 30 or 200 μg rhGNS or vehicle once every two weeks (Day 1, 15, 29, 43, 57, 71, 85) and were euthanized on day 91. Following treatment, total HS and MPS IIID-specific HS (GlcNAc6S) showed dose-dependent reductions in brain and CSF and markers of neuroinflammation were substantially reduced. ICV enzyme replacement therapy with rhGNS restores CNS pathology of adult MPS IIID mice even with treatment at 14-day intervals, demonstrating preclinical efficacy for MPS IIID.

While the practice of medical genetics has been around since the 1940s,1 studies repeatedly show that both health care professionals and their patients feel that they do not have sufficient understanding of genetics.2,3 For patients, this lack of understanding leads to low uptake of genetic testing, lack of follow-through with referrals, and misunderstanding of genetic testing results. Health care professionals often feel unprepared to help and may communicate outdated information about the practice of medical genetics. The ACMG is a good source for explanations of the genetics workforce, as well as clinical guidelines, continuing medical education, and other resources.5 The purpose of this issue is to bridge the gap between medical genetics services and the broader healthcare community.

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1-/-) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1-/- mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

Background Quality health information is key to patient engagement, self-management and an enhanced healthcare experience. There is strong evidence to support involving patients and their families in the development and evaluation of health-related educational material. These factors were the impetus for our high volume joint replacement centre to undertake a qualitative study to elicit patient experiences to inform the development of effective strategies and education along the care continuum for hip and knee replacement. Methods Purposively selected patients from postoperative follow-up clinics were recruited to participate in a focus group or telephone interview. We developed a semi-structured interview guide that addressed four specific aspects of the patient’s experience with educational material: pre-surgery, hospital stay, recovery period and future recommendations. The focus groups and interviews continued to the point of saturation and were audio-recorded and transcribed verbatim. Interview transcripts were coded and then inductively organized into larger categories using thematic analysis. Results Six focus groups and seven telephone interviews were conducted, totalling 32 participants. One of the key themes that emerged was a need for more education concerning pain management post-operatively; specifically, patients wanted more information on expected levels of pain, pain medication usage, management of side effects and guidelines for weaning off the medication. There was surprising variability in patients’ descriptions of their pre-surgery, surgery and recovery experiences. These corresponded to an equally diverse range of preferences for educational content, delivery and timing. Many patients reported using the web while others preferred traditional formats for information delivery. There was some interest in receiving education using mobile technology. Conclusions Our findings validate the importance of multi-modal patient education tailored to individual preferences and experiences, which may differ according to such characteristics as gender and age. The gap in pain management information is a critical finding for healthcare providers working with patients undergoing joint replacement. Developing pain management education in different formats that addresses frequently asked questions will enhance patient engagement and, their overall experience and recovery.

A biomarker in spinal fluid reflects brain disease in a rare genetic disorder, with implications for how we diagnose and monitor the disease.

Purpose In response to COVID-19 related health care access restrictions, telemedicine was introduced to continue to provide necessary health care access in Ontario, Canada. This study examined the role of a telephone assessment (triage) in streamlining referral consultation in patients with low back pain who were referred to a spine specialty surgical clinic. Methods This was an observational study of patients presenting with low back pain with or without leg pain. The virtual interview was conducted by an experienced Advanced Practice Physiotherapist (APP) via telephone. The clinician documented the current symptoms, reviewed referral information including diagnostic imaging and made decisions regarding surgical appropriateness. Patients with cauda equina syndrome, metastatic spinal cord compression lesions, infection and fractures were excluded. Descriptive analysis and general linear modeling were conducted. Results A consecutive sample of 100 patients, 50 females (average age = 58, SD: 16, range 20–87 years) participated in the virtual assessment. Of 100 participants, 41 (41%) were deemed appropriate to proceed for an in-person assessment, with 36% being considered as potential surgical candidates (33 patients were seen by a spine surgeon and 3 were referred to a hip surgeon for hip arthritis). Fifty-nine (59%) patients did not require an in-person visit to the clinic. The most prominent reason for subsequent surgical assessment was leg dominant pain (neurogenic claudication/radiculopathy) with concordant imaging findings (27, 75%). There was a statistically significant association between surgical candidacy and presence of leg symptoms secondary to disc herniation or claudication ( p  = 0.0002) with no association with the scores of the PROMs or isolated imaging ( P  > 0.05). Conclusion A structured virtual telephone interview was an effective means of triaging patients with LBP with and without leg pain with a potential of reducing the number of unnecessary visits to a spine surgeon. Radicular pain to the lower extremity was the most common symptom among participants who were directed to the surgeon.

Background The purposes of this study were to examine the reliability and factorial and convergent validity of a virtual performance measure (VPM) in patients with osteoarthritis (OA) of the hip joint and to compare the known-group validity of the VPM with traditional self-report and performance-based outcomes. Methods The VPM score was based on the results of 10 videos showing increasing difficulty in performing specific functional tasks. Patients were requested to choose the video that best reflected their own level of function. Clinical presentation and radiological findings were documented. Self-report measures were the lower extremity functional score (LEFS) and pain scale. The performance-based measures were the 30- second Chair Stand Test (CST) and the 40-meter fast paced walk test (40 m FPWT) test. Results Data of 100 patients, 64 (64%) females, mean age: 67 ±10 were examined. The Cronbach’s alpha coefficient that examined internal consistency of the VPM total score was 0.88. Factor analysis showed two distinct domains. Moderate correlations were observed between the VPM total score and the LEFS, pain score, and 40 m FPWT ( r  > 0.50). The VPM and the LEFS were able to differentiate between candidates and non-candidates for hip arthroplasty and between those with and without assistive walking devices. There was no statistically significant difference between the overall accuracy of the VPM and LEFS in the area under the curve value (0.72 vs. 0.71) with respect to candidacy for surgery. Conclusions This study provides substantial evidence towards the validity and reliability of the VPM outcome measure in patients with moderate to severe OA of the hip joint. Digitally based outcome measures have the potential of enhancing remote measurement of functional difficulties in specific situations. Clinical trial number Not applicable.

Purpose Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. Methods In addition to intravenous ERT and hematopoietic cell transplantation, patients ( N  = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. Results Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. Conclusion Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.

Significance Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating and currently untreatable disease affecting mainly the brain. The cause is lack of the lysosomal enzyme, α– N -acetylglucosaminidase (NAGLU), and storage of heparan sulfate. Using a mouse model of MPS IIIB, we administered a modified NAGLU by injection into the left ventricle of the brain, bypassing the blood–brain barrier. The modification consisted of a fragment of IGFII, which allows receptor-mediated uptake and delivery to lysosomes. The modified enzyme was taken up avidly by cells in both brain and liver, where it reduced pathological accumulation of heparan sulfate and other metabolites to normal or near-normal levels. The results suggest the possibility of treatment for MPS IIIB. Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α– N -acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood–brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood–brain barrier, the fusion protein (“enzyme”) in artificial cerebrospinal fluid (“vehicle”) was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1–28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.

Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease. Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry. Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice. Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker.