Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease resulting in multisystemic disease manifestations, significant disease burden, and early mortality for some individuals. Enzyme replacement therapy (ERT) with olipudase alfa (Xenpozyme) is the first disease-specific treatment indicated for noncentral nervous system manifestations of ASMD in children and adults. During the 1-year primary analysis of the ASCEND placebo-controlled trial in 36 adults with ASMD, olipudase alfa treatment reduced sphingomyelin storage and was associated with clinically significant improvements relative to placebo in multiple endpoints. An open-label extension of the ASCEND trial followed 35 of 36 adults during olipudase alfa treatment for up to 5 years. Mean time on olipudase alfa was 4.2 ± 1.0 years; mean compliance was 90% ± 13%. During long-term olipudase alfa treatment, percent predicted diffusing capacity for carbon monoxide (DLCO) increased (mean 50.1% ± 10.8% at baseline vs. 66.5% ± 13.3% at final assessment; mean change from baseline of 35.9% ± 27.5% (p < 0.0001). Mean baseline spleen volume of 11.5 ± 4.6 multiples of normal (MN) decreased to 4.8 ± 2.1 MN at final assessment, mean change from baseline -57.5% ± 10.1% (p < 0.0001) and mean baseline liver volume (1.5 ± 0.4 MN) decreased to 0.95 ± 0.23 MN at final assessment, (mean change from baseline -36.8% ± 11.5%, p < 0.0001). Plasma lyso-sphingomyelin levels decreased by 72% from baseline to final assessment. Overall, improvements in clinical parameters occurred regardless of baseline severity. No new safety issues emerged during the trial extension and 98% of treatment emergent adverse events were mild/moderate. Improvements in visceral ASMD disease with olipudase alfa treatment will significantly impact the disease burden for those with this progressive multiorgan disorder.

OBJECTIVE:To evaluate feasibility and diagnostic and process qualities as well as the clinical benefit of newborn screening (NBS) for urea cycle disorders (UCDs). METHODS:Between 2016 and 2023, 624 480 neonates were enrolled in the German NBS pilot study, including NBS for UCDs by tandem mass spectrometry. In addition, patients with confirmed cases were enrolled in an observational, multicenter outcome study assessing clinical and neurodevelopmental outcomes. RESULTS:NBS for UCDs demonstrated high sensitivity (100%) and specificity (99.988%) with a positive predictive value (PPV) of 0.2. Nineteen cases (7 ornithine transcarbamoylase deficiency, 7 argininosuccinate synthetase 1 deficiency, 4 argininosuccinate lyase deficiency, and 1 carbamoylphosphate synthetase 1 deficiency) were confirmed, yielding a cumulative birth prevalence of 1:32 867 newborns. Despite short process times, more than 50% of screened individuals with a UCD were already symptomatic at first NBS report. Retrospective analyses indicated that integration of metabolite ratios (eg, ornithine/citrulline) may further enhance PPV. Outcome data from 25 individuals revealed higher rates of metabolic decompensations and hospitalizations in mitochondrial UCDs vs cytosolic forms. At last follow-up, 55% showed disease-related symptoms, and mean IQ was reduced in symptomatic individuals, but mortality was lower than previously reported. CONCLUSION:NBS for UCDs is technically feasible and enables early diagnosis. Although early-onset decompensations remain difficult to prevent, screening reduces mortality. Refinement of the screening algorithm may further improve specificity and clinical benefit.

This study assessed quality of life (QoL) changes over time amongst caregivers of patients with alpha-mannosidosis, a rare autosomal recessive lysosomal storage disorder with progressive multi-systemic effects. An international online survey was distributed to caregivers of patients aged ≥ 10 years, including visual analogue scales (VAS; timepoints 5 years prior and current) and multiple choice and open text questions. Survey questions related to five QoL domains (physical health, mental health, family and social life, relationships with partners/family/friends and ability to work/attend education). Forty-three caregiver responses from 16 countries were analysed. Caregivers looked after 43 patients: 16 untreated patients (UP), six who had undergone allogenic haematopoietic stem cell transplantation (HSCT) and 21 receiving enzyme replacement therapy (ERT). From 5 years prior to the time of survey participation, physical health slightly improved for caregivers of ERT and HSCT patients (mean ± standard deviation changes in VAS − 0.1 ± 2.8 and − 0.2 ± 1.2, respectively) but slightly declined among UP caregivers (+ 0.7 ± 0.9). Mental health improved for caregivers of HSCT patients (-1.0 ± 4.7) but stabilised and worsened for ERT and UP caregivers, respectively (ERT: 0.0 ± 2.3; UP: +1.4 ± 1.9). Family and social life scores improved among caregivers of HSCT patients (-1.0 ± 3.5) but slightly declined and worsened for ERT (+ 0.1 ± 2.3) and UP (+ 1.1 ± 1.4) caregivers, respectively. Relationship scores slightly improved for caregivers of ERT and HSCT patients (both − 0.2) but worsened among UP caregivers (+ 1.3 ± 1.7). There were slight improvements in ability to work or attend education for caregivers of ERT and HSCT patients. Although a causal relationship between disease-modifying treatment and caregiver QoL could not be determined, mostly due to small subgroup sizes and age differences between HSCT patients, ERT patients and UP, caregivers of patients receiving ERT or HSCT generally experienced stable or improved/slightly improved QoL outcomes over the 5-year study period. In contrast, caregivers of UP consistently reported deterioration across physical, mental, social and relational QoL domains. These patterns suggest that access to disease-modifying treatment could help mitigate declines in caregiver QoL, highlighting the need to routinely assess caregiver-reported outcomes and support caregiver needs alongside patient management in alpha-mannosidosis.

Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by progressive spastic paraplegia, developmental delay, epilepsy, and episodic hyperammonemia. Evidence on prevalence and clinical presentation is scarce. Therefore, epidemiology and the phenotypical spectrum were assessed in Germany, Austria, and Switzerland (DACH region). We conducted a questionnaire-based, cross-sectional study of confirmed ARG1-D patients in the DACH region. Patients were stratified into early-diagnosed (newborn screening [NBS] or high-risk family screening [HR]) and diagnosed after symptom onset. We evaluated clinical, biochemical, and therapeutic characteristics of individuals with confirmed ARG1-D. Epidemiological prevalence estimates were derived using national population data. A total of 20 patients were identified (Germany: 12, Austria: 7, Switzerland: 1). Eight were diagnosed early (NBS: 4, HR: 4) and 12 after symptom onset. Symptomatically diagnosed patients (median age 11 years) presented with a broad range of clinical manifestations, specifically progressive spastic paraplegia (67%), epilepsy (58%), dystonia (46%), developmental delay (58%), and hepatopathy (50%). Median age at diagnosis was 35 months in symptomatic patients versus 1 month in early-diagnosed patients (p = 0.03). Estimated pediatric prevalence was 1:1042080 in the DACH region, with high regional differences. Hyperammonemia was reported in 72%. Enzyme therapy had been initiated in 21%; 2 patients underwent liver transplantation. ARG1-D is a rare disease with a prevalence of approximately 1:1000000 individuals, and a complex and progressive clinical phenotype. Detection via NBS or HR allows early diagnosis and treatment initiation, potentially altering the clinical outcome.

To analyse ocular manifestations of MPS in the posterior segment of the eye, in particular retinal and optic disc pathologies, compared to healthy controls. This prospective study analyzed structural and functional posterior eye changes in 29 MPS patients (58 eyes) compared to 29 healthy, age- and gender-matched controls. Examinations included visual acuity testing, orthoptic status, intraocular pressure (IOP) measurement, visual field testing, slit-lamp examination and fundus examination, Spectral-Domain Optical Coherence Tomography (SD-OCT), OCT-Angiography (OCT-A) and High Magnification Module® (HMM®) imaging. LogMAR visual acuity (p < 0.001) and IOP (p < 0.001) were significantly worse/higher in MPS patients. Visual field defects showed a concentric restriction pattern, resembling to pigmentary retinopathy. Fundus examination of 56 eyes revealed optic disc atrophy in two eyes (all MPS II), atrophic macula in two eyes (both MPS II) and pigmentary retinopathy in twelve eyes (6 MPS II, 6 MPS IV). Total retinal thickness was significantly reduced in the parafoveal (p < 0.001) and perifoveal (p < 0.001) macula area in MPS, especially in MPS II patients. Peripapillary retinal nerve fiber layer thickness correlated positively with IOP (p = 0,015) in the MPS group. OCT-A findings revealed reduced capillary density of the parafoveal and perifoveal retina in 8/22 eyes in the MPS group (2 MPS I, 4 MPS II, 2 MPS IV). Rarefaction of the photoreceptor mosaic was observed in some MPS patients on HMM imaging. MPS patients exhibit impaired visual acuity and visual fields, higher IOP, and mircostructural and microvascular alterations of the optic disc and retina compared to healthy subjects.

Background:In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (NCT02612129), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a post-hoc primary endpoint in NPC-002, discusses its validation, and presents the results of the post-hoc primary analysis. Methods:To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study (N = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS. Results:Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 post-hoc primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol (N = 34) versus 2.05 (0.54) with placebo (N = 16), and a treatment effect in favor of arimoclomol over placebo of -1.70 (p = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was -0.23 (1.02) with arimoclomol (N = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of -2.21 (p = 0.0077). Conclusion:The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo.

OBJECTIVE Although newborn screening (NBS) programs were expanded with the implementation of tandem mass spectrometry in the late 1990s, the impact on long-term clinical and cognitive outcomes of adolescents and young adults with inherited metabolic diseases (IMDs) has remained fairly unknown for most IMDs. METHODS A prospective, multicenter, observational study is performed in Southwest Germany (NGS2025, DRKS-ID: DRKS00013329). For systematic follow-up from preschool up to adulthood, individuals with IMDs identified by NBS between 1999 and 2014 were included. RESULTS In total, 257 (124 boys, 133 girls) screened individuals with at least 1 study visit in adolescence were followed until median age of 13.7 years. During the observation period, most did not develop permanent disease-specific signs (70.1%) or metabolic decompensations (55.2% of those at risk), had normal cognitive outcome (81.4%; IQ mean [SD], 98 [15]), and attended regular primary (91.2%) and secondary schools (90.8%). Nonetheless, NBS and early start of treatment did not prevent metabolic decompensations in 69 (44.8%) individuals at risk, and in 33 of them, metabolic decompensation occurred already before the NBS result was available. Permanent disease-specific symptoms were more frequently observed in patients experiencing metabolic decompensations compared with those without decompensations (75% vs 12.8%). Reliable therapy adherence was associated with better long-term outcome. CONCLUSION NBS for IMDs is a highly successful program of secondary prevention for most early-diagnosed and early-treated individuals with an IMD, allowing the start in an independent life; however, therapeutic effectiveness and quality remain a relevant limitation in some diseases.

Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.

Alpha-mannosidosis is a rare recessive lysosomal storage disorder with progressive multi-systemic impacts. In the absence of standardized monitoring protocols, there is insufficient understanding of disease progression over time. This study explored the evolution of the burden of illness and quality of life (QoL) experienced by patients with alpha-mannosidosis via an international patient and caregiver-based survey. The online survey was distributed to adult patients/caregivers of patients ≥ 10 years old. It included visual analogue scales (VAS; timepoints 5 years ago and now), multiple choice, and open text questions. We report a subset of functional and QoL data: walking ability, pain/discomfort, ability to self-care, and mental health. Analyses include 51 responses from 18 countries: 26 patients were on velmanase alfa enzyme replacement therapy (ERT), seven had been treated with hematopoietic stem cell transplantation (HSCT) and 18 were untreated patients (UP). Over 5 years, VAS scores showed the least decline in walking ability for HSCT patients (+ 0.1 ± 1.9) compared to patients receiving ERT (+ 0.7 ± 1.2) and UP (+ 1.8 ± 2.0). A trend towards improvement in pain was only observed for those on ERT (-0.2 ± 2.0), both for pediatric and adult patients. Ability to self-care improved for patients treated with HSCT (-1.0 ± 1.8) and slightly improved with ERT (-0.3 ± 1.5) but worsened for UP (+ 0.6 ± 0.9). Similarly, a trend towards improvement in mental health scores was observed for patients on ERT (-0.4 ± 2.2). Alpha-mannosidosis is associated with a substantial and progressive burden in UP, including deterioration in walking ability, pain, self-care and mental health. The survey results suggest that treatment with ERT or HSCT may slow this natural progression of alpha-mannosidosis, with these patients following a different disease trajectory to those solely receiving supportive care. This study could inform the natural pathway of alpha-mannosidosis to recognize patients’ needs, courses of care, and the design of interventional studies.

BACKGROUND:This paper presents efficacy and safety outcomes from the 48-month open-label extension (OLE) of the phase 2/3 NPC-002 trial (NCT02612129) which evaluated arimoclomol treatment in patients with Niemann-Pick disease type C (NPC). Arimoclomol was recently approved by the US Food and Drug Administration for treatment of NPC in combination with miglustat. METHODS:Patients with NPC who completed the double-blind (DB) phase of the randomized controlled NPC-002 trial were eligible to continue in the OLE, during which all patients received arimoclomol in addition to routine clinical care. Primary efficacy outcomes were the 5-domain NPC Clinical Severity Scale (5DNPCCSS), and the rescored 4-domain NPCCSS (R4DNPCCSS), which was introduced post-hoc. Additional outcomes included NPC-specific measures (full scale NPCCSS, and NPC clinical database [NPC-cdb] score), and safety evaluations. RESULTS:Of the 50 patients who started the DB phase, 41 entered the OLE phase, with 29 completing 48 months. During the OLE, mean (SD) 5DNPCCS and R4DNPCCSS scores increased by 3.2 (4.8) and 2.7 (4.2) over 48 months, respectively. Among patients switching from placebo to arimoclomol after the DB phase, mean annual change in 5DNPCCSS decreased from 2.0 (on placebo) to 0.1 in the first year of receiving arimoclomol and mean annual change in R4DNPCCSS decreased from 1.9 to 0.2, indicating slowing of disease progression. Annual scores for both endpoints remained numerically smaller throughout the OLE than during the DB phase. The score pattern in the subset of patients who received miglustat as part of their standard care regime in addition to arimoclomol (N = 33) was similar to that seen in the total population. 17-domain NPCCSS (excluding hearing domains) and NPC-cdb results further supported sustained efficacy of arimoclomol. Arimoclomol was well-tolerated over 48 months, with no new safety concerns identified. CONCLUSION:The OLE of the NPC-002 trial provides evidence for a sustained reduction in disease progression for at least 5 years in a heterogeneous population of NPC patients receiving arimoclomol in addition to routine clinical care, with no new safety concerns. These results align with the statistically significant and clinically meaningful reduction in disease progression observed over 12-months in the DB phase, further highlighting the potential of arimoclomol as an effective and well tolerated disease modifying treatment for NPC.

Purpose: Alpha-mannosidosis is an ultrarare lysosomal storage disorder characterized by considerable diagnostic delays due to symptom heterogeneity and disease rarity. This study evaluated disease manifestation and clinical course between patients with varying disease severity to identify factors causing delayed diagnosis. Methods: Retrospective chart data were collected from 25 patients diagnosed at age ≥ 16 years categorized as having mild (n = 14) or moderate-severe disease (n = 11) across 11 centers in 7 countries. Results: Diagnostic delays were longer in patients with mild versus moderate-severe disease (mean [range]: 26.8 [10-46] vs 19.7 [14-30] years). Hearing impairment and learning/communication disability were common first signs in patients with mild and moderate-severe disease, respectively. Learning/communication disability was the most common key diagnostic sign for both groups. Symptoms appeared later in those with mild disease, although disease presentation was similar. Genetic testing confirmed diagnosis in 90% of patients; 64% of patients with mild disease had compound heterozygous variants vs 9% of those with moderate-severe disease. Patients on enzyme replacement therapy had improved or stabilized clinical conditions, indicating treatment importance regardless of age. Conclusion: This study underscores the need for improved diagnostic algorithms to facilitate timely diagnosis and treatment of patients with alpha-mannosidosis. Early suspicion and testing for alpha-mannosidosis in patients with hearing, motor, and learning impairments, along with continued reassessment of adults awaiting confirmed diagnosis are crucial.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (GLA) gene, leading to an increased risk for white matter lesion (WML), stroke and cerebral microbleeds. Utilizing MRI data from the prospective observational FAMOUS study we assessed MRI characteristics of FD and treatment effects of migalastat. 19 patients with pathogenic (PV) and 14 patients with likely benign genetic variants (LBV: p.A143T, p.D313Y, and p.S126G) underwent MRI at baseline and 24 month-follow up under migalastat treatment. WML load, using Fazekas and Scheltens scores, basilar artery diameter (BAD), and the occurrence of strokes and cerebral microbleeds were assessed. Patients were compared by variant type (PV/LBV) and presence of arterial hypertension. WML load was low to moderate and remained stable. Four PV patients showed progress by visual examination. WML load was similar between PV and LBV groups. Patients with arterial hypertension had a higher Scheltens score. PV patients had higher BAD. No patient showed cerebral microbleeds. One PV patient with coincident multiple sclerosis demonstrated a positive central vein sign. Our data suggest that microangiopathic lesion load remains relatively stable under migalastat. Antihypertensive therapy may be important to reduce WML in FD. Further studies are needed to assess the cerebral effect of migalastat therapy.

BACKGROUND:Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) was approved in Europe in 2006. Nevertheless, data on the long-term outcome of infantile onset Pompe disease (IOPD) patients at school age is still limited. OBJECTIVE:We analyzed in detail cardiac, respiratory, motor, and cognitive function of 15 German-speaking patients aged 7 and older who started ERT at a median age of 5 months. RESULTS:Starting dose was 20 mg/kg biweekly in 12 patients, 20 mg/kg weekly in 2, and 40 mg/kg weekly in one patient. CRIM-status was positive in 13 patients (86.7%) and negative or unknown in one patient each (6.7%). Three patients (20%) received immunomodulation. Median age at last assessment was 9.1 (7.0-19.5) years. At last follow-up 1 patient (6.7%) had mild cardiac hypertrophy, 6 (42.9%) had cardiac arrhythmias, and 7 (46.7%) required assisted ventilation. Seven patients (46.7%) achieved the ability to walk independently and 5 (33.3%) were still ambulatory at last follow-up. Six patients (40%) were able to sit without support, while the remaining 4 (26.7%) were tetraplegic. Eleven patients underwent cognitive testing (Culture Fair Intelligence Test), while 4 were unable to meet the requirements for cognitive testing. Intelligence quotients (IQs) ranged from normal (IQ 117, 102, 96, 94) in 4 patients (36.4%) to mild developmental delay (IQ 81) in one patient (9.1%) to intellectual disability (IQ 69, 63, 61, 3x <55) in 6 patients (54.5%). White matter abnormalities were present in 10 out of 12 cerebral MRIs from 7 patients. CONCLUSION:Substantial motor, cardiac, respiratory, and cognitive deficits are frequent in IOPD long-term survivors who started ERT before 2016. The findings of this study can be valuable as comparative data when evaluating the impact of newer treatment strategies including higher enzyme dosage, immunomodulation, modified enzymes, or early start of treatment following newborn screening.