Inborn Errors Of Intermediary Metabolism Research Articles

3D Printing of Dietary Products for the Management of Inborn Errors of Intermediary Metabolism in Pediatric Populations.

The incidence of Inborn Error of Intermediary Metabolism (IEiM) diseases may be low, yet collectively, they impact approximately 6-10% of the global population, primarily affecting children. Precise treatment doses and strict adherence to prescribed diet and pharmacological treatment regimens are imperative to avert metabolic disturbances in patients. However, the existing dietary and pharmacological products suffer from poor palatability, posing challenges to patient adherence. Furthermore, frequent dose adjustments contingent on age and drug blood levels further complicate treatment. Semi-solid extrusion (SSE) 3D printing technology is currently under assessment as a pioneering method for crafting customized chewable dosage forms, surmounting the primary limitations prevalent in present therapies. This method offers a spectrum of advantages, including the flexibility to tailor patient-specific doses, excipients, and organoleptic properties. These elements are pivotal in ensuring the treatment's efficacy, safety, and adherence. This comprehensive review presents the current landscape of available dietary products, diagnostic methods, therapeutic monitoring, and the latest advancements in SSE technology. It highlights the rationale underpinning their adoption while addressing regulatory aspects imperative for their seamless integration into clinical practice.

A Review of Disparities and Unmet Newborn Screening Needs over 33 Years in a Cohort of Mexican Patients with Inborn Errors of Intermediary Metabolism.

Advances in an early diagnosis by expanded newborn screening (NBS) have been achieved mainly in developed countries, while populations of middle- and low-income countries have poor access, leading to disparities. Expanded NBS in Mexico is not mandatory. Herein, we present an overview of the differences and unmet NBS needs of a group of Mexican patients with inborn errors of intermediary metabolism (IEiM), emphasizing the odyssey experienced to reach a diagnosis. We conducted a retrospective observational study of a historical cohort of patients with IEiM from a national reference center. A total of 924 patients with IEiM were included. Although 72.5% of the diseases identified are detectable by expanded NBS, only 35.4% of the patients were screened. The mortality in the unscreened group was almost two-fold higher than that in the screened group. Patients experienced a median diagnostic delay of 4 months, which is unacceptably long considering that to prevent disability and death, these disorders must be treated in the first days of life. Patients had to travel long distances to our reference center, contributing to their unacceptable diagnostic odyssey. This study highlights the urgent need to have an updated, expanded NBS program with adequate follow up in Mexico and promote the creation of regional medical care centers. We also provide compelling evidence that could prove valuable to decision makers overseeing public health initiatives for individuals impacted by IEiM from middle- and low-income countries.

Update on breastfeeding in newborns with inborn errors of intermediary metabolism.

Inborn errors of intermediary metabolism (IEiM) are a group of monogenic disorders that affect a metabolic pathway of proteins, carbohidrates, or lipids; when not treated timely, IEiM are associated with high morbidity and mortality. To date, nutritional therapy is the cornerstone of treatment for patients with IEiM, which aims to prevent the accumulation of toxic metabolites by restricting the substrates involved in the affected pathway. Nutritional management in infants includes a metabolic formula free of the nutrients involved in IEiM and breastmilk or infant formula. Because of its amino acid profile, the content of essential fatty acids, and protection against disease, breast milk is an excellent food for patients with IEiM. This literature review on breastfeeding in some IEiM aims to serve as a guide for health care personnel involved in the medical care of these patients. Breastfeeding can be successfully carried out in patients with IEiM as long as there is a close and continuous follow-up, preferably in specialized centers. The nutrition professional and the pediatrician should individualize the recommendations to provide on-demand breastfeeding in conjunction with metabolic formula or quantified breastfeeding to achieve a good clinical evolution in this group of patients.

Evaluation of Body Composition, Physical Activity, and Food Intake in Patients with Inborn Errors of Intermediary Metabolism.

Children with inborn errors of intermediary metabolism (IEiM) must follow special diets that restrict their intake of essential nutrients and may compromise normal growth and development. We evaluated body composition, bone mineral density, physical activity, and food intake in IEiM patients undergoing dietary treatment. IEiM patients (n = 99) aged 5–19 years and healthy age- and sex-matched controls (n = 98) were recruited and underwent dual-energy X-ray absorptiometry to evaluate anthropometric characteristics and body composition. Data on food intake and physical activity were also collected using validated questionnaires. The height z-score was significantly lower in IEiM patients than controls (−0.28 vs. 0.15; p = 0.008), particularly in those with carbohydrate and amino acid metabolism disorders. Significant differences in adiposity were observed between patients and controls for the waist circumference z-score (−0.08 vs. −0.58; p = 0.005), but not the body mass index z-score (0.56 vs. 0.42; p = 0.279). IEiM patients had a significantly lower total bone mineral density (BMD) than controls (0.89 vs. 1.6; p = 0.001) and a higher risk of osteopenia (z-score < −2, 33.3% vs. 20.4%) and osteoporosis (z-score < −2.5, 7.1% vs. 0%), but none presented fractures. There was a significant positive correlation between natural protein intake and BMD. Our results indicate that patients with IEiM undergoing dietary treatment, especially those with amino acid and carbohydrate metabolism disorders, present alterations in body composition, including a reduced height, a tendency towards overweight and obesity, and a reduced BMD.

The ratio of maximal handgrip force and maximal cycloergometry power as a diagnostic tool to screen for metabolic myopathies

Metabolic myopathies comprise a diverse group of inborn errors of intermediary metabolism affecting skeletal muscle, and often present clinically as an inability to perform normal exercise. Our aim was to use the maximal mechanical performances achieved during two functional tests, isometric handgrip test and cycloergometer, to identify metabolic myopathies among patients consulting for exercise-induced myalgia. Eighty-three patients with exercise-induced myalgia and intolerance were evaluated, with twenty-three of them having a metabolic myopathy (McArdle, n = 9; complete myoadenylate deaminase deficiency, n = 10; respiratory chain deficiency, n = 4) and sixty patients with non-metabolic myalgia. In all patients, maximal power (MP) was determined during a progressive exercise test on a cycloergometer and maximal voluntary contraction force (MVC) was assessed using a handgrip dynamometer. The ratio between percent-predicted values for MVC and MP was calculated for each subject (MVC%pred:MP%pred ratio). In patients with metabolic myopathy, the MVC%pred:MP%pred ratio was significantly higher compared to non-metabolic myalgia (1.54 ± 0.62 vs. 0.92 ± 0.25; p < 0.0001). ROC analysis of MVC%pred:MP%pred ratio showed AUC of 0.843 (0.758–0.927, 95% CI) for differentiating metabolic myopathies against non-metabolic myalgia. The optimum cutoff was taken as 1.30 (se = 69.6%, sp = 96.7%), with a corresponding diagnostic odd ratio of 66.3 (12.5–350.7, 95% CI). For a pretest probability of 15% in our tertiary reference center, the posttest probability for metabolic myopathy is 78.6% when MVC%pred:MP%pred ratio is above 1.3. In conclusion, the MVC%pred:MP%pred ratio is appropriate as a screening test to distinguish metabolic myopathies from non-metabolic myalgia.

Neurological Involvement in Inherited Metabolic Diseases: An Overview

Neurological involvement is a typical feature of several inherited metabolic diseases. The onset of signs and/or symptoms may appear as early as the first days of life or after an interval of normal or near-normal growth and development. Metabolic decomposition usually presents with a severe clinical phenotype, which include poor feeding, vomiting, lethargy, seizures, and loss of consciousness. This spectrum of manifestations is often fatal; however, severe neurological sequelae and/or regression of neurodevelopmental milestones can be the prominent signs in those who survive. Overall, treatable inborn errors of metabolism can be divided in three groups, namely: (Group 1) inborn errors of intermediary metabolism giving rise to acute or chronic intoxication; (Group 2) inborn errors of intermediary metabolism affect in genergetic processes; and (Group 3) inborn errors involving cellular organelles, including lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. The spectrum of neurological manifestations includes developmental delay, seizures and epilepsy, pyramidal and extrapyramidal signs, movement disorders, vision and hearing impairment, peripheral neuropathy, and psychiatric abnormalities. The main anatomical/imaging patterns reflects selective vulnerability of nervous system substance and include atrophy, (predominantly) symmetrical abnormalities, and dysmyelination, As several patients with neurometabolic diseases responds favorably to therapeutic trials, early detection and early intervention is of utmost importance to prevent catabolic-related damage and to revert to normal or near-normal parameters neurodevelopmental milestones.

Inborn Errors of Intermediary Metabolism in Critically Ill Mexican Newborns

Inborn errors of intermediary metabolism (IEiM) are complex diseases with high clinical heterogeneity, and some patients who have severe enzyme deficiencies or are subjected to stress (catabolism/i...

Tandem Mass Spectrometry Newborn Screening for Inborn Errors of Intermediary Metabolism: Abnormal Profile Interpretation

Expanded newborn screening for inherited metabolic disorders using tandem mass spectrometry was introduced in 1990's and is widely used around the world. In contrast to conventional screening methods, tandem mass spectrometry does not measure single analytes but identifies and quantifies metabolite profiles; one single blood spot analyzed provides information of about 60 metabolites including amino acids, acylcarnitines and related ratios that enable the diagnosis of approximately 50 different diseases. However, the interpretation of these profiles can become quite complex. The aim of this work is to present in an easy and practical manner a comprehensive compilation of information needed for tandem mass neonatal screening profile interpretation, and basic actions for immediate follow up of abnormal results, including the tests that are required for confirmatory purposes. Other conditions not attributable to metabolic disorders which can lead to an abnormal profile of these markers are also described as well as a series of general recommendations which would be useful for health professionals who are beginning newborn screening for inborn errors of intermediary metabolism using tandem mass spectrometry.

The monitoring of trace elements in blood samples from patients with inborn errors of metabolism

Patients having inborn errors of intermediary metabolism (IEMs) may have element deficiencies related to dietary treatment. Our objective was to study several elements [cobalt (Co), copper (Cu), zinc (Zn), selenium (Se), manganese (Mn), molybdenum (Mo) and magnesium (Mg)] in patients with IEMs with and without dietary treatment and to compare these results with those established in a healthy paediatric population. We studied 72 patients with IEMs (age range 2 months-44 years; median 10.5 years), with and without protein-restricted dietary treatment. Control values were established in 92 subjects (age range 1 day-42 years; median 6.5 years). Dietary treatment consisted of a natural protein-restricted diet supplemented with a special formula, depending on the specific metabolic defect. Samples were analysed with an Agilent 7500ce-ICP mass spectrometer. Significant differences were observed when we compared patients under dietary treatment and control values for Se and Co (P < 0.0001). No differences were observed for the other elements when the different groups were compared, except for Co (IEM patients without dietary treatment vs control group; P = 0.003). For Se and cobalamin, the daily intake of our patients (Se 48 ± 16 µg/day; cobalamin 3.5 µg/day) was slightly higher than the recommended daily averages (RDAs) (40 µg/day and 1.8 µg/day, respectively). We concluded that IEM patients under dietary treatment showed significantly lower selenium values in spite of correct supplementation, reinforcing the idea that these patients should be regularly monitored, at least for this element. Further investigations seem advisable about Se and Co availability in special diets.

Clinical approach to treatable inborn metabolic diseases: An introduction

In view of the major improvements in treatment, it has become increasingly important that in order for first-line physicians not to miss a treatable disorder they should be able initiate a simple method of clinical screening, particularly in the emergency room. We present a simplified classification of treatable inborn errors of metabolism in three groups. Group 1 includes inborn errors of intermediary metabolism that give rise to an acute or chronic intoxication. It encompasses aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias. Clinical expression can be acute or systemic or can involve a specific organ, and can strike in the neonatal period or later and intermittently from infancy to late adulthood. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins. Group 2 includes inborn errors of intermediary metabolism that affect the cytoplasmic and mitochondrial energetic processes. Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable. Group 3 involves cellular organelles and includes lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Among these, some lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies. Physicians can be faced with the possibility of a treatable inborn error in an emergency, either in the neonatal period or late in infancy to adulthood, or as chronic and progressive symptoms--general (failure to thrive), neurological, or specific for various organs or systems. These symptoms are summarized in four tables. In addition, an extensive list of medications used in the treatment of inborn errors is presented.

Mitochondrial damage induced by fetal hyperphenylalaninemia in the rat brain and liver: Its prevention by melatonin, Vitamin E, and Vitamin C

Abnormal oxidative stress was observed in hyperphenylalaninemia and other inborn errors of intermediary metabolism, owing to the accumulation of toxic metabolites, free radical production and increased LPO products. In our model of maternal hyperphenylalaninemia, pregnant rats were injected with 300 mg/kg BW l-phenylalanine (PHE) and 50 mg/kg BW p-chlorophenylalanine (PCPA) dissolved in saline. In this research study, we measured LPO-by-products, i.e., malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) and we demonstrated that maternal hyperphenylalaninemia increased both markers of oxidative stress in the brain and liver mitochondria of the pups. We also demonstrated that administration of melatonin, Vitamin E, and Vitamin C, in this order of potency, prevented the oxidative damage to the mitochondria, especially in the brain. We therefore conclude that maternal hyperphenylalaninemia induces a clear state of oxidative stress that is somehow directly involved in brain and liver impairment, which can be prevented by melatonin, Vitamin E, and Vitamin C.

Oxidative stress in patients with phenylketonuria

Phenylketonuria (PKU) is an autossomal recessive disease caused by phenylalanine-4-hydroxylase deficiency, which is a liver-specific enzyme that catalyzes the hydroxylation of l-phenylalanine (Phe) to l-tyrosine (Tyr). The deficiency of this enzyme leads to the accumulation of Phe in the tissues and plasma of patients. The clinical characterization of this disease is mental retardation and other neurological features. The mechanisms of brain damage are poorly understood. Oxidative stress is observed in some inborn errors of intermediary metabolism owing to the accumulation of toxic metabolites leading to excessive free radical production and may be a result of restricted diets on the antioxidant status. In the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid-reactive species (TBA-RS) and total antioxidant reactivity (TAR) in the plasma of PKU patients. The activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were also measured in erythrocytes from these patients. It was observed that phenylketonuric patients present a significant increase of plasma TBA-RS measurement, indicating a stimulation of lipoperoxidation, as well as a decrease of plasma TAR, reflecting a deficient capacity to rapidly handle an increase of reactive species. The results also showed a decrease of erythrocyte GSH-Px activity. Therefore, it is presumed that oxidative stress is involved in the pathophysiology of the tissue damage found in PKU.

Errores congénitos del metabolismo con manifestaciones neurológicas de presentación neonatal

Congenital metabolic diseases are considered as rare diseases because of their low incidence and their clinical symptoms at onset. Sometimes they can just begin in the neonatal period. Their progressive knowledge and the availability of specific and sensitive biochemical procedures allow us to diagnose many congenital metabolic diseases, which were not recognized some years ago. We reviewed the 52 patients with congenital metabolic diseases diagnosed for the last 25 years in our centre, evaluating the clinical presentation, neurological symptoms, complementary exams and clinical evolution. The mean age at onset of symptoms was 5 days and the mean age at diagnosis was 88 days of age. We considered a first group of 36 patients with inborn errors of intermediary metabolism, in whom hypotonia, weight loss and seizures are the main symptoms. The second group was composed of 8 patients with defective energy metabolism, who showed abnormal respiratory rhythm and hypotonia. Finally, we considered 8 patients with diseases of the complex molecules, who presented with hypotonia and cataracts as common symptoms at onset. The more common neurological symptoms in this period were hypotonia (60%), sensorial deficit (35%) and refractory seizures (23%). The complementary laboratory tests in the first phases of the diseases allowed us to suspect a congenital metabolic disease especially among intermediary and energy defects. EEG registration and CSF samples were important to diagnose some inborn errors of intermediary metabolism. In the first steps, the neuroimaging was less orientative, even if it allow the exclusion of other diseases. More than half of the patients with inborn errors of metabolism with onset in the neonatal period died within the first year of life. It is really important to suspect these diseases in the neonatal period so as to achieve an early diagnosis and therapy which may reduce the morbimortality.

Alteraciones del sistema antioxidante en errores congénitos del metabolismo intermediario

Oxidative stress may be implied in the pathogenic mechanisms of inborn errors of intermediary metabolism (IEIM).The evaluation of the antioxidant status in IEIM by the measurement of erythrocyte antioxidant enzyme activities, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase and catalase.34 patients with IEIM: 1) eleven with organic acidurias on protein restricted diet; 2) nine without special diet; 3) five patients with aminoacidopathies on protein restriction; 4) three patients with galactosemia and six with aminoacidopathies on protein free diet. Erythrocyte antioxidant enzymes were measured by spectrometric procedures adapted to the Cobas Fara II analyser.SOD activity was significantly higher in groups 2 and 4 (p= 0.009, p= 0.001, respectively), and significantly lower in group 3 (p= 0.001) compared with age matched controls. SOD activity was significantly higher in the patients with IEIM on protein free diet (groups 2 and 4) compared with those on protein restricted diet (groups 1 and 3; p= 0.002) or with controls (p= 0.003). GPx activity was found significantly lower in group 1 patients (p= 0.004), and higher in group 2 (p= 0.029) compared with controls.35% of the patients with IEIM had SOD activity above the control range, most of them with organic acidurias or homocystinuria, suggesting an induction of enzyme protein synthesis owing to an excess of free radical generation. The lower activities observed in patients on natural protein restriction may likely be due to a deficient bioavailability of antioxidant cofactors.

Principles and performance: assessing the evidence.

Despite the apparent rigour of the systematic review process there are a number of reasons why it may not accurately reflect the true state of current knowledge. For inborn errors of intermediary metabolism in general, the formal quality of literature on treatment is poor, partly because the rarity of the conditions makes systematic study difficult, partly because of the self-evident evidence paradox with treatments that are so obviously life-saving, and partly because of the widespread use of biochemical normalisation as a proxy outcome. In the field of newborn screening there is a paucity of formal trials so that assessment must be either by the 'causal pathway' approach or by reference to screening "criteria". The causal pathway approach may be misleading in that there are discontinuities, for example in projecting from known incidence (clinically diagnosed cases) to the incidence expected on screening. The criteria-based approach suffers from qualitative descriptors, such as "important" and "adequate", with no clear end-points, whilst in the context of neonatal screening some of the Wilson and Jungner criteria conflict with current evidence-based views. These problems are illustrated by reference to two reviews recently produced as part of the UK Health Technology Assessment Programme.

Oral health implications in children with inborn errors of intermediary metabolism: a review.

Children with inborn errors of metabolism form an important group of children at risk of oral pathology. Their management includes dietary therapies which aim to promote normal growth and development but which are often highly cariogenic. It is important for paediatricians, dietitians and paediatric dentists to liaise closely in the management of these children. This paper reviews these disorders and the limited literature that exists on the oral health implications of those conditions that rely on dietary manipulation for their management, and presents suggestions for their dental care.

Tocopherol in inborn errors of intermediary metabolism

Red blood cell tocopherol was measured in a group of 92 children with inborn errors of intermediary metabolism to evaluate the peroxidative damage in different mitochondrial and cytosolic defects, and to consider the need for treatment or vitamin supplementation. Tocopherol was determined by HPLC with UV detection. Results were expressed in nanomoles red blood cell tocopherol per gram protein. Significant differences (Mann-Whitney; P < 0.001) were found between tocopherol levels in untreated patients: 19 with mitochondrial defects versus 23 with cytosolic enzyme or transport defects, and versus 58 age-matched reference values. In conclusion, mitochondrial enzyme deficiencies, either amino and organic acidurias or defects of energy metabolism, seem to produce an excess of free radicals with the consequent utilization of tocopherol as antioxidant. This is not apparent in the cytosolic enzyme defects studied, whose tocopherol levels are in the normal range. Treatment with tocopherol completely corrects the deficient antioxidant status.

BACK TO BASICS

Many inborn errors of intermediary metabolism present during periods of poor oral intake or intercurrent illness. Under these conditions, the body switches to a predominantly catabolic state, when glycogen, fat, and protein are mobilized as alternative energy sources. If a genetic defect already exists in any of these catabolic pathways, the problem is accentuated because the catabolic state demands a high flux of metabolite through these pathways. Therefore, a cardinal principle in the management of children who have IEM is to prevent them from lapsing into a catabolic state. This can be done through: 1) aggressive nutrition management to promote positive nitrogen balance and decrease accumulation of toxic metabolites, and 2) immunizations to minimize the possibility of viral or bacterial illness. When catabolism does occur, high-dose glucose infusion is a potent method for turning off the catabolic state. This simplistic view of the catabolic pathways neglects many details in each of the metabolic pathways and diseases cited in the article and questions. Nevertheless, it should provide a useful framework for explaining some of the clinical findings encountered in caring for this special group of patients. A partial list of more commonly encountered IEMs is contained in the Table. The different parts of the biochemical pathways discussed previously are combined into Figure 6.

Metabolic and degenerative diseases associated with epilepsy.

Identifying the specific etiology of epilepsy is often difficult. The search for the cause often leads the clinician to suspect inborn errors of intermediary metabolism and other degenerative metabolic diseases. Although these uncommon diseases are often difficult to determine, a correct diagnosis is critical for treatment and genetic counseling. A review of the relevant biochemistry will aid in understanding the pathophysiology of seizures in these conditions. The stream-lined approach to the initial laboratory evaluation that is offered will enable the clinician to screen for most metabolic and degenerative diseases that are associated with epilepsy.

Intercurrent illness in inborn errors of intermediary metabolism.

Metabolic decompensation may occur in patients with disorders of intermediary metabolism during intercurrent illness. To prevent complications it is normal practice to change the diet to an 'emergency regimen'. The mainstay of this is a high carbohydrate intake, using soluble glucose polymer, given as frequent drinks by day and during the night. Additional therapy is given for some disorders. Practical details of the treatment are outlined.