Rani H. Singh

Long‐chain fatty acid oxidation disorders (LC‐FAOD) are rare inherited defects of mitochondrial β‐oxidation that impair energy generation during fasting or metabolic stress. Clinical manifestations range from neonatal hypoketotic hypoglycemia and cardiomyopathy to hepatopathy, recurrent rhabdomyolysis, and chronic myopathy. Although newborn screening (NBS) enables early detection, management remains inconsistent due to limited evidence, broadening phenotypic spectrum, and regional practice variation. An international multidisciplinary workgroup of 34 members, including clinicians, nurses, dietitians, and patient representatives, systematically reviewed the literature (1990–2022) using PubMed, Embase, and Web of Science. Evidence was graded using an adapted Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and consensus was achieved through a modified Delphi–Nominal Group–Delphi methodology, with agreement defined as ≥ 75%. Especially when evidence was low, expert consensus was the basis for this guideline. Recommendations address diagnosis, dietary management, fasting tolerance, use of medium‐chain fat sources, exercise and illness protocols, pregnancy care, and long‐term monitoring. Evidence quality ranged from very low to moderate. Strong consensus was reached for critical clinical interventions. Standardized approaches for diagnostic work‐up, management during metabolic stress, and follow‐up monitoring were developed to promote uniform care across age groups, disease groups, and phenotypic severity. This international guideline integrates available evidence and expert consensus to provide standardized recommendations for diagnosis, treatment and lifelong management of LC‐FAOD. They aim to harmonize clinical practice, improve patient outcomes, and support global implementation of evidence‐based metabolic care.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are transforming obesity management, yet landmark trials often incompletely measure and report a central mediator of response: dietary intake. Because GLP-1RAs promote weight loss primarily by suppressing appetite and reducing energy consumption, capturing changes in dietary intake is essential to interpreting efficacy, safety, and translation into clinical care. This perspective argues that failure to measure and report comprehensive dietary intake raises concerns under four core bioethical principles. It undermines autonomy by limiting evidence for shared decision-making across the treatment continuum. It challenges non-maleficence because inadequate energy, protein, and micronutrient intake may contribute to lean mass loss and nutrient deficiencies, particularly in vulnerable populations. It weakens beneficence because failing to report a measurable mediator diminishes the scientific value of research requiring substantial investment and participant burden. It raises justice concerns because the equitable distribution of assessment burden and access to resulting nutritional care cannot be evaluated without transparent reporting. To meet the ethical and scientific obligations of clinical research, future trials should preregister dietary intake as a key secondary or safety endpoint. Investigators should report total energy, macronutrient, and micronutrient distribution at baseline and serial follow-up alongside dietary assessment methods, food composition databases, and assessor training. Journal editors, funders, and regulatory bodies should support development of consensus-based, nutrition-specific reporting recommendations aligned with CONSORT principles and encourage preregistration of dietary trial endpoints. Registered dietitian nutritionists should be prospectively integrated into GLP-1RA trial teams from design through data interpretation. Advancing the standard of obesity care requires that the research community look beyond the scale and ground clinical translation in the nutritional context in which pharmacotherapy operates.

Background: Medium chain acyl CoA dehydrogenase deficiency (MCADD) is a rare, autosomal recessive disorder of fatty acid β-oxidation, which is typically diagnosed via newborn screening in the United States. Nutrition management during times of wellness and emergency care during times of illness are necessary to optimize outcomes. While guidelines for care have been published, there is variability in management between clinics. Body: The 2023 MCADD Patient and Family Education Summit with Providers was a global virtual summit of parents/carers of children with MCADD, adult patients, and healthcare providers to explore current trends and to identify unmet needs related to MCADD management. The summit included presentations by specialists and open discussions between patients, parents/carers and providers. We identified areas in which patients/carers and providers were in agreement (e.g., provision of emergency letters), and areas where there appeared to be discordance (e.g., provision of sick day protocols and use of home glucose monitors). Conclusion: The summit provided an innovative model for education and research, effectively engaging a global audience around patient-centered priorities and to advance research. Creating more opportunities for such educational and discussion forums could benefit both attendees and those involved in MCADD or other rare genetic disorders research, potentially improving patient outcomes.

Background/Objectives: Casein glycomacropeptide (cGMP) has been modified to enable its suitability as a low phenylalanine (Phe) protein substitute (PS) in phenylketonuria (PKU). No data is available about its global usage. Methods: A 60-item multiple choice and short answer/extended response questionnaire examining the use of modified cGMP in PKU was distributed globally to dietitians and physicians via web-based professional inherited metabolic disorder groups. Results: Respondents (n = 208) from 45 countries across 6 continents completed the questionnaire. Of these, 83.7% (n = 174) were dietitians/nutritionists, 14.9% (n = 31) medical doctors/physicians and 1.4% (n = 3) other health professionals, caring for both paediatric and adult patients (59.1%), paediatrics only (25.0%) or adults only (15.9%). cGMP PS were reported as not available in their centre/hospital by 19.7% (n = 41), mostly in Africa, South America, and southern and western Asia. The main reasons included lack of regulatory approval (65.8%), not promoted by manufacturers (41.5%), and cost (29.3%). An estimated 25% of represented patients globally were using cGMP PS; 78.4% (n = 163) following refusal/poor adherence with Phe-free amino acids and 54.8% (n = 114) for adult patients recommencing dietary treatment. There were concerns about the residual Phe in cGMP negatively impacting blood Phe levels in children n = 145) adjusted dietary Phe prescription according to the cGMP Phe content, particularly in regions with a higher percentage of severe PKU variants. Commonly perceived clinical advantages with cGMP were improved taste/palatability (93.2%, n = 194) and fewer gastrointestinal symptoms (55.8%, n = 116). Perceived clinical disadvantages were residual Phe (72.1%, n = 150), lack of data in children < 3 years (48.1%, n = 100), and the high energy content of some brands (45.2%, n = 94). There were concerns that cGMP PS were too high in sugar (34.1%, n = 71) and dissatisfaction or uncertainty about the adequacy of its Phe (66.3%) and amino acid (34.1%) content. Conclusions: There is global inconsistency in access to cGMP PS suitable for PKU, and in the interpretation of evidence-based research. Some professionals have significant concerns about its nutritional composition particularly residual Phe, limiting its estimated use to approximately 25% of PKU patients globally.

Background: In phenylketonuria (PKU) patients, dried blood spot (DBS) sampling remains the standard method for monitoring phenylalanine (Phe) levels. However, delays in reporting results can hinder timely dietary adjustments. Patients and caregivers have expressed a preference for point-of-care testing (POCT) devices that enable home-based monitoring. Objectives: Our aim was to compare blood Phe measurements in PKU patients and caregiver usability of a POCT system with DBS, which is the standard practice monitoring method. Methods: Twenty participants (eighteen children with PKU and two healthy controls) were recruited. Caregivers of children with PKU were asked to perform blood Phe measurements at home under the supervision of a researcher, using both the POCT device (Egoo Phe system) and DBS sampling. Healthy controls collected the same number of samples using both methods in a hospital setting. The POCT system required 40 µL of blood and used an enzymatic, bioluminescent detection system. DBS samples were analyzed by tandem mass spectrometry (TMS) and required two blood spots (approximately 100 µL of blood). The Egoo Connect App, linked via Bluetooth to the POCT device, displayed results after 29 min. Caregiver usability of the POCT system was assessed using questionnaires at each visit. Results: A total of 100 paired samples were collected. Median values were 274 μmol/L (range: 30–1039) for POCT and 270 μmol/L (range: 20–1190) for DBS. POCT readings were a mean of 4.6% higher than DBS with a noticeable strong correlation observed (y = 1.017x; R² = 0.8450; p < 0.0001). The usability of the POCT system improved with caregiver practice, and all caregivers expressed a preference for POCT over DBS. Conclusions: The POCT system for blood Phe demonstrated strong concordance with DBS and high caregiver acceptance, highlighting its potential to transform PKU care through faster, patient-driven monitoring and more timely clinical decision-making.

Background: The autosomal recessive disorder N-acetylglutamate synthase (NAGS) deficiency is the rarest defect of the urea cycle, with an incidence of less than one in 2,000,000 live births. Hyperammonemic crises can be avoided in individuals with NAGS deficiency by the administration of carbamylglutamate (also known as carglumic acid), which activates carbamoyl phosphatase synthetase 1 (CPS1). The aim of this case series was to introduce additional cases of NAGS deficiency to the literature as well as to assess the role of nutrition management in conjunction with carbamylglutamate therapy across new and existing cases. Methods: We conducted retrospective chart reviews of seven cases of NAGS deficiency in the US and Canada, focusing on presentation, diagnosis, medication management, nutrition management, and outcomes. Results: Five new and two previously published cases were included. Presenting symptoms were consistent with previous reports. Diagnostic confirmation via molecular testing varied in protocol across cases, with consecutive single gene tests leading to long delays in diagnosis in some cases. All patients responded well to carbamylglutamate therapy, as indicated by normalization of plasma ammonia and citrulline, as well as urine orotic acid in patients with abnormal levels at baseline. Although protein restriction was not prescribed in any cases after carbamylglutamate initiation, two patients continued to self-restrict protein intake. One patient experienced two episodes of hyperammonemia that resulted in poor long-term outcomes. Both episodes occurred after a disruption in access to carbamylglutamate, once due to insurance prior authorization requirements and language barriers and once due to seizure activity limiting the family’s ability to administer carbamylglutamate. Conclusions: Follow-up of patients with NAGS deficiency should include plans for illness and for disruption of carbamylglutamate access, including nutrition management strategies such as protein restriction. Carbamylglutamate can help patients with NAGS deficiency to liberalize their diets, but the maximum safe level of protein intake to prevent hyperammonemia is not yet known. Patients using this medication should still monitor their diet closely and be prepared for any disruptions in medication access, which might require immediate dietary adjustments or medical intervention to prevent hyperammonemia.

Choline is an essential nutrient for brain development and function that is attained through high-protein foods, which are limited in the phenylalanine-restricted diet of people with phenylketonuria (PKU). This study compared choline consumption among individuals with PKU to a reference sample from the National Health and Nutrition Examination Survey (NHANES), and identified treatment and diet-related factors that may modulate choline needs. Participants were individuals with PKU (n = 120, 4–61 years) managed with dietary therapy alone (n = 49), sapropterin dihydrochloride for ≥1 year (n = 38), or pegvaliase for ≥1 year with no medical food (n = 33). NHANES participants were not pregnant or nursing and came from the 2015–2018 cycles (n = 10,681, 4–70 years). Dietary intake data were used to estimate total usual intake distributions for choline, and mean probability of adequacy (MPA) was calculated as a summary index of nutrient adequacy for four methyl-donor/co-factor nutrients that impact choline utilization (folate, vitamin B12, vitamin B6, and methionine). Only 10.8% (SE: 2.98) of the total PKU sample (14.7% [SE: 4.03] of children; 6.8% [SE: 2.89] of adults) achieved the adequate intake (AI) for choline, while 12.2% (SE:0.79) of the NHANES sample met the recommended level. Adults receiving pegvaliase were the most likely to exceed the AI for choline (14.82% [SE: 4.48]), while adults who were on diet therapy alone were the least likely (5.59% [SE: 2.95]). Without fortified medical foods, individuals on diet therapy and sapropterin would not be able to achieve the AI, and MPA for other methyl donor/co-factor nutrients would be reduced. More frequent monitoring of choline intake and increased choline fortification of medical foods could benefit this population.