Please join us in Halifax, Nova Scotia as we host the second Canadian Symposium on Lysosomal Diseases (CSLD). We invite Physicians, Researchers, Registered Nurses, Genetic Counsellors and Trainees to attend this in-person Symposium. A virtual platform will be available for guests who are unable to attend in-person.
Canadian and international leaders and experts will present innovative trends and solution-focused best practices in the diagnosis and management of lysosomal diseases.
Due to the pandemic, the health, safety and wellbeing of attendees is of paramount importance. The CSLD will be organized in accordance with the Province of Nova Scotia’s health and safety guidance.
1725 Market Street, Halifax, Nova Scotia
The Prince George Hotel, features a distinguished level of service that fits Four Diamond standards. The hotel is centrally located in the heart of downtown Halifax, and features a fine dining restaurant, a lively Lobby Bar, an outdoor rooftop patio along with the many standard amenities you may expect. The property is connected to the Downtown Halifax Link, a convenient network of climate-controlled pedways that link together various entertainment venues and buildings around downtown Halifax. The property features excellent meeting facilities well suited to the requirements of the CSLD program.
CSLD Organizers have secured a preferred conference rate of $229 CAD, for single/double rooms available until September 13, 2022.
You may also reserve your accommodation now by calling the hotel reservation line:
1-800-565-1567 and referencing that you are attending the CSLD event.
Venue: The Prince George Hotel, Halifax
Abstract
The current standard of care for the treatment of Pompe disease is enzyme replacement therapy (ERT). ERT has been shown to improve metrics of function (6MWT) and respiratory status (FEV) in adults, and survival in children. In spite of these benefits, many patients are still left with significant disability and adjunctive therapies could play a role by improving functional capacity of patients. The first mention of the potential for nutrition and exercise therapy preceded the use of ERT and was coined Nutritional and Exercise Therapy (NET) by Dr. A. Slonem. Patients who followed NET therapy showed an attenuation of their functional decline. A subsequent study reported that a greater response to ERT was seen in patients who were doing regular exercise and suggested that exercising during and infusion could enhance delivery and uptake of ERT. However, our murine data using the GAA-/- model found no evidence for enhanced ERT uptake or efficacy but it did improve strength and function by activating autophagy and mitochondrial biogenesis. Studies using combined resistance and endurance exercise interventions in Pompe patients on ERT showed improvements in function that were even greater than those seen for ERT alone (additive). The initial NET dietary suggestions were to have a high protein intake (+ alanine) to act as a form of substrate reduction therapy (SRT) and ensure adequate amino acids for muscle protein synthesis. This recommendation appears reasonable and congruent with our data in muscular dystrophy and Pompe patients showing that a substantial proportion are deficient in dietary protein intake and many micronutrients, including vitamin D. We have also found that a high proportion of all of our MD and Pompe patients have body fat percentages in the obese range using DEXA scans in spite of only a few showing obesity with BMI. Consequently, strategies to lower body fat, whilst maintaining lean mass should lower the risk of metabolic syndrome in patients but are currently lacking. Nutraceutical interventions that are likely to provide improvements in body composition and function in Pompe disease are likely to work if they can improve any one of three known pathophysiological issues; mitochondrial dysfunction, oxidative stress and autophagic block. We have shown that a 7 ingredient supplement reduced body fat and maintained muscle mass in young and middle aged men and women and will be studying this in several neuromuscular disorders given the high prevalence of sarcopenic obesity. We have recently shown that a combined nutraceutical approach with mitochondrial enhancers, anti-oxidants and an autophagy enhancer (1,3 butandiol) improved function and strength in the GAA-/- mice receiving ERT (vs ERT alone). Another group found that the addition of certain anti-oxidants (idebenone and NAC) led to an increase in GAA activity in a few of the tissues studied and a small reduction in glycogen in the quadriceps muscle. Overall, the optimal therapy for patients with Pompe disease will involve ERT, optimal nutrition (adequate protein, identification and replacement of deficiencies) and there is likely a role from nutraceutical interventions that target the final common pathways of mitochondrial dysfunction, oxidative stress and impaired autophagy.
Session Objectives
1) To evaluate the theoretical and clinical aspects of exercise as a therapy for Pompe disease.
2) To review the habitual nutritional intake and dietary recommendations for patients with Pompe disease.
3) To explore the theory behind nutraceutical interventions and the data for their use in patients with Pompe disease.
Introduction:
Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders with an impaired glycosaminoglycan catabolism. Depending on disease severity, clinical manifestations appear between 2 and 4 years old. Enzyme replacement therapy and/or hematopoietic stem cell transplant are available for patients with MPS I, II, VI, and VII. The importance of early detection (newborn screening) and treatment to prevent severe and irreversible complications, improve the outcome and delay the onset of symptoms has been often emphasized. The Provincial Neonatal Urine Screening Program in Quebec is a unique program where 21-day-old babies are screened for inherited metabolic disorders using dried urine spots (DUS).
Objectives:
1) To optimize and validate a populational screening assay for the analysis of heparan sulfate (HS), dermatan sulfate (DS) normalized to creatinine; and
2) To establish HS and DS reference values at 21 days of age.
Method:
DUSs were extracted, evaporated under a nitrogen flow, and a methanolysis reaction was performed. Deuterated HS and DS standards were used. Samples were analyzed using an Acquity H-Class/Xevo TQ-S micro system (Waters Corp.).
Results:
A one-minute chromatographic method allowed the absolute quantitation of HS, DS, and creatinine. Method validation showed high precision (< 9 %RSD) and accuracy (< 7% bias) for all analytes. Reference values/normalized to creatinine were established in DUS from 500 newborns (21-day-old) (HS: 34.6 6.2 mg/mmol; DS: 17.3 3.9 mg/mmol).
Conclusion:
This multiplex assay might be used to screen MPSs for all newborns in the province of Quebec as part of an evaluative research project.
Objectives:
Outcomes reported in studies of mucopolysaccharidoses (MPS) in children vary considerably, making comparisons across studies challenging. Toward the development of a core outcome set (COS), in partnership with patients and providers, we sought stakeholder opinions of MPS outcomes.
Methods:
We invited children with MPS, parents/caregivers, and health professionals (providers and policy-makers) to participate in web-based Delphi surveys circulated internationally. In round 1, participants were asked to rate the importance (increasing importance on a scale of 1-9) of 68 outcomes identified from a literature review and previous survey of children/caregivers. In rounds 2 and 3, participants were shown their previous rating and a summary of ratings from each stakeholder group and asked to re-rate all outcomes. In round 3, participants were also asked to rank their top ten outcomes.
Results:
There were 107, 64, and 58 participants in rounds 1, 2, and 3, respectively. Among children/caregivers, the highest rated outcomes in round 3 were disease progression (mean rating 8.8), neurologic changes (8.5), and life expectancy (8.5). Professionals rated disease progression (8.7), cognitive function (8.6) and quality of life (8.4) most highly. The outcomes participants most often ranked among their top three in importance were, for both groups: pain, cognitive function, disease progression, and quality of life. We observed modest differences in ratings between children/caregivers with experience of neuronopathic and non-neuronopathic MPS subtypes.
Conclusions:
Our findings illuminate stakeholder priorities for outcomes of pediatric MPS. A workshop will be held to discuss the findings and seek consensus on the final COS.
Introduction:
Sphingolipidoses are rare genetic diseases caused by the accumulation of sphingolipid substrates in organs, tissues, and biological fluids resulting in neurotoxicity and systemic clinical manifestations for affected patients. Newborn mass spectrometry enzyme activity screening tests in dried blood spots has emphasized the importance of early detection. To our knowledge, there are no robust urine quantitative methods for the simultaneous analysis of biomarkers for these sphingolipidoses: Fabry disease, Krabbe disease, Gaucher disease, NiemannPick disease types A/B, GM1 and GM2 gangliosidoses, and metachromatic leukodystrophy, which could be used for a non-invasive high-risk screening.
Objectives:
1) Develop/validate a tandem mass spectrometry methodology for the quantitation of 21 urinary lysosphingolipids and related analogs normalized to creatinine for 8 sphingolipidoses;
2) Measure these urine biomarker levels in patients; and
3) Establish normal values in age- and gender-matched controls.
Methods:
Urine samples (500 L) and 8 different calibrator curves were extracted with their respective internal standards using solid phase extraction cartridges. Eluted samples were evaporated to dryness, resuspended, and analyzed using an Acquity H-Class UPLC-Xevo TQ-S Micro mass spectrometer (Waters Corp.).
Results:
All analyte recovery ranges were over 94%. Galactosylsphingosine and glucosylsphingosine were well separated by UPLC allowing the differentiation between Krabbe disease and Gaucher disease.Results showed different biomarker levels between the controls and untreated patient groups, except for two treated GM1 and GM2 gangliosidoses.
Conclusions:
This robust urinary lysosphingolipid/creatinine multiplex assay can be applicable to high-risk screening of 8 different diseases. The method will be adapted for urine filter paper samples.
Abstract
Farber disease (FD) is a rare lysosomal storage disease with a variable spectrum of severity and organ system pathology resulting from acid ceramidase enzyme deficiency. This results in ceramide accumulation which is a proinflammatory and proapoptotic lipid that has been implicated in the pathogenesis of multiple disorders. Untreated, acid ceramidase enzyme deficiency leads to progressive disease, with significant morbidity and premature death in most cases. Acid ceramidase is encoded by the ASAH1 gene, and ASAH1 variants are known to be associated with the Farber phenotype, as well as another rare disease called spinal muscular atrophy with progressive myoclonic epilepsy. Similar to other LSDs, there is a wide heterogeneity in clinical presentation. Treatment remains suboptimal with few disease modifying therapeutic options to date. This presentation will focus on the pathophysiology, presentation, and natural history of Farber disease. Existing and future therapies for management of this ultrarare disorder will also be reviewed.
Session Objectives
1) To understand the phenotypes associated with ASAH1 gene mutations
2) To be aware of current treatment options for Farber disease
Lysosomal Storage Diseases (LSDs) are a group of rare inherited recessive metabolic disorders characterised by the paucity of necessary lysosomal enzyme(s) required for the stepwise breakdown of specific metabolites. The build-up of metabolites will cause dysfunction in various organs and metabolic pathways, leading to neurodegeneration, increased physical limitations, and death. Common LSDs are Mucopolysaccharidoses (MPS) and sphingolipidoses, such as Farber disease. Clinical research focusing on lipidomic analyses has led to the discovery of the involvement of various sphingolipid species in LSDs. Sphingolipids, a complex family of ubiquitous lipids with a common sphingoid base, are believed to be significant players in regulating inflammation and fibrosis in multiple diseases, including LSDs, metabolic and neurodegenerative disorders. Hence, our current understanding postulates that the imbalance of circulating sphingolipids contributes to the pathogenesis of LSDs. In our translational lipidomics research laboratory, we try to identify potential biomarkers for various LSDs by evaluating the concentration of sphingolipid species in the blood of LSD patients. Our ultimate goals are: 1) to better understand the pathophysiology of the LSDs, 2) to facilitate early diagnosis for better effectiveness of treatments, 3) to gauge disease burden and 4) to monitor the impact of therapies at clinical and biochemical levels. In this poster, we will present targeted sphingolipidomics analyses performed with our in-house methods to quantify the concentration of various families of sphingolipids in LSD patients. Different chemistries are applied to extract and separate diverse families of sphingolipids from plasma and then quantify them by Liquid Chromatography-Tandem Mass Spectrometry.
Objectives:
High-quality patient registries that collect meaningful longitudinal data can promote an improved understanding of natural history and facilitate research on intervention effectiveness. The Canadian MPS Society is partnering with the INFORM RARE research network to co-design and implement a patient-oriented, longitudinal Canadian registry for mucopolysaccharidoses (MPS): the Canadian MPS Registry.
Design and methods:
We co-developed a list of core values to facilitate a shared vision among registry partners: sustainability to support long-term relevance; accessibility within and outside current networks, while maintaining participant privacy; scalability to other disease groups; recognition of the registry as a public benefit; direct benefit to patients and their families (e.g., regarding data ownership and access); and building capacity for research that responds to patient priorities. The registry will use the National Organization for Rare Disorders IAMRARE(r) Platform. Our governance structure includes a multi-disciplinary steering committee to make key decisions about data collection, access, and use. The registry also benefits from INFORM RAREs comprehensive patient engagement strategy.
Results:
For eligible participants (children aged 18 years or younger receiving care in Canada for MPS) and with informed consent, the registry will collect and store patient-, caregiver- and clinician-reported data informed by core outcome sets for MPS. Participants will own their own registry data and have the option to share their data with external research networks.
Conclusions:
The Canadian MPS Registry is a patient-oriented longitudinal registry designed to support innovative observational and intervention research that will ultimately improve care and outcomes for patients with MPS.
Abstract
Fabry disease (FD) is characterized by a GLA gene mutation causing deficiency of the lysosomal alpha-galactosidase A activity which affects almost all cells and tissues. This is an X-linked disease but with females being variably affected and not just carriers. Accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids triggers inflammation, fibrosis and thrombosis. The disease onsets in utero with symptoms and signs by early childhood. It progresses thereafter with chronic renal failure, cardiomyopathy and strokes that shorten life span. Variant late onset disease with mainly cardiac or renal features is associated with certain GLA mutations. In Canada, FD patients were treated initially via the CFDI study sponsored by government and industry between 2006 and 2014. Based upon outcomes data from the CFDI, FPT governments agreed in 2014 to reimburse FD drug costs. The CFDI has continued since as a disease registry focused on outcomes data and biomarkers with 607 patients enrolled to date. Canadian FD treatment guidelines serve as the basis for FD drug coverage with both chaperone and enzyme replacement therapy. An expert committee reviews all published literature and updates the guidelines regularly by consensus. The committee vets all applications for drug therapy to ensure that they meet current guidelines.
Objectives
1) Understand the Canadian Fabry Disease treatment guidelines
2) Know how to use the various drugs for treatment of Fabry disease
3) Be aware of complications of treatment for Fabry disease
Introduction:
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene. The alpha-galactosidase A (-Gal A) deficiency leads to the accumulation of substrates such as globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), in the vascular endothelium, tissues and biological fluids. Metabolomic studies revealed novel urine and plasma biomarkers: the analogs of lyso-Gb3. Some of these analogs were associated with clinical manifestations of the disease for patients having late-onset cardiac variant mutations. To our knowledge, there is no test available for a full profile of lyso-Gb3 and analogues in dried blood spots (DBS).
Objectives:
1) Develop/validate a quantitation method for lyso-Gb3 and its analogues in DBS; and
2) Compare and establish correlations between DBS and plasma biomarker levels.
Methods:
DBS and plasma samples were collected from 19 Fabry patients. DBS punches (5-mm) were eluted and purified by solid phase extraction. Plasma samples (100 L) were purified similarly. After evaporation, the resuspended samples were analyzed by UPLC-mass spectrometry (MS/MS) (Acquity I-Class-Xevo TQ-S, Waters Corp.).
Results:
This validated method showed good intraday and interday accuracy and precision results of <15%. DBS were stable at room temperature for shipping by regular mail and remained stable for 14 days at 22C and 208 days at 20C. Good correlations for lyso-Gb3 and analogue levels were obtained between DBS and plasma.
Conclusions:
This comprehensive test allows the analysis of a complete profile of Fabry biomarkers for screening/monitoring/follow-up of patients while reducing the shipping costs of samples to laboratories.
A 56-year-old male presented with anasarca and nephrotic syndrome. He underwent a renal biopsy, which demonstrated typical features of Fabry disease (FD), and was subsequently confirmed to have classic FD through biochemical and molecular studies. He began agalsidase alfa (ReplagalTM, Takeda/Shire) enzyme replacement therapy in 2012. In January 2019, he enrolled in the clinical trial for an oral substrate reduction therapy, lucerastat (Idorsia Pharmaceuticals Ltd); at this time, treatment with agalsidase alfa was discontinued. Over the subsequent three years, the patients pain scores and quality of life improved. No progression of cardiac or central nervous system manifestations were noted. However, the patients eGFR has decreased progressively from 55 mL/min in 2013, to 51 mL/min in 2015, to 35 ml/min in December 2018 at screening prior to the dispensing of lucerastat, to 23 mL/min in 2022 (normal eGFR 60 mL/min). Recent albumin:creatinine (UACR) was 340 (N UACR <2mg/mmol) and protein:creatinine (PCR) was 359 (N PCR <25 mg/mmol).The patient was previously prescribed courses of ACE-1 inhibitors, which were not well-tolerated; the patient currently takes bisoprolol, rosuvastatin, and Tylenol-3 prn, in addition to the lucerastat.
Given that re-initiation of enzyme replacement therapy is an option for this patient, agalsidase beta (FabrazymeTM, Sanofi Genzyme) will be added to his lucerastat regime. We will discuss in detail the patients clinical course and FD-specific and renal-specific therapies, including the choice of which intravenous enzyme replacement therapy option to reintroduce.
Treatment of Fabry disease (FD) in asymptomatic males with classic phenotype by age 16 years has been recommended in some guidelines; this is based upon expert opinion as supporting data are minimal. We studied younger patients in the multicentre CFDI registry established in 2006 with data on 607 patients and compared those on and off therapy to determine if there were better outcomes associated with earlier treatment.
Methods:
Baseline characteristics and clinical outcomes were examined in all patients 25 years old on enrollment with at least 6 months of data in the CFDI registry. Treatment with enzyme replacement therapy and chaperone was according to Canadian FD guidelines.
Results:
140 patients met entry criteria, 55M, 85F with 30M and 11F receiving treatment; 25M and 74F did not. Most patients had classical genotype. Baseline characteristics varied little amongst patient groups. Treated patients had longer follow up than untreated, M mean 138.9 vs 103 months; F 153.4 vs. 103.7 months. There were no patient deaths. Fabry clinical events in the untreated were acute hearing loss M2 and F1. There were 8 events in treated M4 and F3 patients. Event rates were low for young patients at 0.064 events/1000 patient days for treated M, 0.0593 for treated F, 0.026 for untreated M and 0.0043 for untreated F.
Conclusions:
CFDI registry data show low clinical event rates as expected for younger Fabry patients despite classical phenotype. Earlier therapy did not reduce clinical event rates over an average of almost 10 years follow up.
Session Objectives
Overview of the major advances in diagnosis and management of patients with Gaucher disease that have started in 1985 with the cloning of the glucocerebrosidase gene (GBA1) and in 1991 with the introduction of the first enzyme replacement therapy (ERT).
Recognize the differences in the safety and efficacy profiles of the different therapeutic choices available today and the way we manage GD in the era of choices.
Appreciate the unmet needs related to neuronopathic GD, comorbidities and the challenges of recruitment to new clinical trials including gene therapy.
Introduction:
Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by the glucocerebrosidase enzyme deficiency. GD type 1 is the less severe form of the disease and accounts for approximately 95% of all GD patients. GD type 1 patients might suffer from bone, hematological, and visceral complications, as well as mild neurological impairments. The most currently used molecular biomarker for the diagnostic, monitoring and follow-up of GD is glucosylsphingosine (lyso-Gb1) measured in plasma.
Objective:
To perform untargeted metabolomic studies in urine and plasma to discover novel GD biomarkers that could be more sensitive and would better correlate with clinical manifestations than lyso-Gb1.
Methodology:
For the untargeted metabolomic studies performed in urine and plasma, the samples were purified by solid phase extraction, separated by ultra-performance liquid chromatography (Acquity, Waters), and analyzed by time-of-flight mass spectrometry (Synapt G1, Waters). Multivariate statistical analyses were performed to discover GD biomarkers.
Results:
The urine metabolomic study revealed 14 GD biomarkers corresponding to lyso-Gb1, 9 lyso-Gb1 analogs with modified sphingosine moieties, and 4 polycyclic lyso-Gb1 analogs. The plasma metabolomic study showed lyso-Gb1, 4 lyso-Gb1 analogs, N-palmitoyl-O-phosphocholineserine, and sphingosylphosphorylcholine as GD biomarkers. The polycyclic lyso-Gb1 analogs were significantly more sensitive than the other biomarkers detected in urine. The levels of some biomarkers correlated with disease severity and clinical manifestations of GD.
Conclusion:
We believe that the analysis of a complete GD biomarker panel would give a better monitoring and overview of the health status of GD patients than the analysis of only lyso-Gb1.
Renal phospholipidosis is most commonly due to Fabry disease (FD), with deficient activity of lysosomal -galactosidase A. We present a case of Sertraline-induced renal phospholipidosis mimicking Fabry nephropathy. A 34-year-old woman was referred for evaluation of persistent proteinuria. She had gestational hypertension with low grade proteinuria 4 years prior. Post-partum, the hypertension resolved but trace proteinuria persisted. In clinic, she had proteinuria of 1.41 g/day but no Fabry disease-related symptoms except mild fatigue. Medication was Sertraline 100 mg daily for depression x 8 years. Physical examination was normal. Urinalysis showed 1+ protein, hyaline and granular casts plus few dysmorphic RBCs. Renal ultrasound showed a horseshoe kidney. CRP 22.93, ANA and anti-DNA antibody were positive, but other serologic tests were normal. eGFR 120.5 ml/min/1.73m2. Renal biopsy showed mild focal segmental glomerulosclerosis with 2/19 glomeruli globally sclerosed. Zebra bodies consistent with Fabry disease were noted. GLA analysis, -galactosidase activity, plasma lysoGb3 and urine Gb3 were normal. She was diagnosed with renal phospholipidosis from Sertraline and switched to desvenlafaxine. Proteinuria fell gradually to 0.52 g/day 27 months later with eGFR unchanged. Podocyte zebra bodies indicate glycolipid accumulation and can be due to diseases such as Niemann-Pick disease, Nail-Patella syndrome and FD as well as drug-induced renal phospholipidosis, of which chloroquine is the most common cause. Sertraline, an amphiphilic drug, is a very rare cause of renal phospholipidosis with only one prior report in a kidney transplant (Naseer et al Clin Nephrol 2022;8:46). Careful patient evaluation is required to avoid misdiagnosis and possible mistreatment.
Venue: The Prince George Hotel, Halifax
Abstract
Many enzymes function within the complex and crowded environment of the cell in which their activity is regulated by an array of binding partners. Understanding the function and regulation of enzymes within their native environment therefore depends on the availability of high-quality methods and tools that can faithfully report on their activities within living cells. We have been working toward this goal with the aim of enabling accurate and precise monitoring of the cellular activity of glycoside hydrolases. In this presentation we will describe our stepwise advance of fluorescence-quenched substrates for this goal. We will discuss our recent advances to generate synthetic substrates that, when cleaved by a glycosidase, yield a dramatic dark-to-light increase in fluorescence that is stably retained within cells. We show how the modular assembly of these probes enables convenient installation of bright commercial fluorophores that are photostable and environmentally insensitive. Simple protocols for the use of these substrates are defined that enable use in both fluorescence microscopy and flow cytometry. We illustrate the value of these fluorescence-quenched glycosidase substrates for sensitive quantitation of disease-relevant human a-galactosidase, b-glucocerebrosidase, and a-N-acetylgalactosaminidase activities. Finally, we show the quantitative uses of these substrates for live cell imaging of enzyme activity in patient cells, measuring engagement of glycosidases by inhibitors within cells, and in cell-based high-throughput screening.
Session Objectives
Describe to the clinical community new substrates that enable quantitative measuring of the activity of various glycosidases within lysosomes.
Define the current scope and potential of these substrates as well as how they can currently be used.
Gain insight from clinical researchers as to the potential uses of such substrates within clinics and laboratories.
The Journey of a Teenager with MPS Type I Post-Bone Marrow Transplant
Jenna Black
J is a 15-year-old male with severe Mucopolysaccharidosis type 1 (MPS 1) (IDUApG197Bc695A>G) (intron 3), also known as Hurler Syndrome. Hurler Syndrome is a progressive multisystem lysosomal storage disease caused by a mutation in the alpha-L-iduronidase (IDUA) gene. Around 1 in 100000 children are born with Hurler Syndrome with symptoms manifesting within the first year of life. J was tested for Hurler Syndrome because of his coarse facies and hearing loss. He was diagnosed at 8 months of age with a urine glycosaminoglycan level of 78 mg/mmol creat (ref range 4-13). and leukocyte IDUA enzyme activity at 2.7 nmol/hr/mg protein (ref range 6-15). He was started on enzyme replacement therapy and received a bone marrow transplant at 17 months. Js case contributes a unique view into how psychosocial health contributes to the success of a child growing up with a severe metabolic disease. In only 15 years, J has lived through a stem-cell transplant, 3 corneal transplant surgeries, 5 orthopedic surgeries, mobility limitations, hearing loss, sleep disturbances, Attention Deficit Hyperactivity Disorder, anxiety, anger management issues, and countless specialist appointments. This case highlights the role of parents, grandparents, social workers, peers, schools, and the internet in Js journey to where he is now; a creative and resilient teenager with many successes and many struggles. From this story, healthcare providers and families alike can learn about the psychosocial interventions that have helped J and his team tackle severe MPS 1 post-bone marrow transplant.
Transient Acute Monocular Vison Loss in a Boy with Fabry Disease
Seham Hamoud
Fabry disease is an X-linked lysosomal storage disorder secondary to alpha-galactosidase deficiency leading to progressive globotriaosylceramide deposition. It is a multisystem disorder with bimodal age of onset depending on the severity of the enzyme deficiency. We report a rare complication of Fabry disease in a pediatric patient who developed a sudden monocular vision loss secondary to central retinal vein occlusion (CRVO). To our knowledge, this is the first pediatric case in the literature. An 11-year-old male known to have a classical clinical phenotype of Fabry disease (GLA mutation, complete deletion of exons 2 and 3), with a Mainz severity score of 10/76 who presented with acute painless loss of vision in the left eye. Within 15 minutes, his vision began to return in a patchy fashion, and subsequently, he regained normal vision. A detailed ophthalmology assessment including an optical coherence tomography test (OCT) revealed retinal hemorrhage which was consistent with a resolved CRVO. He was confirmed to have bilateral mild cornea verticillata. An extensive hematological assessment was non-contributory. Although no underlying coagulopathy was found, he was treated with acetylsalicylic acid (ASA) and subsequently began enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg IV infusion every two weeks. Central retinal vein occlusion is a rare complication of Fabry disease. Such diagnosis should be on the differential diagnosis of transient visual loss in patients with Fabry disease. Whether ERT will prevent or treat CRVO in Fabry disease is unknown.
Abstract
The mucopolysaccharidoses (MPSs) are a group of inborn errors of metabolism caused by the deficiency of lysosomal hydrolases that degrade glycosaminoglycans (GAGs). These disorders are associated with a progressive accumulation of different types of GAGs within the cells of various organs and are characterized by somatic manifestations (facial dysmorphisms, hepatosplenomegaly, cardiac, respiratory, and skeletal involvement) and may have neurological involvement. These manifestations are variably associated in each disorder. In most cases the disease phenotypes encompass a spectrum ranging from severe to attenuated clinical forms. Because of the multisystem involvement in these patients, initial clinical assessment should include the evaluation of different organs and systems. Biochemical and genetic investigations are/or required to confirm the diagnosis. These include the analysis of urinary GAGs, the demonstration of a specific enzyme defect, and the identification of pathogenic variants in the relevant gene. Management of mucopolysaccharidoses requires supportive care and multidisciplinary treatment of a variety of systemic complications. Specific treatment is based on different approaches and currently include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT). ERT results in improvement of somatic manifestations and of motor performance and in reduced GAG urinary excretion. However, other clinical features respond to a lesser extent to therapy, including the central nervous system. Several therapeutic approaches aiming to address unmet treatment needs are in clinical development. This presentation will review the latest developments on classification, diagnosis, and management of the MPSs.
Session Objectives
1) To discuss the classification, relative frequency of the different type and the epidemiology of MPS
2) To discuss the present status and future directions of MPS diagnosis
3) To discuss the current therapeutic strategies and the new treatments in development
Pompe disease
John Mitchell
Fabry disease
Michael West
Gaucher disease
Ramona Salvarinova
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9996-U | 166403-T | 2022-04-26
