Long-chain fatty acid oxidation disorders (lcFAODs) are genetic disorders of energy metabolism that are associated with a risk of metabolic decompensation, especially during catabolic episodes. With improvement in diagnostics and treatment, more women with lcFAODs now reach child-bearing age. So far, little is known about the risk and outcome of pregnancies, particularly in women with more severe forms of lcFAODs. We performed an international web-based survey among health care professionals involved in the care of individuals with lcFAODs and collected data on 89 pregnancies in 39 women (mild VLCAD deficiency n = 8, severe VLCAD deficiency n = 10, LCHAD deficiency n = 4, CPT2 deficiency n = 14, CPT1 deficiency n = 3). There were 72 live births, 12 spontaneous miscarriages, and one stillbirth at 41 weeks of gestation. Four women were still pregnant at the time of the survey. In 25 women, the diagnosis was known before the first pregnancy, whereas 14 had at least one pregnancy before diagnosis. Most women remained metabolically stable during pregnancy, although 19% of women had at least one metabolic decompensation during pregnancy. Forty-one percent of babies were delivered by spontaneous vaginal delivery, 33% after induced labor, and 19% by an elective Caesarean section. Most deliveries were uncomplicated, with preventive i.v. glucose infusions given in 50%. However, 21% of mothers developed a metabolic decompensation in the postpartum period. No maternal deaths were reported. In conclusion, our data show that the outcome of pregnancies in lcFAOD patients is generally favorable, despite a significant risk of metabolic decompensation during the postpartum period.

Objectives:To determine whether boys with VUS detected through Newborn screening (NBS) for Adrenoleukodystrophy (ALD) develop adrenal insufficiency (aiALD) and cerebral ALD (cALD) at rates comparable to those with pathogenic variants, and to evaluate the relationship between C26:0-lysophosphatidylcholine (C26:0-LPC) levels and clinical outcomes. Methods:We conducted a retrospective multicenter cohort study (2013-2025) across six US centers, including 201 males identified through NBS in 19 states. Variants were classified as pathogenic (n=65), likely pathogenic (n=45), or VUS (n=88). Primary outcomes were development of aiALD and cALD; secondary outcomes included C26:0-LPC levels. Statistical analyses included Kaplan-Meier, mixed-effects regression, and Cox models. Results:201 males with ABCD1 variants identified through NBS for ALD. Median age at last follow-up was 4.2 years (IQR 2.5-7.9). Overall, 26% developed aiALD (54% pathogenic, 16% likely pathogenic, 11% VUS), and 8% developed cALD (11%, 9%, and 4.5%, respectively). Pathogenic/likely pathogenic variants were associated with higher odds of aiALD than VUS (OR 5.8; 95% CI 2.16-15.58; p=0.001). At 150 months, 39% of individuals with pathogenic/likely pathogenic variants remained free of aiALD versus 85% with VUS. C26:0-LPC levels were higher in pathogenic variants and correlated with genotype (p=0.0006). Higher levels were associated with increased aiALD risk and earlier onset (HR 1.38 per 0.1 µmol/L; 95% CI 1.20-1.59; p<0.0001). Conclusions:Boys with VUS had lower rates of aiALD and lower C26:0-LPC levels than those with pathogenic variants, although some developed disease. C26:0-LPC correlates with genotype and risk, supporting its role in variant classification and risk-stratified surveillance. What’s Known on This Subject:Newborn screening for X-linked adrenoleukodystrophy has increased identification of variants of uncertain significance, accounting for up to 50% of screen-positive cases in some states. These are often associated with borderline biomarker levels, and their natural history remains poorly understood. What This Study Adds:Screen-positive individuals with VUS had substantially lower rates of disease onset than those with pathogenic variants. Newborn biomarker levels also correlated with variant pathogenicity and disease onset, which may aid future variant classification and risk stratification.

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.

AbstractIngestion of fructose and galactose may result in elevated lactate concentrations in patients with glycogen storage disease type 1 (GSD1). In this randomized cross‐over pilot study, 7 patients with GSD 1a (6) and GSD1b (1) orally consumed a common‐size fructose and galactose from either 200 mL of skimmed milk, 200 mL juice or 200 mL water. This was given after a night with their usual dietary treatment using either cornstarch, glycosade or continuous feed. P‐lactate and ‐glucose were measured 2 h before dosing (T = −120 min and −60 min). At baseline (T = 0), p‐lactate, p‐glucose, p‐triglycerides, p‐uric acid and p‐alanine were measured just before dosing. P‐lactate and p‐glucose were measured every 30 min for 4 h. Four hours after the consumption (T = 240 min, end‐of‐test), levels of p‐lactate, p‐glucose, p‐triglycerides, p‐uric acid and p‐alanine were measured. P‐lactate increased in three patients with mean of 0.3 mmol/L (range 0.2–0.6 mmol/L) after consuming milk. The highest level was seen after 60 min. A decrease was seen in three patients. P‐lactate increased in four patients with a mean increase at 1.3 mmol/L (range 0.2–2.2 mmol/L) after consuming 200 mL juice. A peak increase was seen after the first 30 min in two patients whereas the peak in the remaining two patients was at 60 min; all values decreased to baseline values after further 60 min. In two patients, p‐lactate was unchanged, respectively, decreased after juice ingestion. Calculation of galactose and fructose AUC percentage change after challenge did not reveal consistent increase or decreases.

BACKGROUND AND OBJECTIVE:This nationwide, single-cohort study provides a comprehensive analysis of the epidemiology of X-linked adrenoleukodystrophy (ALD) in Denmark. We examined incidence, age at symptom onset, and sex-stratified survival outcomes to explore differences in symptom development. Findings were compared with international cohorts to contextualize the Danish results. METHODS:We included all individuals with genetically confirmed ALD residing in Denmark, with no age restrictions. Patients were born between 1911 and 2020. Clinical data were retrospectively extracted from medical records. Where available, dried blood spots collected at birth and stored in the Danish National Biobank were analyzed using liquid chromatography-mass spectrometry to quantify C26:0-lysophosphatidylcholine (C26:0-LPC). Cumulative incidence functions were used to estimate the risk of developing specific ALD phenotypes over time. RESULTS:A total of 113 individuals (49 males, 64 females) met inclusion criteria. The point prevalence of ALD was 1.42 per 100,000, and the average birth incidence from 1932 to 2023 was 1.81 per 100,000 (males: 1.7; females: 1.9). Thirty-four distinct pathogenic ABCD1 variants were identified, with c.1679C > T, p.(Pro560Leu) being the most common (21 cases). By age 60, 76 % of males had developed adrenomyeloneuropathy (AMN), 44 % had developed cerebral ALD (cALD), and 44 % had adrenal insufficiency. Among females, 80 % had developed AMN by the same age. AMN was associated with the longest diagnostic delay, averaging 8 years in males and 9 years in females. DISCUSSION:This study offers a rare, nationwide view of ALD spanning over a century of births alongside measurement of C26:0-LPC in historical, neonatally collected dried blood spot cards from 14 individuals in this cohort. While the birth incidence aligns with some other natural history studies, it remains lower than in countries with universal newborn screening. The high frequency of AMN in both sexes highlights the need for greater clinical awareness. Notably, our findings confirm that the majority of women with ALD will develop neurological symptoms over time, challenging the long-standing perception of female carriers as largely asymptomatic. The relatively low detection of cALD and adrenal insufficiency in adults suggests possible underdiagnosis and calls for improved long-term follow-up, especially in adult neurology and endocrinology.

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.

Asparaginase is an essential drug in the treatment of acute lymphoblastic leukemia, and discontinuation of asparaginase therapy due to clinical toxicity or silent inactivation may lead to reduced event-free survival. Common toxicities include hypersensitivity reactions, acute pancreatitis, thrombosis, hepatotoxicity, and hyperlipidemia. In addition, several small case series have described asparaginase-associated hyperammonemia (AAH), the true frequency and clinical importance of which, both short-and long term, remains unclear. Descriptions vary from asymptomatic patients to those with severe, acute encephalopathy leading to withdrawal of asparaginase therapy. The cause and management of the problem remains elusive. This review summarizes current knowledge on AAH, including its pathogenesis, clinical presentation, and possible interventions.

Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1). All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1. We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Background Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria. Methods APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 mu mol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH 4 deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin ( forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days -1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640). Findings APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, >= 15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (-63%, SD 20) compared with placebo (1%, 29; least squares mean change -395 center dot 9 mu mol/L, SE 33 center dot 8; p<0 center dot 0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events. Interpretation Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Current literature lacks consensus on initial assessments and routine follow-up care of patients with Alpha-Mannosidosis. This Delphi panel aimed to generate and validate recommendations on best practices for initial assessment of newly diagnosed patients, routine follow-up care, and integrated care coordination of patients with Alpha-Mannosidosis.

Enzyme replacement therapy (ERT) using velmanase alfa previously showed promising efficacy and safety outcomes for up to 4 years of therapy in patients with alpha-mannosidosis. This pooled analysis from two multicenter, open-label phase IIIb extension trials rhLAMAN-07 (N = 13; NCT01908712) and rhLAMAN-09 (N = 8; NCT01908725) evaluated the long-term effects of velmanase alfa. Sixteen patients who previously completed phase I-III rhLAMAN-02/-03/-04/-05/-08 trials and five ERT-naive patients were enrolled. Patients received 1 mg/kg velmanase alfa once weekly. Endpoints included changes from treatment baseline (before initial dose of velmanase alfa in any trial) in serum oligosaccharides, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function (forced vital capacity [FVC], % predicted), serum immunoglobulin G (IgG) levels, and adverse events. The overall cohort comprised 21 patients, divided by age at treatment baseline into pediatric (n = 14) and adult subgroups (n = 7). Distance walked according to 6MWT increased or stabilized in pediatric patients, while in adults either stabilization or slight decline was observed. Similarly, pediatric patients performed better in the 3MSCT. Changes in FVC, % predicted, were comparable in both subgroups up to similar to 6 years of observation, diverging thereafter. Overall, sustained serum oligosaccharide clearance and serum IgG level increase was observed upon treatment initiation and persisted until last common observation. Velmanase alfa treatment was generally well tolerated, with the majority of reported adverse events being of mild-to-moderate intensity. With follow-up of up to 12 years, long-term efficacy and safety outcomes indicate continued benefits of velmanase alfa in patients with alpha-mannosidosis.