Search Results (15)

Background: Newborn screening (NBS) is a preventive healthcare program aiming at identifying the inborn errors of metabolism (IEMs) in asymptomatic infants to reduce the risk of severe complications. The aim of this study was to report the first years (2016–2020) of the expanded NBS program in the Lombardy region, Italy. Methods: Dried blood spots were collected from newborns’ heels at 48–72 h after birth. FIA-MS/MS was performed to evaluate specific biochemical markers. Genetic confirmation was achieved via Sanger or NGS on newborns and reported to a clinical reference center (CRC). Results: A total of 343,507 newborns were tested; 1414/343,507 resulted as positive to NBS and were reported to the CRC. A total of 209 newborns were diagnosed with IEMs: 206 infants received a diagnosis of IEM through NBS, confirmed by genetic analysis; three neonates were not positive to NBS but were subsequentially diagnosed with IEMs. A total of 1208/343,507 were false positive cases. Twenty-seven types of IEMs were diagnosed in 209 patients: 111 newborns were affected by aminoacidemias, 11 by urea cycle disorders, 27 by organic acidemias, 34 by fatty acid oxidation disorders, and 26 by secondary conditions. Conclusions: We report here for the first time the IEM incidence and distribution in the Lombardy region in the first five years of NBS. Full article

Background: Expanded Newborn Screening (ENS) allows the early identification of many inherited metabolic diseases (IMDs) for which timely treatment can modify the natural history. For most IMDs, diagnosis by ENS is pre-clinical. However, clinical symptoms may emerge for certain conditions before screening results become available. Methods: We describe six cases of patients with early-onset IMDs born between 2013 and 2023, who were admitted or transferred to Sant’Orsola University Hospital in Bologna (Italy). Results: Over the study period, 379,013 newborns underwent ENS in the Italian region of Emilia-Romagna. Excluding cases of congenital hypothyroidism, pre-clinical diagnoses from ENS were 410. In addition, six cases of IMD presented with early-onset clinical symptomatology, an antecedent to the outcome of newborn screening (incidence over 11 years of 1.58 cases per 100,000 infants). Among these patients, three were diagnosed with Urea Cycle Disorders (UCDs)—two with Citrullinemia type I (CIT1) and one with Argininosuccinic Acidemia (ASA); two were diagnosed with Methylmalonic Acidemia (MMA); and one was found to have Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD). Conclusions: Our 11-year experience with ENS has shown that clinical onset can occur between the second and fourth day of life, though rare. Even if dried blood spot (DBS) collection was performed 24–48 h after birth, the time required for sample transportation and processing would still delay result availability, making early intervention unlikely. Therefore, our experience supports performing ENS at 48–72 h, as currently implemented in Italy, while also highlighting the advantages and limitations of earlier screening. Full article

Background/Objectives: The present study updates the Spanish registry of patients with urea cycle disorders (UCD), originally established in 2013, to provide comprehensive epidemiological data and evaluate the impact of therapeutic strategies and newborn screening (NBS) on clinical outcomes. Methods: This retrospective, multicenter study focuses on 255 Spanish UCD patients. It includes all living and deceased cases up to February 2024, analyzing demographic, clinical, and biochemical variables. Results: The incidence of UCD in Spain over the past decade was 1:36,063 births. The most common defects were ornithine transcarbamylase deficiency (OTCD) and argininosuccinate synthetase deficiency. Early-onset (EO) cases comprised 32.7%, and 10.6% were diagnosed through NBS. Global mortality was 14.9%, higher in carbamoylphosphate synthetase 1 deficiency (36.8%) and male OTCD patients (32.1%) compared to other defects (p = 0.013). EO cases presented a higher mortality rate (35.8%) than late-onset (LO) cases (7.1%) (p < 0.0001). The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410–1793) than in survivors at 294 µmol/L (IQR 71–494) (p < 0.0001). Diagnosis through NBS improved survival and reduced neurological impairment compared to symptomatic diagnosis. Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis. Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients. Conclusions: This updated analysis highlights the positive impact of NBS and advanced treatments on mortality and neurologic outcomes. Persistent neurological challenges underscore the need for further therapeutic strategies. Full article

Amino acid (AA)-related inherited metabolic disorders (IMDs) and urea cycle disorders (UCDs) require strict dietary management including foods low in protein such as fruits, vegetables and starchy roots. Despite this recommendation, there are limited data on the AA content of many of these foods. The aim of this study is to describe an analysis of the protein and AA content of a range of fruits, vegetables and starchy roots, specifically focusing on amino acids (AAs) relevant to AA-related IMDs such as phenylalanine (Phe), methionine (Met), leucine (Leu), lysine (Lys) and tyrosine (Tyr). AA analysis was performed using high-performance liquid chromatography (HPLC) on 165 food samples. Protein analysis was also carried out using the Dumas method. Foods were classified as either ‘Fruits’, ‘Dried fruits’, ‘Cruciferous vegetables’, ‘Legumes’, ‘Other vegetables’ or ‘Starchy roots’. ‘Dried fruits’ and ‘Legumes’ had the highest median values of protein, while ‘Fruits’ and ‘Cruciferous vegetables’ contained the lowest median results. ‘Legumes’ contained the highest and ‘Fruits’ had the lowest median values for all five AAs. Variations were seen in AA content for individual foods. The results presented in this study provide useful data on the protein and AA content of fruits, vegetables and starchy roots which can be used in clinical practice. This further expansion of the current literature will help to improve diet quality and metabolic control among individuals with AA-related IMDs and UCDs. Full article

Strict adherence to a diet is an essential pillar of long-term treatment for many inborn errors of metabolism (IEMs). Tools that educate patients about dietary management can positively condition adherence and prevent morbidity. We designed a free online dietary calculation program (Odimet^®, version 2.1.) for IEMs patients in 2008, updated in 2022, that provides detailed information on the content of amino acids, protein, lipids, carbohydrates, vitamins and minerals in >3000 food products, including specific medical foods for IEM. We analyzed the statistics on visits to Odimet^® to evaluate its usefulness for long-term dietary management during a 5-year period focusing on three periods: pre-pandemic (15 March 2018–14 March 2020); pandemic 1 (15 March 2020–14 March 2021); and pandemic 2 period (15 March 2021–15 March 2023), in 120 patients with the following distribution: 84 patients with phenylketonuria (PKU); 12 with maple syrup urine disease (MSUD); 11 with urea cycle disorders (UCDs); and 13 with classical galactosemia. The evolutionary levels of their specific metabolic markers were evaluated, showing that globally, both pediatric and adult patients maintain a good metabolic control, even during a pandemic (median levels of phenylalanine in pediatric PKU patients 213.4 µmol/L and 482.3 µmol/L in adults; of leucine in MSUD patients: 144.2 µmol/L; of glutamine in UCDs: 726.8 µmol/L; and of galactose 1-phosphate levels in galactosemia: 0.08 µmol/L). The proportion of patients using Odimet^® ranges from 78–100%. An increase in the number of diets being calculated was observed during COVID-19 pandemic. Currently, 14,825 products have been introduced (3094 from the general database, and 11,731 added by users to their own profiles). In 2023 63 emergency dietary adjustments in the studied intoxication-type pathologies were calculated in Odimet^®. Our results suggest that its regular use contributes to maintaining metabolic stability in IEMs patients, allowing them to adapt their menus to their lifestyle, and represents a powerful complementary tele-health tool which can be used to perform remote real-time dietary follow-up. Full article

Despite major improvements brought about by the introduction of taste-masked formulations of 4-phenylbutyrate (PB), poor compliance remains a significant drawback to treatment for some pediatric and dysphagic patients with urea cycle disorders (UCDs). This study reports on the development of a cyclodextrin (CD)-based orally disintegrating tablet (ODT) formulation for PB as an alternative to existing formulations. This is based on previous reports of the PB taste-masking potential of CDs and the suitability of ODTs for improving compliance in pediatric and dysphagic populations. In preliminary studies, the interactions of PB with α and βCD in the solid state were characterized using X-ray diffraction, scanning electron microscopy, dissolution, and accelerated stability studies. Based on these studies, lyophilized PB-CD solid systems were formulated into ODTs after wet granulation. Evaluation of the ODTs showed that they had adequate physical characteristics, including hardness and friability and good storage stability. Notably, the developed αCD-based ODT for PB had a disintegration time of 28 s and achieved a slightly acidic and agreeable pH (≈5.5) in solution, which is suitable for effective PB-CD complexation and taste masking. The developed formulation could be helpful as an alternative to existing PB formulations, especially for pediatric and dysphagic UCD patients. Full article

Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate–Talk–Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring. Full article

Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 μmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments. Full article

(1) Background: Phenotypic diversity and long-term health outcomes of individuals with urea cycle disorders (UCDs) have been described in detail. However, there is limited information on the burden on affected families. (2) Methods: To evaluate the family burden in parents with children suffering from UCDs, we used validated questionnaires. Socio-demographic characteristics were evaluated, and an adapted version of the Parental Need Scale for Rare Diseases questionnaire was used. The survey was conducted in families of UCD patients cared for at the University Children’s Hospital Heidelberg. (3) Results: From April to November 2021, 59 participants were interviewed (mothers n = 34, fathers n = 25). The affected patients most frequently suffered from ornithine transcarbamylase deficiency (OTC-D) (female n = 12, male n = 12), followed by argininosuccinate synthetase deficiency (ASS-D, n = 13) and argininosuccinate lyase deficiency (ASL-D, n = 8). About one-third of the participants were “dissatisfied” or “extremely dissatisfied” with health professionals’ disease knowledge. In addition, 30% of the participants reported a medium or high need for “additional information on the development of their children”, and 44% reported a medium or high need “for information on available services”. A majority of 68% reported a need for additional support regarding services such as support groups (42%) or psychological counseling (29%). (4) Conclusions: Our study indicates that there is an unmet need for sufficient information about the development of children with UCDs, as well as for information about available support services for families with UCD patients. Furthermore, the results highlight the importance of establishing or improving family-centered care approaches. This pilot study may serve as a template for the assessment of the family burden associated with other inherited metabolic diseases. Full article

Low-protein diets (LPDs) are the mainstream treatment for inborn errors of intermediary protein metabolism (IEIPM), but dietary management differs worldwide. Most studies have investigated pediatric populations and their goals such as growth and metabolic balance, showing a tendency toward increasing overweight and obesity. Only a few studies have examined nutritional status and dietary intake of adult IEIPM patients on LPDs. We assessed nutritional parameters (dietary intake using a 7-day food diary record, body composition by bioimpedance analysis, and biochemical serum values) in a group of 18 adult patients with urea cycle disorders (UCDs) and branched chain organic acidemia (BCOA). Mean total protein intake was 0.61 ± 0.2 g/kg/day (73.5% of WHO Safe Levels) and mean natural protein (PN) intake was 0.54 ± 0.2 g/kg/day; 33.3% of patients consumed amino acid (AA) supplements. A totally of 39% of individuals presented a body mass index (BMI) > 25 kg/m² and patients on AA supplements had a mean BMI indicative of overweight. All patients reported low physical activity levels. Total energy intake was 24.2 ± 5 kcal/kg/day, representing 72.1% of mean total energy expenditure estimated by predictive formulas. The protein energy ratio (P:E) was, on average, 2.22 g/100 kcal/day. Plasmatic levels of albumin, amino acids, and lipid profiles exhibited normal ranges. Phase angle (PA) was, on average, 6.0° ± 0.9°. Fat mass percentage (FM%) was 22% ± 9% in men and 36% ± 4% in women. FM% was inversely and significantly related to total and natural protein intake. Data from IEIPM adults on LPDs confirmed the pediatric trend of increasing overweight and obesity despite a low energy intake. A low protein intake may contribute to an increased fat mass. Nutritional parameters and a healthy lifestyle should be routinely assessed in order to optimize nutritional status and possibly reduce risk of cardiovascular degenerative diseases in adult UCD and BCOA patients on LPDs. Full article

Low-protein diets (LPDs) are the main treatment for urea cycle disorders (UCDs) and organic acidemias (OAs). In most cases, LPDs start in childhood and must be continued into adulthood. The improved life expectancy of patients with UCDs and OAs raises the question of their consequences on nutritional status in adult subjects. As this topic has so far received little attention, we conducted a review of scientific studies that investigated the nutrient intake and nutritional status in adult patients with UCDs and branched chain organic acidemias (BCOAs) on LPD. Methods: The literature search was conducted in PubMed/MEDLINE, Scopus, EMBASE and Google Scholar from 1 January 2000 to 31 May 2020, focusing on nutrient intake and nutritional status in UCD and OA adult patients. Results: Despite protein restriction is recommended as the main treatment for UCDs and OAs, in these patients, protein intake ranges widely, with many patients who do not reach safety levels. When evaluated, micronutrient intake resulted below recommended values in some patients. Lean body mass resulted in most cases lower than normal range while fat body mass (FM) was often found normal or higher than the controls or reference values. Protein intake correlated inversely with FM both in adult and pediatric UCD patients. Conclusions: The clinical management of adult patients with UCDs and BCOAs should include an accurate assessment of the nutritional status and body composition. However, as little data is still available on this topic, further studies are needed to better clarify the effects of LPDs on nutritional status in adult UCD and BCOA patients. Full article

N-acetylglutamate synthase deficiency (NAGSD) is an extremely rare urea cycle disorder (UCD) with few adult cases so far described. Diagnosis of late-onset presentations is difficult and delayed treatment may increase the risk of severe hyperammonemia. We describe a 52-year-old woman with recurrent headaches who experienced an acute onset of NAGSD. As very few papers focus on headaches in UCDs, we also report a literature review of types and pathophysiologic mechanisms of UCD-related headaches. In our case, headaches had been present since puberty (3–4 days a week) and were often accompanied by nausea, vomiting, or behavioural changes. Despite three previous episodes of altered consciousness, ammonia was measured for the first time at 52 years and levels were increased. Identification of the new homozygous c.344C>T (p.Ala115Val) NAGS variant allowed the definite diagnosis of NAGSD. Bioinformatic analysis suggested that an order/disorder alteration of the mutated form could affect the arginine-binding site, resulting in poor enzyme activation and late-onset presentation. After optimized treatment for NAGSD, ammonia and amino acid levels were constantly normal and prevented other headache bouts. The manuscript underlies that headache may be the presenting symptom of UCDs and provides clues for the rapid diagnosis and treatment of late-onset NAGSD. Full article

The practice of newborn screening has been in place in the USA since the 1960s, with individual states initially screening for different numbers of disorders. In the early 2000s many efforts were made to standardize the various disorders being screened. Currently, there are at least 34 disorders that each state is mandated to include on their screening panel. Of those 34 disorders, the majority are inborn errors of metabolism (IEM) which include urea cycle disorders (UCD), citrullinemia (CIT) and argininosuccinic aciduria (ASA), as well as a number of fatty acid oxidation disorders. We present here four cases of infants who had critical newborn screens (NBS) in the Commonwealth of Virginia and underwent genetic testing because their clinical presentation and follow-up laboratory studies were not consistent with the disorder that was flagged by NBS. These newborns were found to be carriers for two different IEMs (in three cases) or compound heterozygotes (in one case). Currently no guidelines exist with respect to the appropriate way to manage these children who may or may not be symptomatic in the newborn period. We propose some general recommendations for management based on our experience with these four probands, and discuss the necessity for further conversation and collaboration between physicians encountering these not-so-infrequent presentations. Full article

Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes, cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological effects include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of the plasma ammonia level at presentation and duration of a hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days of life with plasma ammonia and glutamine of 677 and 4024 micromol/L respectively, and was found to have a missense mutation in Exon 4 (p. R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. Despite compliance, he suffered recurrent acute hyperammonemic episodes triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI-based disease biomarkers. Full article

Urea cycle disorders (UCDs) comprise a group of recessive and one X-linked inherited errors of protein metabolism that, due to insufficient detoxification of excess nitrogen, can lead to severe neurological disease. The key feature, but at the same time only a surrogate marker of UCDs, is the resulting mild to severe hyperammonemia. Biochemical analysis is needed to strengthen the suspicion of any underlying UCD but remains for the majority of cases rather indicative than diagnostic due to the lack of definite markers. Thus, in order to confirm a specific UCD, mutation analysis or enzyme assays are the methods of choice. Because of the drastic clinical complications of severe hyperammonemia, an early diagnosis before onset of symptoms would be desirable. The best way to achieve this would be to implement a general newborn screening for these disorders. However, there are several challenges that need to be overcome before newborn screening for UCDs can be introduced. This review will briefly describe the technical and clinical challenges involved in newborn screening for UCDs and will then discuss current experiences with this approach. Full article