Search

The article discusses endocrine disorders in adult patients with inherited metabolic diseases, emphasizing the importance of diagnosis and long-term management. It highlights the prevalence of endocrine complications in patients with inherited metabolic diseases, such as diabetes mellitus, hypogonadism, adrenal insufficiency, and thyroid dysfunction. The study conducted at a tertiary referral center for endocrinology and inherited metabolic diseases reveals the need for specialized care and multidisciplinary approaches to address these complex health issues. The authors stress the significance of early detection, appropriate screening, and tailored management strategies for patients with inherited metabolic diseases and associated endocrine disorders. [Extracted from the article]

Inherited metabolic disorders (IMDs), previously considered as a paediatric sub-specialisation are more and more prevalent in adults, thanks to improved survival, and the expansion of diagnostic tools detecting attenuated–late onset forms in adulthood. Italy is one of the countries with the highest number of IMDs screened by dry blood spots in neonates, allowing them to receive early treatments and to reach adult age. Despite this, awareness of IMDs is still low by the adult medical community, with difficulties in transition and transfer of patients to adult services and unmet patient needs. In 2022, a collaboration between the adult metabolic working group of the Italian Society for the Study of Inherited Metabolic Disorders and Neonatal Screening (SIMMESN) and the European Reference Network for Hereditary Metabolic Disorders (MetabERN) was established to face problems linked to IMDs in adulthood. "The Statement of Udine" was developed to guide further steps towards improvements in inherited metabolic medicine in adults, referencing the experience from the UK. The aim of this paper is to present "The Statement of Udine" explaining its background and its possible applications. • Adult metabolic patients are progressively increasing, presenting new challenges for national health systems. • The knowledge of adult metabolic medicine (AMM) should quickly increase and improve in the next few years. • The "Statement of Udine" should guide next steps for AMM improvement in countries poor advanced in this field. [ABSTRACT FROM AUTHOR]

Background: Newborn screening programmes offer an opportunity to obtain dried blood spots (DBS) cards that contain a wealth of biological information that can be stored for long periods and have potential benefits for research and quality assurance. However, the storage and secondary uses of DBS cards pose numerous ethical, clinical, and social challenges. Empirical research exploring public attitudes is central to public policy planning as it can indicate whether or not there is broad public support, define public concerns, and ascertain the circumstances required to alleviate concerns and ensure support. This study aims to describe the clinical experience and attitudes towards newborn screening and investigate the perceptions and expectations of Hong Kong parents and healthcare providers regarding the retention of DBS cards and their usage for research. Methods: We conducted semi-structured in-person interviews with 20 parents and healthcare providers in Hong Kong. Thematic analysis was conducted. Results: Awareness of the significant research value of secondary uses of dried blood spot cards is low. Parents and healthcare providers support the storage and secondary uses of DBS cards with some concerns, including privacy and confidentiality breaches, the risk of discrimination or stigmatisation based on genetic information, and their inability to oversee the use of their child's biospecimen. Parents, however, prioritise their child's health over privacy concerns and support identifiable storage using pseudonymity to gain more information about their children's health. Conclusion: Child information takes precedence over potential concerns over privacy, underscoring the significance of engaging patients and the public in shaping public policy related to biobanking and healthcare research, in line with cultural and social values. [ABSTRACT FROM AUTHOR]

Background: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD. Methods: This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported. Results: Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients' total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment. Conclusions: The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations. [ABSTRACT FROM AUTHOR]

Inherited metabolic disorders (IMDs) are a growing group of genetic diseases caused by defects in enzymes that mediate cellular metabolism, often resulting in the accumulation of toxic substrates. The liver is a highly metabolically active organ that hosts several thousands of chemical reactions. As such, it is an organ frequently affected in IMDs. In this article, we review current approaches for liver‐directed gene‐based therapy aimed at metabolite detoxification in a variety of IMDs. Moreover, we discuss current unresolved challenges in gene‐based therapies for IMDs. [ABSTRACT FROM AUTHOR]

We report on the largest single dataset of patients with PMM2‐CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease‐associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2‐CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration:NCT03173300. [ABSTRACT FROM AUTHOR]

Managing Inherited Metabolic Disorders (IMDs) at risk for hypoglycemia, such as Glycogen Storage Diseases (GSDs), Hereditary Fructose Metabolism Disorders (HFMDs) and Congenital Hyperinsulinism (CH), poses challenges in dietary treatments and blood glucose monitoring. The effectiveness of Continuous Glucose Monitoring (CGM) remains a subject of ongoing debate, with IMD guidelines maintaining caution. Therefore, a systematic evaluation is needed to understand the potential benefits of CGM during dietary interventions. A systematic literature review was conducted in PubMed according to the PICOS model and PRISMA recommendations on studies published from January 01, 2003, up to October 15, 2023 (PROSPERO CRD42024497744). The risk of bias was assessed using NIH Quality Assessment Tools. Twenty-four studies in GSDs (n = 13), CH (n = 10), and HFMDs (n = 1) were analyzed. In GSDs, Real-time CGM (Rt-CGM) was associated with metabolic benefits during nutritional interventions, proving to be an accurate system for hypoglycemia detection although with some concerns about reliability. Rt-CGM in CH, primarily involving children, also showed potential benefits for glycemic control and metabolic stability with acceptable accuracy, although its use during dietary changes was limited. Few experiences on Flash Glucose Monitoring (FGM) were reported, with some concerns about reliability. Overall, the studies analyzed presented different designs, and their quality was predominantly fair or poor. Heterogeneity and limited consensus on reliability and glycemic targets underscore the need for prospective studies and future recommendations for the use of CGM in optimizing nutritional status and providing personalized dietary education in individuals with IMDs prone to hypoglycemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Newborn screening programmes offer an opportunity to obtain dried blood spots (DBS) cards that contain a wealth of biological information that can be stored for long periods and have potential benefits for research and quality assurance. However, the storage and secondary uses of DBS cards pose numerous ethical, clinical, and social challenges. Empirical research exploring public attitudes is central to public policy planning as it can indicate whether or not there is broad public support, define public concerns, and ascertain the circumstances required to alleviate concerns and ensure support. This study aims to describe the clinical experience and attitudes towards newborn screening and investigate the perceptions and expectations of Hong Kong parents and healthcare providers regarding the retention of DBS cards and their usage for research. Methods We conducted semi-structured in-person interviews with 20 parents and healthcare providers in Hong Kong. Thematic analysis was conducted. Results Awareness of the significant research value of secondary uses of dried blood spot cards is low. Parents and healthcare providers support the storage and secondary uses of DBS cards with some concerns, including privacy and confidentiality breaches, the risk of discrimination or stigmatisation based on genetic information, and their inability to oversee the use of their child’s biospecimen. Parents, however, prioritise their child’s health over privacy concerns and support identifiable storage using pseudonymity to gain more information about their children's health. Conclusion Child information takes precedence over potential concerns over privacy, underscoring the significance of engaging patients and the public in shaping public policy related to biobanking and healthcare research, in line with cultural and social values.

Abstract Background Long-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD. Methods This retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported. Results Patients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients’ total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment. Conclusions The significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype–phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants. [ABSTRACT FROM AUTHOR]

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals. [ABSTRACT FROM AUTHOR]

Background: Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP. Methods: We conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times ("high excretors"); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN). Results: During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy. Conclusion: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP. [ABSTRACT FROM AUTHOR]

Copyright of Gazi Journal of Health Sciences is the property of Gazi University Faculty of Health Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Inherited metabolic disorders (IEMs) can be represented in children and adolescents by psychiatric disorders. The early diagnosis of IEMs is crucial for clinical outcome and treatment. The aim of this review is to analyze the most recurrent and specific psychiatric features related to IEMs in pediatrics, based on the onset type and psychiatric phenotypes. Methods: Following the PRISMA Statement, a systematic literature review was performed using a predefined algorithm to find suitable publications in scientific databases of interest. After removing duplicates and screening titles and abstracts, suitable papers were analyzed and screened for inclusion and exclusion criteria. Finally, the data of interest were retrieved from the remaining articles. Results: The results of this study are reported by type of symptoms onset (acute and chronic) and by possible psychiatric features related to IEMs. Psychiatric phenomenology has been grouped into five main clinical manifestations: mood and anxiety disorders; schizophrenia-spectrum disorders; catatonia; eating disorders; and self-injurious behaviors. Conclusions: The inclusion of a variety of psychiatric manifestations in children and adolescents with different IEMs is a key strength of this study, which allowed us to explore the facets of seemingly different disorders in depth, avoiding possible misdiagnoses, with the related delay of early and appropriate treatments. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate the diagnostic capabilities of Chinese laboratories for inherited metabolic disorders (IMDs) using gas chromatography-mass spectrometry (GC-MS) on urine samples. Meanwhile, based on the result of the pilot external quality assessment (EQA) scheme, we hope to establish a standardized and reliable procedure for future EQA practice. Methods: We recruited laboratories that participated in the EQA of quantitative analysis of urinary organic acids with GC-MS before joining the surveys. In each survey, a set of five real urine samples was distributed to each participant. The participants should analyze the sample by GC-MS and report the "analytical result", "the most likely diagnosis", and "recommendation for further tests" to the NCCL before the deadline. Results: A total of 21 laboratories participated in the scheme. The pass rates were 94.4% in 2020 and 89.5% in 2021. For all eight IMDs tested, the analytical proficiency rates ranged from 84.7% - 100%, and the interpretational performance rate ranged from 88.2% - 97.0%. The performance on hyperphenylalaninemia (HPA), 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), and ethylmalonic encephalopathy (EE) samples were not satisfactory. Conclusions: In general, the participants of this pilot EQA scheme are equipped with the basic capability for qualitative organic acid analysis and interpretation of the results. Limited by the small size of laboratories and samples involved, this activity could not fully reflect the state of clinical practice of Chinese laboratories. NCCL will improve the EQA scheme and implement more EQA activities in the future. [ABSTRACT FROM AUTHOR]

The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine–glycine–one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options. [ABSTRACT FROM AUTHOR]

BackgroundNeonatal deaths often result from preventable conditions that can be addressed with appropriate interventions. This study aims to analyze the distribution of the causes of neonatal death and explore genetic variations that lead to congenital anomalies in Northwest China.MethodsThis multi-center observational study was conducted across six medical centers in Shaanxi province, Northwest China. Clinical data were retrospectively collected from neonates admitted between 2016 and 2020. Kaplan-Meier analysis was utilized to estimate survival rates, while high-throughput sequencing platforms were employed to detect mutations causing congenital anomalies.ResultsAmong 73,967 neonates requiring hospital care, 424 neonatal deaths were recorded, leading to a neonatal mortality rate of 0.57%. The primary causes of death included neonatal respiratory distress syndrome (23.8%), birth asphyxia (19.8%), neonatal septicemia (19.3%), and congenital anomalies (13.6%). The leading causes of neonatal deaths due to congenital anomalies were congenital heart defects (38.6%), bronchopulmonary dysplasia (14.0%), and inherited metabolic disorders (10.5%). Genetic analysis identified 83 pathogenic or likely pathogenic variants in 23 genes among the neonates with congenital anomalies, including four novel mutations (c.4198+1G>T, c.1075delG, c.610-1G>A, c.7769C>T) in the ABCC8, CDKL5, PLA2G6, and NIPBL genes.ConclusionCongenital anomalies represent a significant and preventable cause of neonatal deaths in Northwest China. Early detection of congenital anomalies through genetic testing and comprehensive prenatal care are crucial for reducing neonatal mortality rates and improving pregnancy outcomes.

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Dbt haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

Selective screening for inherited metabolic disorders (IMD) began in Cyprus in 1990. Over the last thirty-three years 7388 patients were investigated for IMD and 200 diagnoses were made (diagnostic yield 2.7%). The existence of a single laboratory of Biochemical Genetics for the whole island facilitated the creation of a national registry for IMD. The minimal prevalence of IMD in Cyprus is 53.3 cases per 100,000 live births. The most common group are disorders of amino acid metabolism (41.0%), followed by disorders of carbohydrate metabolism (16.5%), disorders of complex molecule degradation (16.5%), mitochondrial disorders (10.5%) and disorders of vitamin and co-factor metabolism (5.5%). Hyperphenylalaninaemia is the most common IMD (14.0%) followed by galactosaemia (7.0%), glutaric aciduria type I (5.5%) and MSUD (4.0%). Some disorders were found to have a relatively high incidence in specific communities, for example Sandhoff disease among the Cypriot Maronites and GM1 gangliosidosis in one particular area of the island. Other disorders were found to have a relatively higher overall incidence, compared to other Caucasian populations, for example galactosaemia, glutaric aciduria type I and MSUD, while fatty acid oxidation defects, Gaucher disease and classic PKU were found to have a relatively lower incidence. Molecular characterization of selected disorders revealed many novel genetic variants, specific to the Cypriot population.

An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise.

Background and aims: Defective enzymes, cofactors, or transporters of metabolic pathways cause inherited metabolic disorders (IMDs), a group of genetic disorders. Several IMDs have serious consequences for the affected neonates. Newborn screening for IMDs is conducted by measuring specific metabolites between 3 and 7 days of life. Herein, we analyzed the incidence, spectrum, and genetic characteristics of IMDs in newborns in the Zhuzhou area. Methods: Tandem mass spectrometry was conducted on 90,829 newborns who were admitted to the Women and Children Healthcare Hospital of Zhuzhou and requested for screening for IMDs. These newborns were subsequently subjected to next-generation sequencing and further validated using Sanger sequencing. Results: 30 IMDs cases were found in 90,829 cases of newborns screened for IMDs, and the overall incidence was 1/3,027. The incidence of amino acid, organic acid, fatty acid oxidation and urea cycle disorders were 1/8,257, 1/18,165, 1/7,569, and 1/45,414, respectively. Additionally, 9 cases of maternal IMDs were found in our study, and unreported gene mutations of 3 cases IMDs were identified. Conclusion: Our data indicated that IMDs are never uncommon in zhuzhou, meanwhile, we also found that primary carnitine deficiency was the only disorder of fatty acid oxidation in Zhuzhou, and the incidence (1/7,569) was higher than the national level, organic acid metabolic diseases are mostly inherited. Therefore, our study has clarified the disease spectrum and genetic backgrounds, contributing to the treatment and prenatal genetic counseling of these disorders in this region. [ABSTRACT FROM AUTHOR]

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits. [ABSTRACT FROM AUTHOR]

BackgroundAcute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP.MethodsWe conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times (“high excretors”); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN).ResultsDuring acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy.ConclusionThis study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.

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.

Abstract Background Inherited metabolic disorders (IMDs) usually occurs at young age and hence it severely threatening the health and life of young people. While so far there lacks a comprehensive study which can reveals China’s nationwide landscape of IMDs. This study aimed to evaluate IMDs incidence and regional distributions in China at a national and province level to guide clinicians and policy makers. Methods The retrospective study conducted from January 2012 to March 2021, we analyzed and characterized 372255 cases’ clinical test information and diagnostic data from KingMed Diagnostics Laboratory. The samples were from 32 provincial regions of China, the urine organic acids were detected by gas chromatography-mass spectrometry (GC–MS), amino acids and acylcarnitines in dried blood spots were detected by liquid chromatography-tandem mass spectrometry (LC–MS/MS). We did a statistical analysis of the distribution of the 16 most common IMDs in amino acid disorders and organic acidemias, and then paid special attention to analyze the age and regional distributions of different IMDs. The statistical analyses and visualization analysis were performed with the programming language R (version 4.2.1). Results There were 4911 positive cases diagnosed, which was 1.32% of the total sample during the ten-year study period. Most diseases tended to occur at ages younger than 18 year-old. The Ornithine Transcarbamylase Deficiency tended to progress on male infants who were less than 28 days old. While the peak of the positive case number of Citrin Deficiency disease (CD) was at 1–6 months. Different IMDs’ had different distribution patterns in China’s provinces. Methylmalonic Acidemias and Hyperphenylalaninemia had an imbalanced distribution pattern in China and its positive rate was significantly higher in North China than South China. Conversely, the positive rate of CD was significantly higher in South China than North China. Conclusions Results of this work, such as the differences in distribution pattern of different diseases in terms of age, region, etc. provide important insights and references for clinicians, researchers and healthcare policy makers. The policy makers could optimize the better health screening programs for covering children and infants in specific ages and regions based on our findings.

The article focuses on the challenges of diagnosing and managing porphyrias, rare inherited metabolic disorders with nonspecific symptoms, particularly highlighting the perioperative anaesthetic challenges. Topics include the pathophysiology of porphyrias, their classifications and presentations, and the implications for anaesthetic management, emphasizing the need for a high index of suspicion and careful consideration of anaesthetic drugs to avoid triggering acute porphyric crises.

Inherited metabolic diseases are rare genetic disorders caused by synthesis disorders affecting protein, carbohydrate and lipid metabolisms, impaired enzyme activity, and deficiency of cofactors or transporters. More than 1000 inherited metabolic diseases have been reported. The prevalence of each disease is rare. However, the overall prevalence is not rare as expected. Inherited metabolic diseases can occur at any age, from prenatal to adulthood. The clinical features are mostly progressive when left untreated. Most diseases occur at young ages and often with more than one organ involvement. In Inherited metabolic diseases, eye involvement may be primary or secondary, and the findings may be local or systemic. The toxic effect of abnormal metabolites or accumulation of normal metabolites is usually responsible for the pathogenesis. Early recognition of treatable inherited metabolic diseases is important as it may change the treatment outcome of the patient. Ophthalmological findings may be in the form of cataract, corneal clouding, retinitis pigmentosa, cherry red spot and optic atrophy. Bilateral symmetrical involvement is expected. In this article, eye findings that can be seen in hereditary metabolic diseases will be discussed. [ABSTRACT FROM AUTHOR]

The childhood mortality rate for IMDs is approximately 25 % in populations with no expanded newborn screening program. Although the factors that increase mortality risk are known, an index predicting long-term survival has yet to be established. Two hundred sixty patients who were hospitalized during the first month of their life were screened, and 94 patients diagnosed with IMDs were included in the study. Clinical and laboratory data were assessed to identify any independent prognostic factors for overall survival. Among the 38 patients with IMDs in the exitus group, the presence of dysmorphism, extremity abnormalities, respiratory distress, cyanosis, elevated transaminases, elevated INR, hypoglycemia, hypoalbuminemia, metabolic acidosis, electrolyte imbalance and anemia were associated with poorer survival. Elevated INR (Hazard Ratio [HR]: 0.17, 95 % CI: 0.03–0.87, p=0.034), hypoglycemia (HR: 0.48, 95 % CI: 0.25–0.91, p=0.026) and hypoalbuminemia (HR: 0.09, 95 % CI: 0.03–0.26, p<0.001) were the independent prognostic factors for survival after adjusting for confounding factors. For the prediction of survival, INR, glucose, and albumin were used to structure a novel index (IGAm = INR-Glucose-Albumin metabolic index). The median survival was shorter in the IGAm-high group (2 or 3 points) than in the IGAm-low group (p<0.001). Harrell's c-index was 0.73 for the IGAm index. The devised novel IGAm index can predict long-term survival in patients with IMDs, with a high IGAm index being associated with higher mortality in patients with IMDs. [ABSTRACT FROM AUTHOR]

The determination of the functional impact of variants of uncertain significance (VUS) is one of the major bottlenecks in the diagnostic workflow of inherited genetic diseases. To face this problem, we set up a CRISPR/Cas9‐based strategy for knock‐in cellular model generation, focusing on inherited metabolic disorders (IMDs). We selected variants in seven IMD‐associated genes, including seven reported disease‐causing variants and four benign/likely benign variants. Overall, 11 knock‐in cell models were generated via homology‐directed repair in HAP1 haploid cells using CRISPR/Cas9. The functional impact of the variants was determined by analyzing the characteristic biochemical alterations of each disorder. Functional studies performed in knock‐in cell models showed that our approach accurately distinguished the functional effect of pathogenic from non‐pathogenic variants in a reliable manner in a wide range of IMDs. Our study provides a generic approach to assess the functional impact of genetic variants to improve IMD diagnosis and this tool could emerge as a promising alternative to invasive tests, such as muscular or skin biopsies. Although the study has been performed only in IMDs, this strategy is generic and could be applied to other genetic disorders. [ABSTRACT FROM AUTHOR]

The analysis of organic acids in urine is an important part of the diagnosis of inherited metabolic disorders (IMDs), for which gas chromatography coupled with mass spectrometry is still predominantly used. Ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for urinary organic acids, acylcarnitines and acylglycines was developed and validated. Sample preparation consists only of dilution and the addition of internal standards. Raw data processing is quick and easy using selective scheduled multiple reaction monitoring mode. A robust standardised value calculation as a data transformation together with advanced automatic visualisation tools are applied for easy evaluation of complex data. The developed method covers 146 biomarkers consisting of organic acids (n=99), acylglycines (n=15) and acylcarnitines (n=32) including all clinically important isomeric compounds present. Linearity with r2>0.98 for 118 analytes, inter-day accuracy between 80 and 120 % and imprecision under 15 % for 120 analytes were achieved. Over 2 years, more than 800 urine samples from children tested for IMDs were analysed. The workflow was evaluated on 93 patient samples and ERNDIM External Quality Assurance samples involving a total of 34 different IMDs. The established LC-MS/MS workflow offers a comprehensive analysis of a wide range of organic acids, acylcarnitines and acylglycines in urine to perform effective, rapid and sensitive semi-automated diagnosis of more than 80 IMDs. [ABSTRACT FROM AUTHOR]

Infections represent the main cause of acute metabolic derangements and/or the worsening of the clinical course of many inherited metabolic disorders (IMDs). The basic molecular mechanisms behind the role of infections in these conditions have not been completely clarified. This review points out the different mechanisms behind the relationship between IMDs and infections, providing an overview of this still-under-investigated area. Classically, infections have been considered as the consequence of a compromised immune system due to a biochemical defect of energy production. An adjunctive pathogenetic mechanism is related to a genetically altered protein-attached glycans composition, due to congenital glycosilation defects. In addition, a dietary regimen with a reduced intake of both micro- and macronutrients can potentially compromise the ability of the immune system to deal with an infection. There is recent pre-clinical evidence showing that during infections there may be a disruption of substrates of various metabolic pathways, leading to further cellular metabolic alteration. Therefore, infective agents may affect cellular metabolic pathways, by mediation or not of an altered immune system. The data reviewed here strongly suggest that the role of infections in many types of IMDs deserves greater attention for a better management of these disorders and a more focused therapeutic approach. [ABSTRACT FROM AUTHOR]

Several initiatives at establishing a classification of inherited metabolic disorders have been published previously, some focusing on pathomechanisms, others on clinical manifestations, while yet another attempted a simplified approach of a comprehensive nosology. Some of these classifications suffered from shortcomings, such as lack of a mechanism for continuous update in light of a rapidly evolving field, or lack of widespread input from the metabolic community at large. Our classification-the International Classification of Inherited Metabolic Disorders, or International Classification of Inborn Metabolic Disorders (ICIMD)-includes 1450 disorders, and differs from prior approaches in that it benefited from input by a large number of experts in the field, and was endorsed by major metabolic societies around the globe. Several criteria such as pathway involvement and pathomechanisms were considered. The main purpose of the hierarchical, group-based approach of the ICIMD is an improved understanding of the interconnections between many individual conditions that may share functional, clinical, and diagnostic features. The ICIMD aims to include any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical, and/or pathophysiological features. As new disorders are discovered, we will seek the opinion of experts in the advisory board prior to inclusion in the appropriate group of the ICIMD, thus guaranteeing the continuing relevance of this classification via regular curation and expert advice.

Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.

Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types. [ABSTRACT FROM AUTHOR]

Background: Inherited metabolic disorders (IMDs) usually occurs at young age and hence it severely threatening the health and life of young people. While so far there lacks a comprehensive study which can reveals China's nationwide landscape of IMDs. This study aimed to evaluate IMDs incidence and regional distributions in China at a national and province level to guide clinicians and policy makers. Methods: The retrospective study conducted from January 2012 to March 2021, we analyzed and characterized 372255 cases' clinical test information and diagnostic data from KingMed Diagnostics Laboratory. The samples were from 32 provincial regions of China, the urine organic acids were detected by gas chromatography-mass spectrometry (GC–MS), amino acids and acylcarnitines in dried blood spots were detected by liquid chromatography-tandem mass spectrometry (LC–MS/MS). We did a statistical analysis of the distribution of the 16 most common IMDs in amino acid disorders and organic acidemias, and then paid special attention to analyze the age and regional distributions of different IMDs. The statistical analyses and visualization analysis were performed with the programming language R (version 4.2.1). Results: There were 4911 positive cases diagnosed, which was 1.32% of the total sample during the ten-year study period. Most diseases tended to occur at ages younger than 18 year-old. The Ornithine Transcarbamylase Deficiency tended to progress on male infants who were less than 28 days old. While the peak of the positive case number of Citrin Deficiency disease (CD) was at 1–6 months. Different IMDs' had different distribution patterns in China's provinces. Methylmalonic Acidemias and Hyperphenylalaninemia had an imbalanced distribution pattern in China and its positive rate was significantly higher in North China than South China. Conversely, the positive rate of CD was significantly higher in South China than North China. Conclusions: Results of this work, such as the differences in distribution pattern of different diseases in terms of age, region, etc. provide important insights and references for clinicians, researchers and healthcare policy makers. The policy makers could optimize the better health screening programs for covering children and infants in specific ages and regions based on our findings. [ABSTRACT FROM AUTHOR]

Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B12 deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study "NGS2025" from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B12 deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B12 deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B12, vitamin B6 respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels. [ABSTRACT FROM AUTHOR]

For the extraction and measurement of plasma amino acids using LC/ESI–MS/MS technology, a straightforward and dependable approach has been established. The approach employs a small amount of sample and fully quantifies it using a labeled internal standard of amino acids. Water, formic acid, and methanol were used as the mobile phase in a gradient method to obtain clear separation. On a Shimatzu mass spectrometer 8030, optimized multiple reaction monitoring (MRM) was utilized to find amino acids. All amino acids have coefficients of correlation that range from 0.91 to 0.99, and they are all linear over their respective reference ranges. Precision's intra-day and inter-day coefficients of variation (CV %) ranged from 3.29 to 11.73% and 5.04 to 12.48%, respectively. Amino acid recovery ranged from 92.1 to 108.2%. [ABSTRACT FROM AUTHOR]

Introduction: Inborn errors of metabolism (IEM) are a rare cause of epilepsy in pediatric age group. Prompt diagnosis is essential, as some of these disorders are treatable. Aim: To determine the prevalence, clinical, and etiological profile of metabolic epilepsy in children. Methods: A prospective observational study of children with new onset seizures diagnosed as inherited metabolic disorder in a tertiary care hospital, South India. Results: Among 10,778 children with new onset seizures, 63 (0.58%) had metabolic epilepsy. The male female ratio was 1.3:1. Onset of the seizures were in neonatal period in 12 (19%), infancy in 35 (55.6%), and between one and 5 years of age in 16 (25.4%) children. Generalised seizures were seen in 46 (73%), followed by multiple seizure types (31.7%). The associated clinical features included developmental delay in 37 (58.7%), hyperactivity in 7 (11%), microcephaly in 13 (20.6%), optic atrophy in 12 (19%), sparse hair and/or seborrheic dermatitis in 10 (15.9%), movement disorder in 7 (11%), and focal deficit in 27 (42.9%) patients. Magnetic resonance imaging brain was abnormal in 44 (69.8%) and diagnostic in 28 (44.4%) patients. Causative metabolic errors included vitamin responsive errors in 20 (31.7%), disorders of complex molecules in 13 (20.6%), amino acidopathies in 12 (19%), organic acidemias in 10 (16%), disorders of energy metabolism in 6 (9.5%), and peroxisomal disorders in 2 (3.2%) patients. With specific treatment, seizure freedom could be achieved in 45 (71%) children. Five children lost to follow-up and two died. Among the remaining 56 patients, 11 (19.6%) had a good neurological outcome. Conclusion: Vitamin responsive epilepsies were the most frequent cause of metabolic epilepsy. Early diagnosis and prompt treatment is necessary as only one-fifth had a good neurological outcome.

Inherited metabolic disorders have a specific place among cases of sudden deterioration of the newborn’s condition. Therapies have been developed for some of these disorders. Accurate verification of the diagnosis is extremely important for choosing an optimal treatment strategy. However, treatment is not always successful due to the rapid progression of symptoms. We report a case of citrullinemia diagnosed in a newborn in Vidnoye Perinatal Center.

Abstract Inherited metabolic disorders (IMD) are a group of hereditary diseases wherein the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Estonia's small population and nationwide digitalised healthcare system make it possible to perform an epidemiological study that covers the whole population. A study was performed in Tartu University Hospital, which is the only tertiary care unit in Estonia for diagnosing patients with IMD, to define the prevalence and live birth prevalence of IMDs and the effectiveness of new diagnostic methods on the diagnosis of IMD. During the retrospective study period from 1990 to 2017, 333 patients were diagnosed with IMD. Statistical analysis showed a significant increase in IMD diagnoses per year from 0.47 to 2.51 cases per 100 000 persons (p

A low amino acid (AA)/protein diet is the principal treatment for many inherited amino acid disorders (IMDs). Due to their low AA content, plant foods constitute an essential part of diet therapy. However, data on their AA composition are limited, which leads to an estimation of AA intake from protein content rather than an accurate calculation of true AA intake. This study describes the AA content of a total of 73 plant foods (fruits, n = 12; vegetables, n = 51; and other plant foods, n = 10), with the analysis commissioned by the UK National Society for Phenylketonuria (NSPKU) over 15 years. For all fruits and some vegetables (e.g., rocket, watercress and pea shoots), raw samples were used during analysis. All other vegetables were cooked prior to analysis to represent the usual condition of the food at the time of serving. AA analysis was performed with ion exchange chromatography. The median percentage of protein was 2.0% [0.6–5.4%] for the fruits and vegetables analysed (n = 56), although higher in vegetables than in fruits. Each of the five reported AAs (leucine, lysine, phenylalanine, tyrosine, and methionine) supplied 1–5% per g of protein content. From the heterogeneous range of plant foods analysed, the AA/protein ratios differed significantly (2–5% in fruits and 1–9% in vegetables). There was a strong correlation between the amounts of each of the five AAs in the plant foods, but only a small, moderate correlation between the protein and AA content. Overall, this study provides data on the AA content of several plant foods, which are suitable for patients treated with a low AA/protein diet, including many novel plant options. However, only a limited range of fruits and vegetables were analysed due to the high costs of analysis. Hence, more extensive studies with an increased number of plant foods prepared by different cooking methods and replicate samples are necessary, particularly to examine the relationship between the protein and AA content in depth. [ABSTRACT FROM AUTHOR]

Inherited metabolic diseases are rare genetic disorders caused by synthesis disorders affecting protein, carbohydrate and lipid metabolisms, impaired enzyme activity, and deficiency of cofactors or transporters. More than 1000 inherited metabolic diseases have been reported. The prevalence of each disease is rare. However, the overall prevalence is not rare as expected. Inherited metabolic diseases can occur at any age, from prenatal to adulthood.The clinical features are mostly progressive when left untreated. Most diseases occur at young ages and often with more than one organ involvement. In Inherited metabolic diseases, eye involvement may be primary or secondary, and the findings may be local or systemic. The toxic effect of abnormal metabolites or accumulation of normal metabolites is usually responsible for the pathogenesis. Early recognition of treatable inherited metabolic diseases is important as it may change the treatment outcome of the patient. Ophthalmological findings may be in the form of cataract, corneal clouding, retinitis pigmentosa, cherry red spot and lens dislocation. Bilateral symmetrical involvement is expected. In this article, eye findings that can be seen in hereditary metabolic diseases will be discussed. [ABSTRACT FROM AUTHOR]

As an effective fungicide widely used in agricultural production, the excessive procymidone (PRO) residue has been detected in the environment and food. Our previous study demonstrated that PRO could destroy the intestinal barrier in mice and has a joint toxic effect. To explore the cross‐generational impact of maternal exposure, 10‐week‐old C57BL/6 female mice were orally administrated to 10 and 100 mg/kg body weight/day of PRO during pregnancy and lactation. The offspring obtained nutrients from the maternal through the placenta and breast milk, and PRO residues were detected in the liver, intestine, and feces of F1 generation. Fecal examination found that the residual PRO had been completely metabolized when the offspring mice grew to 35 days. The drug residue of F1 generation male mice was higher than that of female mice. We attributed this result to the difference in cytochrome P450 (CYP450) enzyme expression between male and female mice. The transcriptional levels of CYP1A1, CYP1A2, CYP2D9, and CYP3A4, and CYP450 protein expression levels, were higher in female mice. Furthermore, targeted MS of plasma revealed abnormal amino acid levels. In addition, PRO‐induced hepatic metabolite changes in F0 and F1‐7w mice. KEGG pathway analysis further showed that PRO jointly changed the amino acid biosynthesis pathway of the maternal and offspring. In summary, these results indicated that maternal exposure to PRO during a special period would interfere with self metabolism, and offspring will also have metabolic disorders. [ABSTRACT FROM AUTHOR]

Gene therapy holds significant promise for treating a wide range of genetic disorders by targeting the underlying genetic causes. This abstract reviews current research efforts and advancements in gene therapy, highlighting its potential applications in various genetic disorders such as inherited metabolic disorders, immuno-deficiencies, hemoglobinopathies, and neurological diseases. Key topics discussed include gene therapy strategies, vector design, delivery methods, clinical trials, and emerging technologies such as CRISPR-Cas9 gene editing. The abstract aims to provide a comprehensive overview of the state of gene therapy and its potential impact on the treatment of genetic disorders. [ABSTRACT FROM AUTHOR]

Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.