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Abstract Background Mucopolysaccharidosis type IVa (Morquio A syndrome) and mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) are rare inherited lysosomal storage diseases associated with significant functional impairment and a wide spectrum of debilitating clinical manifestations. These conditions are thought to have higher-than-average prevalence rates in Saudi Arabia due to high rates of consanguineous marriage in the country. There are several unmet needs associated with the management of these diseases in Saudi Arabia. Main body The aim of this manuscript is to contextualize unmet management needs and provide recommendations to optimize diagnosis, multidisciplinary care delivery, and local data generation in this disease area. An expert panel was assembled comprising seven consultant geneticists from across Saudi Arabia. The Delphi methodology was used to obtain a consensus on statements relating to several aspects of mucopolysaccharidosis types IVa and VI. A consensus was reached for all statements by means of an online, anonymized voting system. The consensus statements pertain to screening and diagnosis, management approaches, including recommendations pertaining to enzyme replacement therapy, and local data generation. Conclusion The consensus statements presented provide specific recommendations to improve diagnostic and treatment approaches, promote multidisciplinary care and data sharing, and optimize the overall management of these rare inherited diseases in Saudi Arabia.

Abstract The mucopolysaccharidoses (MPS) are a group of rare, genetic, lysosomal storage disorders characterized by progressive, multisystemic accumulation of glycosaminoglycans. Individuals with severe MPS often present with significant neurological involvement and may exhibit challenging behaviors, including hyperactivity, aggression, and sleep disturbance. These behaviors can cause adverse outcomes and necessitate the development of specific measures to support affected families. Through an analysis of the results reported by Hoffmann et al. in their recent study, this letter outlines important factors that must be considered when evaluating the impact of challenging behaviors associated with MPS, including treatment history, age, sibling and family relationships, the feasibility of daily caregiving, and caregiver burden. These recommendations can help guide future studies to identify the most effective coping strategies to support families of people with MPS who have challenging behaviors.

Abstract In traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs. Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144.

Abstract Background Challenging behavior represents a core symptom in neuropathological mucopolysaccharidoses (MPS) and puts major strain on affected families. Although multimodal approaches including behavioral strategies to treatment could be valuable, there is lack of research to the effectiveness of specific measures. This explorative, cross-sectional study is aimed at the collection of parental experiences regarding effective day-to-day measures against challenging behavior in MPS and focuses on 4 major research questions: First: What is challenging behavior in MPS? Second: Which strategies are helpful in the day-to-day coping with challenging behavior? Third: How strong is parental acceptance of illness and the disorder’s impact on family relationships? Fourth: What are beneficial personal and interfamilial strategies for generally coping with the disorder? Methods A semi structured questionnaire was designed de novo in cooperation with affected families. 37/268 questionnaires were returned (rate: 13.8%), of which 34 (MPS I: n = 8, MPS II: n = 8; MPS III: n = 18) could be included in data analysis in accordance with inclusion criteria. Assessment of challenging symptoms was based on perceived frequency, parent- and child stress. Exploration of possible coping strategies for challenging behavior and general illness-related strain included the evaluation of perceived effectiveness. Questionnaires were completed by patient’s relatives and analyzed for strategies to cope with challenging behavior and the disorder’s impact. STROBE criteria were respected. Results MPS I was reported to show lower frequency and better perceived manageability of challenging behavior than MPS II and -III. Sleep disturbance, hyperactivity, agitation, aggression and orality seemed relevant symptoms regarding frequency and/or parent stress. Reported measures were manifold, worthwhile approaches against challenging behavior appeared to be aiming at distraction, relief and environmental changes. Medication and non-medication approaches were rated similarly effective. Social exchange, private space and networking with other affected families seemed highly important for personal and interfamilial well-being. Conclusions Multimodal mentoring for affected families could be based on the following equivalent pillars: (1) Medication therapy for challenging behavior including evaluation of cost and benefit (2) Guided implementation and re-evaluation of specific behavioral measures against challenging behavior. (3) Psychosocial support of MPS-families, including options for strengthening parental well-being and family functioning. Trial registration This study was registered at clinicaltrials.gov prior to study start (NCT-Number: NCT03161171, Date: 2017/05/19).

Abstract Background Mucopolysaccharidoses (MPS) are rare, inherited disorders associated with enzyme deficiencies that result in glycosaminoglycan (GAG) accumulation in multiple organ systems. Management of MPS is evolving as patients increasingly survive to adulthood and undergo multiple surgeries throughout their lives. As surgeries in these patients are considered to be high risk, this can result in a range of critical clinical situations in adult patients. Results We discuss strategies to prepare for and manage critical clinical situations in adult patients with MPS, including supporting the multidisciplinary team, preoperative and airway assessments, surgical preparations, and postoperative care. We also present eight critical clinical cases (age range: 21–38 years) from four leading inherited metabolic disease centres in Europe to highlight challenges and practical solutions to optimise the care of adult patients with MPS. Critical clinical situations included surgical procedures, pregnancy and a thrombus in a port-a-cath. Conclusions Individualised strategies to manage critical clinical situations need to be developed for each patient to compensate for the heterogeneous symptoms that may be present and the potential complications that may occur. These strategies should include input from the wider MDT, and be coordinated by metabolic specialists with expertise in the management of MPS disorders and surgery in adult patients with MPS.

In traditional clinical trial design, efficacy is typically assessed using a single primary endpoint in a randomized controlled trial to detect an expected treatment effect of a therapy in a narrowly selected patient population. This accepted paradigm is based on clinical evaluations that may not actually capture the breadth of the impact of a disease, which is especially true in the setting of complex, multisystem, rare diseases with small, extremely heterogeneous patient populations. The multi-domain responder index (MDRI) is a novel approach that accommodates complex and heterogeneous disease manifestations and evaluates a broad array of clinical disease without impairing the power or rigor of a study to fully understand a treatment. The MDRI sums the scores corresponding to clinically significant thresholds of change for each component domain in each individual patient, capturing the mean clinically meaningful change across multiple domains within individuals. This novel approach combines and then sums the results of independent domain endpoint responder analyses into one responder score to provide a broad basis for the assessment of efficacy. The impact of a treatment across multiple, physiologically independent domains, can be assessed clinically, reducing the adverse impact of heterogeneity on trial outcomes and allowing eligibility criteria to enroll a wider range of patients, ultimately resulting in efficacy and safety assessments of a therapy across a broad group of heterogeneous patients in rare disease programs.Trial registration The following studies are referenced within this manuscript (CLINICALTRIALS.GOV registration numbers): NCT00912925; NCT00146770; NCT00067470; NCT00104234; NCT00069641; NCT02230566; NCT02377921; NCT02432144. [ABSTRACT FROM AUTHOR]

The mucopolysaccharidoses (MPS) are a group of rare, genetic, lysosomal storage disorders characterized by progressive, multisystemic accumulation of glycosaminoglycans. Individuals with severe MPS often present with significant neurological involvement and may exhibit challenging behaviors, including hyperactivity, aggression, and sleep disturbance. These behaviors can cause adverse outcomes and necessitate the development of specific measures to support affected families. Through an analysis of the results reported by Hoffmann et al. in their recent study, this letter outlines important factors that must be considered when evaluating the impact of challenging behaviors associated with MPS, including treatment history, age, sibling and family relationships, the feasibility of daily caregiving, and caregiver burden. These recommendations can help guide future studies to identify the most effective coping strategies to support families of people with MPS who have challenging behaviors. [ABSTRACT FROM AUTHOR]

Abstract Background Epilepsy is a heterogeneous disease with a broad phenotypic spectrum and diverse genotypes. A significant proportion of epilepsies has a genetic aetiology. In our study, a custom designed gene panel with 112 genes known to be associated with epilepsies was used. In total, one hundred and fifty-one patients were tested (86 males / 65 females). Results In our cohort, the highest probability for the identification of the cause of the disease was for patients with a seizure onset within the first four weeks of life (61.9% clarification rate) – about two times more than other groups. The level of statistical significance was determined using a chi-square analysis. From 112 genes included in the panel, suspicious and rare variants were found in 53 genes (47.3%). Among the 151 probands included in the study we identified pathogenic variants in 39 patients (25.8%), likely pathogenic variants in three patients (2%), variants of uncertain significance in 40 patients (26.5%) and likely benign variants in 69 patients (45.7%). Conclusion Our report shows the utility of diagnostic genetic testing of severe childhood epilepsies in a large cohort of patients with a diagnostic rate of 25.8%. A gene panel can be considered as a method of choice for the detection of pathogenic variants within patients with unknown origin of early onset severe epilepsy.

Background: Challenging behavior represents a core symptom in neuropathological mucopolysaccharidoses (MPS) and puts major strain on affected families. Although multimodal approaches including behavioral strategies to treatment could be valuable, there is lack of research to the effectiveness of specific measures. This explorative, cross-sectional study is aimed at the collection of parental experiences regarding effective day-to-day measures against challenging behavior in MPS and focuses on 4 major research questions: First: What is challenging behavior in MPS? Second: Which strategies are helpful in the day-to-day coping with challenging behavior? Third: How strong is parental acceptance of illness and the disorder's impact on family relationships? Fourth: What are beneficial personal and interfamilial strategies for generally coping with the disorder?Methods: A semi structured questionnaire was designed de novo in cooperation with affected families. 37/268 questionnaires were returned (rate: 13.8%), of which 34 (MPS I: n = 8, MPS II: n = 8; MPS III: n = 18) could be included in data analysis in accordance with inclusion criteria. Assessment of challenging symptoms was based on perceived frequency, parent- and child stress. Exploration of possible coping strategies for challenging behavior and general illness-related strain included the evaluation of perceived effectiveness. Questionnaires were completed by patient's relatives and analyzed for strategies to cope with challenging behavior and the disorder's impact. STROBE criteria were respected.Results: MPS I was reported to show lower frequency and better perceived manageability of challenging behavior than MPS II and -III. Sleep disturbance, hyperactivity, agitation, aggression and orality seemed relevant symptoms regarding frequency and/or parent stress. Reported measures were manifold, worthwhile approaches against challenging behavior appeared to be aiming at distraction, relief and environmental changes. Medication and non-medication approaches were rated similarly effective. Social exchange, private space and networking with other affected families seemed highly important for personal and interfamilial well-being.Conclusions: Multimodal mentoring for affected families could be based on the following equivalent pillars: (1) Medication therapy for challenging behavior including evaluation of cost and benefit (2) Guided implementation and re-evaluation of specific behavioral measures against challenging behavior. (3) Psychosocial support of MPS-families, including options for strengthening parental well-being and family functioning. Trial registration This study was registered at clinicaltrials.gov prior to study start (NCT-Number: NCT03161171, Date: 2017/05/19). [ABSTRACT FROM AUTHOR]

Background: Mucopolysaccharidoses (MPS) are rare, inherited disorders associated with enzyme deficiencies that result in glycosaminoglycan (GAG) accumulation in multiple organ systems. Management of MPS is evolving as patients increasingly survive to adulthood and undergo multiple surgeries throughout their lives. As surgeries in these patients are considered to be high risk, this can result in a range of critical clinical situations in adult patients.Results: We discuss strategies to prepare for and manage critical clinical situations in adult patients with MPS, including supporting the multidisciplinary team, preoperative and airway assessments, surgical preparations, and postoperative care. We also present eight critical clinical cases (age range: 21-38 years) from four leading inherited metabolic disease centres in Europe to highlight challenges and practical solutions to optimise the care of adult patients with MPS. Critical clinical situations included surgical procedures, pregnancy and a thrombus in a port-a-cath.Conclusions: Individualised strategies to manage critical clinical situations need to be developed for each patient to compensate for the heterogeneous symptoms that may be present and the potential complications that may occur. These strategies should include input from the wider MDT, and be coordinated by metabolic specialists with expertise in the management of MPS disorders and surgery in adult patients with MPS. [ABSTRACT FROM AUTHOR]