Retrospective Review of Positive Newborn Screening Results for Isovaleric Acidemia and Development of a Strategy to Improve the Efficacy of Newborn Screening in the UK.

Since the UK commenced newborn screening for isovaleric acidemia in 2015, changes in prescribing have increased the incidence of false positive (FP) results due to pivaloylcarnitine. A review of screening results between 2015 and 2022 identified 24 true positive (TP) and 84 FP cases, with pivalate interference confirmed in 76/84. Initial C5 carnitine (C5C) did not discriminate between FP and TP with median (range) C5C of 2.9 (2.0-9.6) and 4.0 (1.8->70) µmol/L, respectively, and neither did Precision Newborn Screening via Collaborative Laboratory Integrated Reports (CLIR), which identified only 1/47 FP cases. However, among the TP cases, disease severity showed a correlation with initial C5C in 'asymptomatic' individuals (n = 17), demonstrating a median (range) C5C of 3.0 (1.8-7.1) whilst 'clinically affected' patients (n = 7), showed a median (range) C5C of 13.9 (7.7-70) µmol/L. These findings allowed the introduction of dual cut-off values into the screening algorithm to reduce the incidence of FPs, with initial C5C results ≥ 5 µmol/L triggering urgent referral, and those >2.0 and <5.0 µmol/L prompting second-tier C5-isobar testing. This will avoid delayed referral in babies at particular risk whilst reducing the FP rate for the remainder.

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study.

BACKGROUND: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease. METHODS: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete. FINDINGS: Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths. INTERPRETATION: Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment. FUNDING: BioMarin Pharmaceutical.

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study.

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records. A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6-24) and 66 months (35-156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival.

The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.

Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.

Clinical experience with glycerol phenylbutyrate in 20 patients with urea cycle disorders at a UK paediatric centre.

In urea cycle disorders (UCDs) ammonia scavenger drugs, usually sodium-based, have been the mainstay of treatment. Increasingly, glycerol phenylbutyrate (GPB, Ravicti®) is being used but scant real-world data exist regarding clinical outcomes. A retrospective study of UCD patients initiated on or switched to GPB was performed at a UK centre. Data on population characteristics, treatment aspects, laboratory measurements, and clinical outcomes were collected before and after patients started GPB with a sub-group analysis undertaken for patients with ≥12 months of data before and after starting GPB. UCDs included arginosuccinate synthetase deficiency (n = 8), arginosuccinate lyase deficiency (n = 6), ornithine carbamoyltransferase deficiency (n = 3), and carbamoyl phosphate synthetase 1 deficiency (n = 3). In the sub-group analysis (n = 11), GPB resulted in lower plasma ammonia (31 vs. 41 µmol/L, p = 0.037), glutamine (670 vs. 838 µmol/L, p = 0.002), annualised hyperammonaemic episodes (0.2 vs. 1.9, p = 0.020), hospitalisations (0.5 vs. 2.2, p = 0.010), and hyperammonaemic episodes resulting in hospitalisation (0.2 vs. 1.6, p = 0.035) reflecting changes seen in the whole group. Overall, patients exposed to sodium and propylene glycol levels above UK daily limits reduced by 78% and 83% respectively. Mean levels of branched chain amino acids, haemoglobin, and white cell count were unchanged. Two adverse drug reactions (pancytopenia, fatigue/appetite loss) resolved without GPB discontinuation. Patients/families preferred GPB for its lower volume, greater palatability and easier administration. GPB appeared to improve biochemical measures and clinical outcomes. The causes are multi-factorial and are likely to include prolonged action of GPB and its good tolerability, even at higher doses, facilitating tighter control of ammonia.

Management of B-cell lineage acute lymphoblastic leukemia: expert opinion from an Indian panel via Delphi consensus method.

Introduction: Currently, there are no guidelines for the management of B-cell lineage acute lymphoblastic leukemia (B-ALL) from an Indian perspective. The diagnostic workup, monitoring, and treatment of B-ALL vary among different physicians and institutes. Objective: To develop evidence-based practical consensus recommendations for the management of B-ALL in Indian settings. Methods: Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 experts from India constituted the panel. Clinically relevant questions belonging to three major domains were drafted for presentation and discussion: (i) diagnosis and risk assignment; (ii) frontline treatment; and (iii) choice of therapy (optimal vs. real-world practice) in relapsed/refractory (R/R) settings. The questionnaire was shared with the panel members through an online survey platform. The level of consensus was categorized into high (≥ 80%), moderate (60%-79%), and no consensus (< 60%). The process involved 2 rounds of discussion and 3 rounds of Delphi survey. The questions that received near or no consensus were discussed during virtual meetings (Delphi rounds 1 and 2). The final draft of the consensus was emailed to the panel for final review. Results: Experts recommended morphologic assessment of peripheral blood or bone marrow, flow cytometric immunophenotyping, and conventional cytogenetic analysis in the initial diagnostic workup. Berlin-Frankfurt-Münster (BFM)-based protocol is the preferred frontline therapy in pediatric and adolescent and young adult patients with B-ALL. BFM/German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia-based regimen is suggested in adult patients with B-ALL. Immunotherapy (blinatumomab or inotuzumab ozogamicin) followed by allogeneic hematopoietic cell transplantation (allo-HCT) is the optimal choice of therapy that would yield the best outcomes if offered in the first salvage in patients with R/R B-ALL. In patients with financial constraints or prior allo-HCT (real-world practice) at first relapse, standard-intensive chemotherapy followed by allo-HCT may be considered. For subsequent relapses, chimeric antigen receptor T-cell therapy or palliative care was suggested as the optimal choice of therapy. Conclusion: This expert consensus will offer guidance to oncologists/clinicians on the management of B-ALL in Indian settings.

Safety, efficacy, and timing of transplantation(s) in propionic and methylmalonic aciduria.

Propionic (PA) and methylmalonic aciduria (MMA) share many clinical similarities, which include the risk of acute metabolic encephalopathies, and some long-term complications, such as optic neuropathy, pancreatic involvement, developmental disability, and similar management approaches, but they also represent distinct clinical and biochemical entities. In the severe forms of PA and MMA, most long-term complications cannot be prevented with conventional clinical management. Organ transplantation represents a form of partial enzyme replacement to improve the long-term outlook for these disorders. There is evidence that early liver transplant in both disorders greatly improves metabolic stability and reduces the risk of long-term complications. For MMA, early liver transplant reduces methylmalonic acid levels which in turns reduces its effects on kidneys, and therefore slows progression of chronic kidney disease. However, established organ damage cannot be reversed. For patients with MMA who present with chronic kidney disease, consideration should be given for combined liver and kidney transplants. Transplantation in PA and MMA carries a high risk of complications and requires highly specialised pre-operative and peri-operative management. Involvement of a multidisciplinary team is essential and should include metabolic team, nephrologist, hepatologist, hepatobiliary and renal transplant surgeons, anaesthesiologists, cardiologists, intensive care team, dieticians and specialist nurses. These patients require life-long multidisciplinary follow-up. There is increasing evidence in the literature on excellent short to medium-term patient and allograft survival following transplantation when patients are managed by a multidisciplinary team in a specialist centre. Improved early diagnosis and reductions in transplant-related mortality and morbidity have allowed early transplantation to be used electively to further improve the outcome.

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

Reply to Maase et al. Comment on "Jones et al. Application of a Novel Algorithm for Expanding Newborn Screening for Inherited Metabolic Disorders across Europe. Int. J. Neonatal Screen. 2022, 8, 20".

The commentary provided by Maase et al. [...].

Induction of thrombotic thrombocytopenic purpura by dengue virus infection in a critical patient: Role of therapeutic plasma exchange.

Thrombotic thrombocytopenic purpura (TTP) secondary to dengue fever is a very unusual occurrence. Both conditions are fatal and can result in significant mortality and morbidity if left untreated. In this case, we present a young lady who suffered dengue fever followed by microangiopathic anemia, thrombocytopenic purpura, and altered sensorium. Investigations revealed microangiopathic hemolysis; there was no evidence of disseminated intravascular coagulation. As soon as, we diagnosed the patient as having TTP, we treated her with serial plasma exchange therapy, steroids, and monoclonal antibodies such as rituximab. The patient responded very well to the treatment and completely recovered from neurological symptoms and laboratory parameters also normalized. Hence, timely diagnosis and starting appropriate treatment immediately are key factors for successful outcomes.

Preclinical validation and treatment of volumetric modulated arc therapy based total bone marrow irradiation in Halcyon™ ring gantry linear accelerator.

AIM: This study aims​ to report preclinical validation, and the first clinical treatment of total bone marrow irradiation (TMI) and total bone marrow and lymph nodal irradiation (TMLI) using Volumetric modulated arc therapy in Halcyon-E ring gantry linear accelerator. Preclinical validation includes simulation, planning, patient-specific QA, and dry run. MATERIAL AND METHOD: Four patients, two female and two male, with body weights of 116 kg, 52 kg, 64 kg, and 62 kg; with two with chronic myeloid leukemia, one each with acute lymphoblastic leukemia and acute myeloid leukemia (AML) were simulated and planned for TMI/TMLI. Patients were immobilized with a full-body vacuum bag. Head first supine (HFS) and Feet first supine (FFS) CT scans were acquired from head to knee and knee to toe. Planning target volume (PTV) was created with a uniform margin of 6 mm over the total bone marrow/bone marrow + lymph nodes. HFS and FFS PTVs were optimized independently using 6MV unflatten energy for 12 Gy in 6 fractions. Plans were merged to create the resultant dose distribution using a junction bias dose matching technique. The total number of isocenters was ≤ 10 per CT set, and two to four full arcs were used for each isocenter. A junction dose gradient technique was used for dose feathering between arcs between adjacent isocenters. RESULT: Only one female patient diagnosed as AML received the TMLI treatment, while the other three patients dropped out due to clinical complications and comorbidities that developed in the time between simulation and treatment. The result presented has been averaged over all four patients. For PTV, 95% dose was normalised to 95% volume, PTV_V107% receiving 3.3 ± 3.1%. Total lung mean and V12Gy were 1048.6 ± 107.1 cGy and 19.5 ± 12.1%. Maximum lens doses were 489.5 ± 35.5 cGy (left: L) and 497 ± 69.2 cGy (right: R). The mean cardiac and bilateral kidney doses were 921.75 ± 89.2 cGy, 917.9 ± 63.2 cGy (L), and 805.9 ± 9.7 cGy (R). Average Monitor Unit was 7738.25 ± 1056.6. The median number of isocenters was 17(HFS+FFS), average MU/Dose (cGy) ratio per isocenter was 2.28 ± 0.3. CONCLUSION: Halcyon-E ring gantry linear accelerator capable of planning and delivering TMI/TMLI.​​.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

A New Approach to Objectively Evaluate Inherited Metabolic Diseases for Inclusion on Newborn Screening Programmes.

Newborn screening (NBS) programmes are essential in the diagnosis of inherited metabolic diseases (IMDs) and for access to disease modifying treatment. Most European countries follow the World Health Organisation (WHO) criteria to determine which disorders are appropriate for screening at birth; however, these criteria are interpreted and implemented by individual countries differently, creating disparities. Advances in research and diagnostics, together with the promise of new treatments, offer new possibilities to accelerate the expansion of evidence-based screening programmes. A novel and robust algorithm was built to objectively assess and prioritise IMDs for inclusion in NBS programmes. The Wilson and Jungner classic screening principles were used as a foundation to develop individual and measurable criteria. The proposed algorithm is a point-based system structured upon three pillars: condition, screening, and treatment. The algorithm was tested by applying the six IMDs currently approved in the United Kingdom NBS programme. The algorithm generates a weight-based score that could be used as the first step in the complex process of evaluating disorders for inclusion on NBS programmes. By prioritising disorders to be further evaluated, individual countries are able to assess the economic, societal and political aspects of a potential screening programme.

Direct replacement of oral sodium benzoate with glycerol phenylbutyrate in children with urea cycle disorders.

Long-term management of urea cycle disorders (UCDs) often involves unlicensed oral sodium benzoate (NaBz) which has a high volume and unpleasant taste. A more palatable treatment is licenced and available (glycerol phenylbutyrate [GPB], Ravicti) but guidance on how to transition patients from NaBz is lacking. A retrospective analysis of clinical and biochemical data was performed for eight children who transitioned from treatment with a single ammonia scavenger, NaBz, to GPB at a single metabolic centre; UCDs included arginosuccinic aciduria (ASA) (n = 5), citrullinaemia type 1 (n = 2) and carbamoyl phosphate synthetase I deficiency (CPS1) (n = 1). Patients transitioned either by gradual transition over 1-2 weeks (n = 3) or direct replacement of NaBz with GPB (n = 5). Median initial dose of GPB was 8.5 mL/m2/day based on published product information; doses were revisited subsequently in clinic and titrated individually (range 4.5-11 mL/m2/day). Pre-transition and post-transition mean ammonia levels were 37 µmol/L (SD 28 µmol/L) and 29 µmol/L (SD 22 µmol/L), respectively (p = 0.09), and mean glutamine levels were 664 µmol/L (SD 225 µmol/L) and 598 µmol/L (SD 185 µmol/L), respectively (p = 0.24). There were no reductions in levels of branched chain amino acids. No related adverse drug reactions were reported. Patients preferred GPB because of its lower volume and greater palatability. Direct replacement of NaBz with GPB maintained metabolic control and was simple for the health service and patients to manage. A more cautious approach with additional monitoring would be warranted in brittle patients and patients whose ammonia levels are difficult to control.

Application of a Novel Algorithm for Expanding Newborn Screening for Inherited Metabolic Disorders across Europe.

Inherited metabolic disorders (IMDs) are mostly rare, have overlapping symptoms, and can be devastating and progressive. However, in many disorders, early intervention can improve long-term outcomes, and newborn screening (NBS) programmes can reduce caregiver stress in the journey to diagnosis and allow patients to receive early, and potentially pre-symptomatic, treatment. Across Europe there are vast discrepancies in the number of IMDs that are screened for and there is an imminent opportunity to accelerate the expansion of evidence-based screening programmes and reduce the disparities in screening programmes across Europe. A comprehensive list of IMDs was created for analysis. A novel NBS evaluation algorithm, described by Burlina et al. in 2021, was used to assess and prioritise IMDs for inclusion on expanded NBS programmes across Europe. Forty-eight IMDs, of which twenty-one were lysosomal storage disorders (LSDs), were identified and assessed with the novel NBS evaluation algorithm. Thirty-five disorders most strongly fulfil the Wilson and Jungner classic screening principles and should be considered for inclusion in NBS programmes across Europe. The recommended disorders should be evaluated at the national level to assess the economic, societal, and political aspects of potential screening programmes.

Inborn errors of metabolism and their impact in paediatric dentistry.

The management of paediatric patients with inborn errors of metabolism (IEM) presents an unparalleled challenge for paediatric dentists owing to the multiplex of interrelated dental manifestations and metabolic management necessitating modifications to dental care. Inborn errors of metabolism describe a largely heterogenous group of genetic disorders namely attributable to a single gene defect essential for a specific metabolic pathway. Approximately 400 disorders have been described with an overall incidence of 1 in 5000 live births worldwide. Clinical presentation is classically inconspicuous and insidious in the neonatal period with pathophysiology attributable to accumulation of toxic by-products which interfere with normal function, or insufficient synthesis of essential compounds. This paper aims to discuss the primary oral and maxillofacial manifestations across the scope of inborn errors of metabolism, whilst also considering how metabolic treatment has the propensity to complicate dental management.

Understanding disease symptoms and impacts and producing qualitatively-derived severity stages for MPS IIIA: a mixed methods approach.

BACKGROUND: MPS IIIA is a rare, degenerative pediatric genetic disease characterized by symptoms impacting cognition, mobility and behavior; the mean age of death is around 15 years of age. Currently, there are no approved therapies for MPS IIIA. METHODS: A two-year, multi-center, prospective, descriptive cohort study was conducted to document the natural history course of MPS IIIA. In the context of this study, semi-structured interviews were performed with parents of children at study entry and one year later. Interview transcripts were analyzed using thematic analysis methods to identity concepts of interest to children and parents, identify what factors impacted parents' burden the most, and develop qualitatively-derived disease severity stages. Children were sorted into these stages according to the symptoms their parents described at the entry interview. This sorting was compared quantitatively to the sorting of children at baseline according to the child's calendar age and their BSID development quotient (DQ). RESULTS: 22 parents in France, Germany, the Netherlands and the UK were interviewed. Children ranged in age from 28 to 105 months (mean 61.4 months). The conceptual models for children's symptoms and impacts and parents' impacts provided a detailed and comprehensive picture of what it is like for children of various ages and their parents to live with MPS IIIA. Four factors were identified as mediating the burden perceived by parents: state support, family support, time since diagnosis, and parent coping strategy. Four disease stages were developed, accounting for both the presence and the severity of MPS IIIA symptoms. The comparison of children's sorting into these stages with the BSID DQ and the child's calendar age showed strong statistical associations. CONCLUSIONS: The findings of this qualitative research embedded in a natural history study add to the current understanding of MPS IIIA as a complex disease that impacts every aspect of the lives of children and their families. This study demonstrates the unique potential of mixed methods research in rare diseases to address some of the current limitations of more traditional quantitative approaches by providing an individualized, detailed understanding of the patient experience.

An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA.

Mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome) is a rare genetic lysosomal storage disease characterized by early and progressive neurodegeneration resulting in a rapid decline in cognitive function affecting speech and language, adaptive behavior, and motor skills. We carried out a prospective observational study to assess the natural history of patients with MPS IIIA, using both standardized tests and patient-centric measures to determine the course of disease progression over a 2-year period. A cohort of 23 patients (7 girls, 16 boys; mean age 28-105 months at baseline) with a confirmed diagnosis of MPS IIIA were assessed and followed up at intervals of 3-6 months; cognitive function was measured using Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) to derive cognitive development quotients (DQ). Daily living, speech/language development and motor skills were measured using the Vineland Adaptive Behavior Scale (VABS-II). Sleep-wake patterns, behavior and quality-of-life questionnaires were also reported at each visit using parent/caregiver reported outcome tools. All patients had early onset severe MPS IIIA, were diagnosed before 74 months of age, and had cognitive scores below normal developmental levels at baseline. Patients less than 40 months of age at baseline were more likely to continue developing new skills over the first 6-12 months of follow-up. There was a high variability in cognitive developmental age (DA) in patients between 40 and 70 months of age; two-thirds of these patients already had profound cognitive decline, with a DA ≤10 months. The highest cognitive DA achieved in the full study cohort was 34 months. Post hoc, patients were divided into two groups based on baseline cognitive DQ (DQ ≥50 or <50). Cognitive DQ decreased linearly over time, with a decrease from baseline of 30.1 and 9.0 points in patients with cognitive DQ ≥50 at baseline and cognitive DQ <50 at baseline, respectively. Over the 2-year study, VABS-II language scores declined progressively. Motor skills, including walking, declined over time, although significantly later than cognitive decline. No clear pattern of sleep disturbance was observed, but night waking was common in younger patients. Pain scores, as measured on the quality-of-life questionnaire, increased over the study period. The findings of this study strengthen the natural history data on cognitive decline in MPS IIIA and importantly provide additional data on endpoints, validated by the patient community as important to treat, that may form the basis of a multidomain endpoint capturing the disease complexity.