#MSDCon2024

Multiple Sulfatase Deficiency (MSD) is an ultra-rare lysosomal storage disorder (LSD)caused by mutations in the SUMF1 gene. The SUMF1 gene encodes formylglycine-generated enzyme (FGE), the protein responsible for activating all sulfatases in the cell. The reduction or complete loss of FGE causes detrimental accumulation of sulfated substrates in the lysosome, including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Neurological regression is a primary clinical feature of MSD, which suggests that neural cell types are particularly intolerant to dysfunctional lysosomal flux. Therapeutics targeting MSD are currently limited, and there is an urgent need for a reproducible in vitro model of MSD that recapitulates biochemical phenotypes seen in the patient population. To fulfill this need, we recently generated NGN2-induced neurons (NGN2-iN) from induced pluripotent stemcells (iPSC) derived from a patient with MSD. We use a battery of biochemical and molecular techniques to demonstrate that our model reproduces biochemical phenotypes associated with MSD. Patient NGN2-iN display hallmark pathology of MSD seen in humans, including reduced activity of multiple sulfatases and lysosomal accumulation as compared to isogenic controls. Over time, these neuronsalso demonstrate progressive accumulation of GAG subspecies associated with mucopolysaccharidosis type III. Interestingly, these phenotypes worsen in more mature (Day 11) MSD NGN2-iN, as compared to immature (Day 3) MSD NGN2-iN andiPSCs. This observation suggests that neurons are selectively vulnerable to the loss of FGE, and that dysfunction worsens over neuronal maturation. We anticipate that our model will be utilized to compare the selective vulnerability of individual CNS cell types, further our current understanding of MSD pathophysiology, and ultimately aid the development of therapeutics.

High throughput drug screening identified 3rd generation retinoids tazarotene and bexarotene to restore sulfatase activities, lysosomal positioning and reduction of glycosaminoglycan storage in Multiple Sulfatase Deficiency (MSD, MIM#272200) patient derived fibroblasts. MSD is an ultra-rare inherited lysosomal disorder caused by mutations in the Sulfatase-Modifying-Factor 1 gene (SUMF1) resulting in misfolding, accelerated degradation, and reduced functionality of variants of the Formylglycine-generating enzyme (FGE). Tazarotene is currently investigated for its clinical application as an oral treatment for MSD. The potential of unwanted effects trough tazarotene treatment in children requires the timely identification of alternative druggable targets in MSD cells.

Tazarotene and bexarotene bind to retinoic acid receptors (RARs) and retinoid-X-receptors (RXRs), respectively, in MSD fibroblasts. Binding of retinoic acid derivatives to RARs and RXRs initiates formation of homo- and heterodimers that bind to DNA binding motifs thereby initiating transcription of genes. Ultimately, treatment of cells leads to sulfatase activity increase by decelerated degradation of variant FGE. Blocking of RAR and RXR receptors, respectively, is able to abrogate tazarotene and bexarotene function in MSD fibroblasts. Detailed mechanism of retinoid function downstream of RAR and RXR receptors and upstream of FGE stabilization remains unknown.

In recent work we identified tazarotene and bexarotene to induce endoplasmic reticulum stress mediated by the activation of proteins of the unfolded protein response as one putative mode of action of tazarotene and bexarotene response in MSD cells. Treatment of cells with alternative drug substances and compounds targeting downstream signals of retinoic acid signalling mimicked tazarotene and bexarotene treatment in MSD fibroblasts thereby providing first evidence of effective in-vitro MSD treatment with small molecules as alternatives to retinoids.

Multiple Sulfatase Deficiency (MSD) is a rare lysosomal autosomal recessive disease caused by the loss of function of Formylglycine generating enzyme (FGE) and characterised by almost complete lack of all sulfatase activities. An in-house drug repurposing screening assay of circa 800 FDA approved drugs, carried out in the Schlotawa laboratory in Gottingen, identified a family of structurally and functionally related molecules which are able to upregulate sulfatases activity, reducing glycosaminoglycan storage, and reducing lysosomal size in MSD patient derived cell lines.

In this session we will discuss the development of new small molecule sulfatase reactivators for MSD, following-up and building on these recent preliminary findings. We report the design, synthesise and biologically evaluation of a library of retinoid derivatives targeting the RAR and RXR receptors as well as a fragment-based drug discovery approach which builds on the recent crystallographic fragment screenings (CFS) carried out by the Hartmut laboratory in Bielefeld. We have identified the first small molecule to bind the Formylglycine generating enzyme, a key milestone towards the development of a pharmacological chaperone-based drug for MSD and the discovery of the first FGE stabilizer.

Induced pluripotent stem cells (iPSCs) are reprogrammed from patient somatic cells, thereby harboring natural disease-causing variants within the patient’s genetic background. iPSCs can be differentiated into cellular lineages that are difficult to obtain from patients, such as neurons. Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD patients present neurologic symptoms and neurological disability is universal. However, the specific impact of lysosomal storage on neuronal function and degeneration remains unclear. Here we purposed differentiated MSD and isogenic control iPSCs into neurogenin-2-induced neurons (NGN2-iNs) and to characterized and compare them. To generate an iPSC model of MSD, peripheral blood mononuclear cells were isolated from the whole blood of an MSD patient that was homozygous for the recurrent pathogenic variant SUMF1 c.836C>T, p.A279V. Cells were reprogrammed using non-integrating Sendai viral vectors expressing the human factors OCT3/4, SOX2, KLF4, and cMYC. An isogenic control iPSC line was generated in order to reduce variation in the genetic background between groups. We used CRISPR/Cas9 to correct the pathogenic c.836C>T in the MSD iPSC parental line. We next generated a MSD and isogenic control NGN2-iNs by overexpressing NGN2 transcription factor. NGN2-iNs were collected for analyses at Days 3 (D3 NGN2-iN) and 11 (D11 NGN2-iN) of differentiation to compare phenotypes during neuronal development. iPSCs demonstrated neurite outgrowth by Day 3 and had elaborate processes by Day 11. These findings indicate that MSD iPSCs can successfully differentiate into NPCs and NGN2-iNs to produce neural models. In summary, we successfully differentiated iPSC lines into NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.

Background:
Aicardi Goutières Syndrome (AGS) is a common and phenotypically heterogenous leukodystrophy. In general, neurodegenerative disorders of childhood are known to strongly affect the quality-of-life (QoL) and perspective of the whole family and caregiver network. This study explores AGS-related QoL impact in affected children and their caregivers through qualitative interviews and non-concurrently administered validated quality-of-life (QoL) surveys. The goal of this project is to identify disease-specific Health Concepts, to appropriately inform development of disease-specific prospective natural history studies focused on identification of Concept of Interest (COI) and selection of clinical outcome assessments (COAs) able to capture them.

Methods:
The study was designed as mixed-methods. Qualitative interviews (N= 33) and QoL questionnaires (N= 38 to 53) were administered to caregivers of AGS-affected children. The questionnaires included Pediatric Quality of Life-Generic Core (PedsQL-GC) and Family Impact (PedsQL-FI) modules, Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD), and Caregiver TBI-CareQoL. The open-ended interviews with guided questions addressed caregiver’s perception of AGS and determinants of QoL. Interviews were conducted until thematic saturation, and qualitative analyses generated salient themes.

Results:
The CPCHILD (n=46), PedsQL-GC (n=53), CareQol (n=38), and PedsQL-FI (n=49) showed impairment of gross and fine motor abilities. activities of daily living (including personal care and independence in the context of domestic and community environments), and overall health and comfort. CPCHILD and PedsQL-FI showed better performance in our cohort, avoiding floor effect (defined as <20%) in each section and demonstrating high compliance to completion.
In the context of qualitative interviews, there was overall alignment between the emerging themes and the most impacted domains of the QoL questionnaires. Families reported stress surrounding symptoms of AGS, poor neurologic development with communication and motor impairment, and the overall impact of the disease on the family. Small improvements in any of these areas was described as important and meaningful.

Discussion:
The study showed the profound effects of AGS on families with global effects on family life. Gross and fine motor abilities, independence in activities of daily living, and overall health and comfort emerged as relevant Health Concepts, that will be used to develop COI and select COAs. This methodology can be replicated in other rare disorders, to design more patient-centric natural history study protocols and inform design of future clinical trials.

Background:
Aicardi Goutières Syndrome (AGS) is a leukodystrophy characterized by systemic inflammation and severe neurologic impairment. While many children with AGS demonstrate severe motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. One challenge is that most cognitive tests require intact motor function. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior.

Methods:
Individuals with a confirmed clinical and molecular diagnosis of AGS were included. Demographic information and AGS Severity Scale Scores were derived from medical records. The Leiter International Performance Scale 3rd edition (Leiter-3) was administered to subjects and parental assessment of function was captured by the Vineland Adaptive Behavior Scale (VABS) 3rd edition. Motor skills were categorized based on mobility levels captured using the AGS Severity Scale.

Results:
Cognitive and adaptive behavior performance was captured in 57 subjects. The mean age at test administration was 8.51 years (SD=5.15). The median score recorded using Leiter-3 was 51 (IQR=60). On the VABS, the Motor Domain was significantly more impacted than the Communication, Daily Living Skills, and Social Domains (p<0.0001). Performance on the AGS scale strongly correlated with VABS-3 and Leiter-3 scores (Spearman’s rank correlation coefficient: r=0.86, p<0.0001; r=0.87, p<0.0001, respectively). There was strong correlation between domains of the VABS-3 with performance on the Leiter-3 (Spearman’s rank correlation coefficient: range=0.83-0.97). Gross motor and fine motor categorization correlated with VABS-3 and Leiter-3 performance (gross motor: Kruskal-Wallis test, both p<0.0001; fine motor: Mann-Whitney U test, both p<0.0001). Within each gross motor and fine motor category of the AGS Severity Scale, a subset of children scored within the normal IQ range.

Discussion:
Parental assessment of function by the VABS-3 strongly correlated with the directly assessed performance measures (physician-reported AGS scale and Leiter-3). Our data underscores the potential value of the VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients’ abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Formylglycine-generating enzyme (FGE) modifies the active site of all known human sulfatases post-translationally, by conversion of a cysteine to formylglycine. Missense mutations in the gene encoding FGE lead to catalytically impaired or unstable protein variants that are prone to degradation. The resulting lack of sulfatase modification causes the rare disease multiple sulfatase deficiency (MSD). With X-ray protein crystallography, we search for small molecules (fragments) that bind to FGE. In a structure-based approach, the found fragments can be further developed into pharmacological chaperones, that potentially stabilize mutated FGE variants and rescue their activity.

Using the F2X-Entry Screen, a subset of the F2X-Universal library, and additional compounds selected from previous experiments, we soaked preformed crystals of human FGE with fragments to identify hits and interesting binding pockets on the enzyme surface. Data collection at BESSY BL 14.2 and multi data set analysis revealed several unique fragment hits in four interaction sites, including the active site of FGE.
Based on the results of the first fragment screen, two compounds, with overlapping binding positions in an allosteric site, were used for merging and synthesis of several follow-ups. Data collection at DESY P13 revealed Fo-Fc density for one of these follow-ups in a data set from a single crystal which suggests stronger interaction with the enzyme. To evaluate whether the discovered hits and follow-up compounds stabilize the protein or not, we obtained first results from differential scanning fluorimetry.

Additionally, we have started a bigger crystallographic screen with the full F2X-Universal library at BESSY. In this ongoing project, we already found further compounds that interact with FGE in three major binding sites, the results of this experiment complement to the ongoing drug design process.

Multiple sulfatase deficiency (MSD) is an ultra-rare neurometabolic disease caused by insufficient formyl glycine-generating enzyme (FGE) function, which is required for sulfatase activation, and thus results in a deficiency of all cellular sulfatases. MSD is clinically characterized by early developmental delays and severe, progressive neurologic regression that can additionally present with ichthyosis, hepatosplenomegaly, and hearing loss. Furthermore, it has been noted that hydrocephalus can be a feature of MSD, which can be visualized by changes on MRI. Here we report the case of a child with MSD and chronic marked communicative hydrocephalus with MRI brain findings of severe enlargement of the ventricular system and extra-axial CSF spaces, as well as increased lumbar CSF opening pressure. To treat the hydrocephalus, a right-sided ventriculoperitoneal (VP) shunt was placed with laparoscopic assistance.

Background:
Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disorder characterized by the functional deficiency of all sulfatase enzymes. MSD is caused by mutations in the gene SUMF1, encoding a sulfatase modifying factor that activates 17 downstream sulfatases. MSD patients present with combined features of single-sulfatase disorders such as the mucopolysaccharidoses and metachromatic leukodystrophy (MLD). Currently, there are no disease-modifying therapies for MSD. We aimed to develop ex vivo gene therapy with hematopoietic stem cell transplant for MSD, as this approach has proven successful for related disorders.

Methods:
We designed lentiviral vectors encoding either 1) SUMF1 or 2) a downstream sulfatase ARSA that is greatly implicated in the disease. ARSA ex vivo gene therapy is approved by the EMA for MLD and has the potential to be repurposed for patients with MSD.

Results:
In vitro, MSD patient fibroblasts transduced with the lentiviral vectors demonstrated improved biochemical phenotypes including rescue of sulfatase activities and glycosaminoglycan (GAG) accumulation. In vivo, both lentiviral vectors proved efficacious in rescuing biochemical and behavioral phenotypes in MSD mice that underwent hematopoietic stem cell transplant with ex vivo gene therapy. To further augment outcomes, we co-transduced MSD patient fibroblasts with both SUMF1 and ARSA vectors and found that co-expressing these transgenes greatly enhanced biochemical rescue in vitro. We will present the results of our ongoing work evaluating the efficacy of this innovative dual-transgene approach in MSD mice after ex vivo gene therapy.

Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatase. MSD patients frequently carried two loss of function mutations in the SUMF1 gene, encoding a sulfatase modifying factor which activates 17 different sulfatases. MSD patients shown common features of mucopolysaccharidosis, and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Gene therapy may provide a meaningful and long-term therapeutic benefit for MSD patients by delivering a functional copy of the SUMF1 gene to patient cells. We developed a self-complementary vector encoding a codon-optimized human SUMF1 gene (scAAV9/SUMF1), the unaltered design of which could be appropriate for human use. Using a severe Sumf1 knock-out (KO) mouse model of MSD, we tested the benefits of treatment with our vector in mice shortly after birth and later in the disease course by administering virus into the cerebrospinal fluid (CSF) alone or in combination with an intravenous injection. CSF administration of scAAV9/SUMF1 was sufficient to rescue early lethality, normalize behavior and improve newly identified visual and cardiac dysfunctions in KO mice, even when given at an advanced disease stage. We found dose-dependent and long-term restoration of sulfatase activity in tissues, which is accompanied by decreased accumulation of glycosaminoglycans, lysosomal defects and neuroinflammation in the brain. Even at the highest dose tested, scAAV9/SUMF1 was well-tolerated without toxicity from high transgenic SUMF1 expression in KO and wild-type mice or in rats that were treated as part of a GLP-toxicology study. Overall, our preclinical results attest to the safety of scAAV9/SUMF1 delivery and predict a benefit of this treatment to MSD patients.

Background:
Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells.

Methods:
A retrospective data analysis was done on the two siblings who underwent HCT. The data collected included biomarkers including urine glycosaminoglycans, urine sulfatides, untargeted metabolomics in plasma and enzyme assays. The data from neuropsychology evaluation was also collected up to 3 years after HCT.

Results:
Biochemical correction of all the previously deficient enzyme activity in the leukocytes was evident within 3 months post HCT. Urine heparan and dermatan sulfate along with urine sulfatides were normal in the pre and post HCT samples due to the milder phenotype. While single, unique biomarkers were not identified for MSD, multiple consistent metabolic perturbations across patients were noted. Specifically, glycerophospholipids constituted the predominant category of perturbed sub-pathways in both siblings. Arylsulfates and fatty acids and derivatives, exhibited substantial perturbations, representing the second or third largest proportion of perturbed metabolites across the siblings. Additionally, energy-related sub-pathways such as bile acids, cholesterols, sterols, nucleotides, and various amino acids were disrupted. Notably, the relative levels of disruption across these sub-pathways between the siblings are consistent. These results indicate that MSD induces a broad state of metabolic dysregulation. The impact of HCT were monitored by comparing metabolomic profiles pre- and post-HCT. An almost instant neutralization effect introduced by HCT was observed. The correction of abnormalities was further quantitatively analyzed in every sequential post-HCT samples, while the initial post-HCT samples collected at 3 months showed a significant correction, with more than 70% of abnormal concentration levels falling within the normal range. This correction persisted in subsequent post-HCT samples, demonstrating the effectiveness of HCT. These finding align with the biochemical enzyme corrections observed in the patients.

Conclusion:
These data suggest biochemical benefit post-transplant, although the clinical implication of these corrections are unknown, particularly in the context of the siblings’ attenuated phenotype. Long-term follow-up is necessary to evaluate the therapeutic benefit of HCT in MSD.

Background:
Leukodystrophies are rare genetic disorders affecting myelination. The enactment of the Food and Drug Administration (FDA) 1983 Orphan Drug Development Act, in addition to advancements in clinical characterization and diagnostic tools, has led to increasing interest in rare disease drug development. The needs of rare disease drug development and approval is rapidly evolving in the context of the 2022 four-part FDA guidance “Patient-Focused Drug Development” (PFDD), necessitating its adoption in the context of clinical trial readiness. In this study, we propose a multi-component standardized patient-centric approach to the identification of clinical outcome assessments (COAs) for use in the context of clinical trials.

Methods:
We developed a multi-component approach based on FDA’s conceptual model. First, patient caregiver-identified Health Concepts (HC) and derived priorities (Concepts of Interest [COI]) were identified through standardized impact-of-disease questionnaires. This was followed by consensus building on COIs for use in the context of clinical trials (Context of Use [COU]), among a panel of disease experts, through modified eDelphi approach, a multi-round iterative virtual process of anonymized voting on pre-specified themes by an expert panel. Disease experts are identified based on contribution to the field and/or clinical expertise. Identified experts are solicited to vote on statements describing “importance” and “changeability within a pre-defined time frame”, in the COU, of the COIs. COIs are qualified upon reaching 70% agreement on both its importance and changeability. Upon failure to qualify, the statements are clarified and deployed for subsequent voting. Upon eDelphi completion, the caregiver- and expert-identified COIs within COU are aligned. Subsequently, selection of Clinical Outcome Assessments (COAs) capturing COI is performed through similar consensus building among outcome experts, followed by determination of COA fit-for-purpose for application in the COU. A study protocol delineating COA performance is then developed for prospective application in a cohort of affected individuals for validation of the COA and feasibility assessment.

Results:
The results of the consensus building approach to identification of COIs within COU for Aicardi-Goutieres Syndrome is summarized here. A total of 4-rounds of voting was performed among 10 experts each in rounds 1 & 3, and 12 in rounds 2 & 4. The following COIs achieved overall consensus: (i) Motor- postural function, floor mobility, coordination, endurance in physical activity, use of electronic devices, fine motor performance speed and pointing; (ii) Adaptive behavior- use of adaptive/alternative communication, complexity of verbal language, endurance and quality in completion of cognitive tasks, independence in completion of activities of daily living, imitation of activities, preferential looking and communication through behavior; (iii) Neurologic function- visual function and neurologic signs; (iv) skin lesions.

Conclusion:
The proposed approach is the first step towards clinical trial readiness adopting patient-centricity in rare diseases. The outcome is a rigorous COA protocol for prospective application and a panel of validated COAs applicable in clinical trials. This is critical to (i) identify clinical endpoints and determine meaningful changes in the endpoints as required by the FDA guidelines on PFDD, and (ii) inform clinical trial design.

Background:
Leukodystrophies are rare genetic disorders affecting myelination. Emerging therapeutics primarily target the pre-symptomatic population, but there is a knowledge gap on the impact of disease across the lifespan. To address this, we propose a standardized approach to performing retrospective natural history studies using existing medical records.

Methods:
As part of Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into “original” and “imputed” encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments are assigned by child neurologists, using a blinded dual-rater approach and any discrepancies are adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics.

Results:
To date, the records from 922 subjects have undergone this process across the GLIA-CTN database and this includes 300 subjects with Metachromatic leukodystrophy, 220 with Aicardi Goutières Syndrome, 167 with Pelizaeus-Merzbacher Disease, 25 with Multiple Sulfatase Deficiency, and 210 with Hypomyelination with Atrophy of Basal Ganglia and Cerebellum.

Conclusion:
The proposed methodology will enable us to leverage existing medical records to accrue subjects and capture clinical information, specifically pre-symptomatic data, on a large cohort of subjects in a shorter duration. This robust data collection will enable— (i) greater understanding of clinical course across leukodystrophies, and (ii) robust, regulatory-standard data applicable as historic controls in clinical trials.

Introduction:
MicroRNAs (miRNAs) are small RNA molecules that play a crucial role in translation regulation, influencing major cellular processes such as cell fate and development. miRNAs have been implicated in MSD, an ultra-rare neurodegenerative disorder characterized by progressive neurodegeneration leading to the loss of sensory and motor skills.

Methods:
In this study, we present miRNAs that are dysregulated in neurons derived from patient-derived induced pluripotent stem cell and isogenic controls. Next-generation sequencing (NGS) miRNA sequencing was conducted to profile their differential expression, followed by downstream analysis. Initial quality control and annotation were performed on the Illumina BaseSpace platform.

Result and Discussion:
Downstream analysis using Ingenuity Pathway Analysis (IPA) revealed significant upregulation of hsa-miR-1269b, hsa-miR-4516, and hsa-miR-4761-3p in the MSD neurons (FDR p-value < 0.0001). EN2 and HNRNPU emerged as the two most significantly enriched predictive targets for these miRNAs. EN2 plays a role in controlling the development of the central nervous system and dopaminergic neurogenesis, with dysregulation linked to cerebellar hypoplasia and other neurodegenerative disorders. Similarly, HNRNPU, involved in the formation of ribonucleoprotein complexes, is associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) characterized by seizures, early onset epilepsy, hypotonia, autistic features, and intellectual disability. Notably, our analysis identified the KEAP1:NFE2L2 pathway as significantly enriched in our miRNA dataset. This pathway plays a central role in protecting cells against various homeostatic responses, including adaptation to oxidative, inflammatory and metabolic stresses. The NFE2L2 transcriptome has been implicated in protection against numerous chronic diseases, including metabolic and neurodegenerative disorders. In conclusion, our data demonstrates how miRNAs can serve as a signature for neurodegenerative diseases, shedding light on potential molecular mechanisms and therapeutic targets.

Multiple Sulfatase Deficiency (MSD) is an ultra-rare lysosomal storage disorder associated with pathogenic variants in the SUMF1 gene, which is required for sulfatase activation. Despite the known severity of disease, the impact of MSD on affected children, caregivers, and their family is uncharacterized.

Nineteen families affected by MSD participated in our assessments. The Vineland Adaptive Behavior Scales (VABS-3) was administered by a child neurologist to caregivers in the context of an affected individual’s in-person or remote research encounter. Health-related quality of life (HRQOL) surveys were collected electronically, including the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD), Pediatric Quality of Life Inventory Generic Core Scales (PedsQL GC), PedsQL Family Impact Module (FIM), and the Traumatic Brain Injury Caregiver Quality of Life (CareQOL) questionnaires.

All clinical outcome measures demonstrated a range of performance. Most caregivers assessed their children as severely affected (VABS-3 <40 Standard Score across all Domains and Adaptive Behavior Composite Score: n=10/19; 52.63%), with the lowest median scores in the Communication and Motor Skills domains. The Communication domain’s mean performance was significantly lower than the Socialization and Daily Living Skills domains. The Motor Skills domain was significantly lower than the Socialization domain only. The CPCHILD (n=12) identified items within the Comfort and Emotions and Overall Health domains as top priorities when preserving affected individuals’ quality of life. The Comfort and Emotions domain’s mean performance was significantly higher than all other domains. The CPCHILD overall HRQOL remained high (median 80%, IQR 50%). The PedsQL GC (n=14) demonstrated higher mean performance in the Emotional than the School/Work domain only. The CareQOL (n=15) identified caregivers’ significantly higher frequency of a sense of loss for the affected individual and feelings of entrapment. The PedsQL FIM (n=13) demonstrated that there was no significant difference between family functioning and parent HRQOL performance.

In this study, we demonstrated that MSD has profound, global effects on both affected individuals and their caregivers as measured by the VABS-3 and HRQOL surveys. This data will be integral to identifying Health Concepts and related Concept of Interests to inform future clinical trial design.