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1.
PLoS One ; 19(2): e0296390, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38315701

RESUMO

Estradiol is an important regulator of bone accumulation and maintenance. Circulating estrogens are primarily produced by the gonads. Aromatase, the enzyme responsible for the conversion of androgens to estrogen, is expressed by bone marrow cells (BMCs) of both hematopoietic and nonhematopoietic origin. While the significance of gonad-derived estradiol to bone health has been investigated, there is limited understanding regarding the relative contribution of BMC derived estrogens to bone metabolism. To elucidate the role of BMC derived estrogens in male bone, irradiated wild-type C57BL/6J mice received bone marrow cells transplanted from either WT (WT(WT)) or aromatase-deficient (WT(ArKO)) mice. MicroCT was acquired on lumbar vertebra to assess bone quantity and quality. WT(ArKO) animals had greater trabecular bone volume (BV/TV p = 0.002), with a higher trabecular number (p = 0.008), connectivity density (p = 0.017), and bone mineral content (p = 0.004). In cortical bone, WT(ArKO) animals exhibited smaller cortical pores and lower cortical porosity (p = 0.02). Static histomorphometry revealed fewer osteoclasts per bone surface (Oc.S/BS%), osteoclasts on the erosion surface (ES(Oc+)/BS, p = 0.04) and low number of osteoclasts per bone perimeter (N.Oc/B.Pm, p = 0.01) in WT(ArKO). Osteoblast-associated parameters in WT(ArKO) were lower but not statistically different from WT(WT). Dynamic histomorphometry suggested similar bone formation indices' patterns with lower mean values in mineral apposition rate, label separation, and BFR/BS in WT(ArKO) animals. Ex vivo bone cell differentiation assays demonstrated relative decreased osteoblast differentiation and ability to form mineralized nodules. This study demonstrates a role of local 17ß-estradiol production by BMCs for regulating the quantity and quality of bone in male mice. Underlying in vivo cellular and molecular mechanisms require further study.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Aromatase , Transplante de Medula Óssea , Ginecomastia , Infertilidade Masculina , Erros Inatos do Metabolismo , Camundongos , Animais , Masculino , Aromatase/genética , Aromatase/metabolismo , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Porosidade , Camundongos Endogâmicos C57BL , Estrogênios , Estradiol , Células da Medula Óssea/metabolismo , Coluna Vertebral/metabolismo , Camundongos Knockout
2.
Nutrients ; 16(3)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38337708

RESUMO

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


Assuntos
COVID-19 , Galactosemias , Doença da Urina de Xarope de Bordo , Erros Inatos do Metabolismo , Fenilcetonúrias , Distúrbios Congênitos do Ciclo da Ureia , Adulto , Humanos , Criança , Pandemias , Dieta
3.
Arch Pediatr ; 31(1): 85-88, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38168614

RESUMO

The cases were a pair of siblings with a carnitine palmitoyltransferase (CPT2) deficiency detected by tandem mass spectrometry. Their C16 and C18:1 levels were both within the normal range, while C0 was low, and the (C16+C18:1)/C2 ratio was high. Following genetic testing, a novel CPT2 gene mutation was identified in both patients. The male patient had a normal growth rate during 5 years of follow-up after treatment. By contrast, the female patient did not take l-carnitine supplements and died after an infectious disease-associated illness when she was 1 year old. These data emphasize the need to raise awareness about CPT2 deficiency so as to correctly diagnose and accurately manage the disease.


Assuntos
Carnitina O-Palmitoiltransferase , Erros Inatos do Metabolismo , Feminino , Humanos , Lactente , Masculino , Carnitina , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Mutação , Pré-Escolar
4.
BMC Public Health ; 24(1): 222, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238734

RESUMO

BACKGROUND: Many people suffer from body and breath malodour syndromes. One of these is trimethylaminuria, a condition characterized by excretion in breath and bodily fluids of trimethylamine, a volatile and odorous chemical that has the smell of rotting fish. Trimethylaminuria can be primary, due to mutations in the gene encoding flavin-containing monooxygenase 3, or secondary, due to various causes. To gain a better understanding of problems faced by United Kingdom residents affected by body and breath malodour conditions, we conducted a survey. METHODS: Two anonymous online surveys, one for adults and one for parents/guardians of affected children, were conducted using the Opinio platform. Participants were invited via a trimethylaminuria advisory website. Questions were a mix of dropdown, checkbox and open-ended responses. Forty-four adults and three parents/guardians participated. The dropdown and checkbox responses were analysed using the Opinio platform. RESULTS: All participants reported symptoms of body/breath odour. However, not all answered every question. Twenty-three respondents experienced difficulties in being offered a diagnostic test for trimethylaminuria. Problems encountered included lack of awareness of the disorder by medical professionals and reluctance to recognise symptoms. Of those tested, 52% were diagnosed with trimethylaminuria. The main problems associated with living with body/breath malodours were bullying, harassment and ostracism in either the workplace (90%) or in social settings (88%). All respondents thought their condition had disadvantaged them in their daily lives. Open-ended responses included loss of confidence, stress, exclusion, isolation, loneliness, depression and suicidal thoughts. Respondents thought their lives could be improved by greater awareness and understanding of malodour conditions by medical professionals, employers and the general public, and appreciation that the malodour was due to a medical condition and not their fault. CONCLUSIONS: Breath and body malodour conditions can cause immense hardship and distress, both mentally and socially, having devastating effects on quality of life. It would be advantageous to establish a standardised pathway from primary care to a specialist unit with access to a robust and reliable test and diagnostic criteria. There is a need to recognise malodour disorders as a disability, giving affected individuals the same rights as those with currently recognised disabilities.


Assuntos
Erros Inatos do Metabolismo , Metilaminas/urina , Qualidade de Vida , Adulto , Criança , Animais , Humanos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Odorantes , Ansiedade
5.
Mol Genet Metab ; 141(1): 108115, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38181458

RESUMO

Inborn errors of metabolism (IEMs) encompass a diverse group of disorders that can be difficult to classify due to heterogenous clinical, molecular, and biochemical manifestations. Untargeted metabolomics platforms have become a popular approach to analyze IEM patient samples because of their ability to detect many metabolites at once, accelerating discovery of novel biomarkers, and metabolic mechanisms of disease. However, there are concerns about the reproducibility of untargeted metabolomics research due to the absence of uniform reporting practices, data analyses, and experimental design guidelines. Therefore, we critically evaluated published untargeted metabolomic platforms used to characterize IEMs to summarize the strengths and areas for improvement of this technology as it progresses towards the clinical laboratory. A total of 96 distinct IEMs were collectively evaluated by the included studies. However, most of these IEMs were evaluated by a single untargeted metabolomic method, in a single study, with a limited cohort size (55/96, 57%). The goals of the included studies generally fell into two, often overlapping, categories: detecting known biomarkers from many biochemically distinct IEMs using a single platform, and detecting novel metabolites or metabolic pathways. There was notable diversity in the design of the untargeted metabolomic platforms. Importantly, the majority of studies reported adherence to quality metrics, including the use of quality control samples and internal standards in their experiments, as well as confirmation of at least some of their feature annotations with commercial reference standards. Future applications of untargeted metabolomics platforms to the study of IEMs should move beyond single-subject analyses, and evaluate reproducibility using a prospective, or validation cohort.


Assuntos
Erros Inatos do Metabolismo , Humanos , Reprodutibilidade dos Testes , Estudos Prospectivos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/metabolismo , Metabolômica/métodos , Biomarcadores/metabolismo
6.
Metabolism ; 150: 155738, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37981189

RESUMO

Inborn errors of metabolism (IEMs) are a group of more than 1000 inherited diseases that are individually rare but have a cumulative global prevalence of 50 per 100,000 births. Recently, it has been recognized that like common diseases, patients with rare diseases can greatly vary in the manifestation and severity of symptoms. Here, we review omics-driven approaches that enable an integrated, holistic view of metabolic phenotypes in IEM patients. We focus on applications of Constraint-based Reconstruction and Analysis (COBRA), a widely used mechanistic systems biology approach, to model the effects of inherited diseases. Moreover, we review evidence that the gut microbiome is also altered in rare diseases. Finally, we outline an approach using personalized metabolic models of IEM patients for the prediction of biomarkers and tailored therapeutic or dietary interventions. Such applications could pave the way towards personalized medicine not just for common, but also for rare diseases.


Assuntos
Erros Inatos do Metabolismo , Humanos , Erros Inatos do Metabolismo/genética , Doenças Raras/genética , Medicina de Precisão , Fenótipo , Análise de Sistemas
7.
Clin Biochem ; 123: 110703, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38097032

RESUMO

Chronic kidney disease (CKD) affects over 0.5 billion people worldwide across their lifetimes. Despite a growingly ageing world population, an increase in all-age prevalence of kidney disease persists. Adult-onset forms of kidney disease often result from lifestyle-modifiable metabolic illnesses such as type 2 diabetes. Pediatric and adolescent forms of renal disease are primarily caused by morphological abnormalities of the kidney, as well as immunological, infectious and inherited metabolic disorders. Alterations in energy metabolism are observed in CKD of varying causes, albeit the molecular mechanisms underlying pathology are unclear. A systematic indexing of metabolites identified in plasma and urine of patients with kidney disease alongside disease enrichment analysis uncovered inborn errors of metabolism as a framework that links features of adult and pediatric kidney disease. The relationship of genetics and metabolism in kidney disease could be classified into three distinct landscapes: (i) Normal genotypes that develop renal damage because of lifestyle and / or comorbidities; (ii) Heterozygous genetic variants and polymorphisms that result in unique metabotypes that may predispose to the development of kidney disease via synergistic heterozygosity, and (iii) Homozygous genetic variants that cause renal impairment by perturbing metabolism, as found in children with monogenic inborn errors of metabolism. Interest in the identification of early biomarkers of onset and progression of CKD has grown steadily in the last years, though it has not translated into clinical routine yet. This systematic review indexes findings of differential concentration of metabolites and energy pathway dysregulation in kidney disease and appraises their potential use as biomarkers.


Assuntos
Diabetes Mellitus Tipo 2 , Erros Inatos do Metabolismo , Insuficiência Renal Crônica , Adulto , Adolescente , Humanos , Criança , Rim/metabolismo , Insuficiência Renal Crônica/genética , Metabolômica , Biomarcadores , Erros Inatos do Metabolismo/genética
8.
Methods Mol Biol ; 2745: 191-210, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38060187

RESUMO

Inborn errors of metabolism (IEM) are a group of about 500 rare genetic diseases with large diversity and complexity due to number of metabolic pathways involved in. Establishing a correct diagnosis and identifying the specific clinical phenotype is consequently a difficult task. However, an inclusive diagnosis able in capturing the different clinical phenotypes is mandatory for successful treatment. However, in contrast with Garrod's basic assumption "one-gene one-disease," no "simple" correlation between genotype-phenotype can be vindicated in IEMs. An illustrative example of IEM is Phenylketonuria (PKU), an autosomal recessive inborn error of L-phenylalanine (Phe) metabolism, ascribed to variants of the phenylalanine hydroxylase (PAH) gene encoding for the enzyme complex phenylalanine-hydroxylase. Blood values of Phe allow classifying PKU into different clinical phenotypes, albeit the participation of other genetic/biochemical pathways in the pathogenetic mechanisms remains elusive. Indeed, it has been shown that the most serious complications, such as cognitive impairment, are not only related to the gene dysfunction but also to the patient's background and the participation of several nongenetic factors.Therefore, a Systems Biology-based strategy is required in addressing IEM complexity, and in identifying the interplay between different pathways in shaping the clinical phenotype. Such an approach should entail the concerted investigation of genomic, transcriptomics, proteomics, metabolomics profiles altogether with phenylalanine and amino acids metabolism. Noticeably, this "omic" perspective could be instrumental in planning personalized treatment, tailored accordingly to the disease profile and prognosis.


Assuntos
Erros Inatos do Metabolismo , Fenilalanina Hidroxilase , Fenilcetonúrias , Humanos , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Fenilcetonúrias/metabolismo , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Fenilalanina Hidroxilase/genética , Fenótipo , Fenilalanina/genética , Fenilalanina/metabolismo
9.
Mol Metab ; 79: 101859, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38142971

RESUMO

BACKGROUND: Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. METHODS: We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca2+ kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tvHeLa). RESULTS: Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca2+ concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to ß-adrenergic stimulation. CONCLUSIONS: Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca2+ kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada , Ataxia Cerebelar , Células-Tronco Pluripotentes Induzidas , Maleatos , Erros Inatos do Metabolismo , Humanos , Trifosfato de Adenosina/metabolismo , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Células HeLa , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Respiração
10.
PLoS One ; 18(12): e0296073, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38134035

RESUMO

We investigated the differences in quantity and quality of skeletal muscle between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) individuals using abdominal CT. One hundred and seventy-two people with morbid obesity who underwent bariatric surgery and 64 healthy control individuals participated in this retrospective study. We divided the people with morbid obesity into an MHO and MUO group. In addition, nonobese metabolic healthy people were included analysis to provide reference levels. CT evaluation of muscle quantity (at the level of the third lumbar vertebra [L3]) was performed by calculating muscle anatomical cross-sectional area (CSA), which was normalized to patient height to produce skeletal muscle index (SMI). Muscle quality was assessed as skeletal muscle density (SMD), which was calculated from CT muscle attenuation. To characterize intramuscular composition, muscle attenuation was classified into three categories using Hounsfield unit (HU) thresholds: -190 HU to -30 HU for intermuscular adipose tissue (IMAT), -29 to +29 HU for low attenuation muscle (LAM), and +30 to +150 HU for normal attenuation muscle (NAM). People with morbid obesity comprised 24 (14%) MHO individuals and 148 (86%) MUO individuals. The mean age of the participants was 39.7 ± 12.5 years, and 154 (65%) participants were women. MUO individuals had a significantly greater total skeletal muscle CSA than MHO individuals in the model that adjusted for all variables. Total skeletal muscle SMI, SMD, NAM index, LAM index, and IMAT index did not differ between MHO and MUO individuals for all adjusted models. Total skeletal muscle at the L3 level was not different in muscle quantity, quality, or intramuscular composition between the MHO and MUO individuals, based on CT evaluation. MHO individuals who are considered "healthy" should be carefully monitored and can have a similar risk of metabolic complications as MUO individuals, at least based on an assessment of skeletal muscle.


Assuntos
Síndrome Metabólica , Erros Inatos do Metabolismo , Obesidade Metabolicamente Benigna , Obesidade Mórbida , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Masculino , Síndrome Metabólica/metabolismo , Obesidade Mórbida/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Tomografia , Índice de Massa Corporal , Fatores de Risco
11.
Nutrients ; 15(22)2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-38004189

RESUMO

Inborn errors of metabolism (IMDs) are a group of inherited diseases that manifest themselves through a myriad of signs and symptoms, including structural or functional cardiovascular damage. The therapy of these diseases is currently based on enzyme-replacement therapy, chaperone therapy or the administration of supplements and the establishment of personalized dietary plans. Starting from the major signs identified by the pediatric cardiologist that can indicate the presence of such a metabolic disease-cardiomyopathies, conduction disorders or valvular dysplasias-we tried to paint the portrait of dietary interventions that can improve the course of patients with mitochondrial diseases or lysosomal abnormalities. The choice of the two categories of inborn errors of metabolism is not accidental and reflects the experience and concern of the authors regarding the management of patients with such diagnoses. A ketogenic diet offers promising results in selected cases, although, to date, studies have failed to bring enough evidence to support generalized recommendations. Other diets have been successfully utilized in patients with IMDs, but their specific effect on the cardiac phenotype and function is not yet fully understood. Significant prospective studies are necessary in order to understand and establish which diet best suits every patient depending on the inherited metabolic disorder. The most suitable imagistic monitoring method for the impact of different diets on the cardiovascular system is still under debate, with no protocols yet available. Echocardiography is readily available in most hospital settings and brings important information regarding the impact of diets on the left ventricular parameters. Cardiac MRI (magnetic resonance imaging) could better characterize the cardiac tissue and bring forth both functional and structural information.


Assuntos
Cardiomiopatias , Doenças Metabólicas , Erros Inatos do Metabolismo , Criança , Humanos , Estudos Prospectivos , Dieta , Erros Inatos do Metabolismo/diagnóstico
12.
Cell Rep ; 42(11): 113214, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-37917582

RESUMO

Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Erros Inatos do Metabolismo , Humanos , Animais , Camundongos , Fosfatidilgliceróis , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Surdez/genética , Cardiolipinas
14.
Clin Pediatr (Phila) ; 62(12): 1523-1530, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37908170

RESUMO

Inborn errors of metabolism (IEMs) are inherited biochemical/metabolic disorders that are commonly present in the immediate neonatal period. The aim of this retrospective study was to determine the incidence and distribution of IEMs in newborn infants delivered in our hospital and to evaluate its outcome. A total of 16 494 (99.9%) newborn infants were screened for IEMs. We found 29 newborn infants diagnosed with IEMs, representing an incidence of 1 per ~569 live births and a cumulative incidence of 176 per 100 000 live births of the IEM-positive newborn infants. We detected 11 different types of IEMs, and the top 6 categories were endocrinopathies followed by carbohydrates disorders, vitamin-responsive disorders, organic acid defects, and ketogenesis and ketolysis defects. This study does reflect upon the importance of educating the general population about the perils of Consanguineous Marriages (CMs) in order to reduce related disorders significantly, especially in families who have a history of IEMs.


Assuntos
Erros Inatos do Metabolismo , Recém-Nascido , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Incidência , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Triagem Neonatal
15.
Artigo em Alemão | MEDLINE | ID: mdl-37828293

RESUMO

For more than five decades, all newborns in Germany have been offered a screening examination for the early detection of congenital treatable diseases. Since its inception, about 35 million children have been screened in this way.Originally, screening exams only included early detection of phenylketonuria, which, without timely treatment, would lead to mental retardation that could no longer be corrected. The bacteriological Guthrie test allowed the detection of elevated concentrations of phenylalanine. The methods used today are the result of decades of development. They have been expanded to include tests to determine enzyme activities, immunoassays for the early detection of important hormonal disorders such as congenital hypothyroidism, and high-pressure liquid chromatography for the diagnosis of pathologic hemoglobins. The very sophisticated tandem mass spectrometry enables the simultaneous detection of amino acid and fatty acid compounds. Steroids can also be identified. The specificity can be further increased by combining tandem mass spectrometry with chromatographic pre-separation. In recent years, chemical-analytical analyses have been supplemented by genetic diagnostic methods such as quantitative or qualitative polymerase chain reaction (PCR).The current state of laboratory technology is by no means final. Both classical analytics and especially genetic methods are facing further rapid development. Although the expansion of screening is also a consequence of technical development, the inclusion of further congenital diseases is fundamentally dependent on the given therapy. But it is precisely here that many innovations are currently being investigated. Gene therapy is at the forefront of interest.


Assuntos
Erros Inatos do Metabolismo , Fenilcetonúrias , Criança , Recém-Nascido , Humanos , Triagem Neonatal/métodos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia , Alemanha , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Diagnóstico Precoce
16.
Artigo em Inglês | MEDLINE | ID: mdl-37810989

RESUMO

Background: Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field. Methods: A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines. Results: The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited. Discussion: This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes.


Assuntos
Coreia , Discinesias , Erros Inatos do Metabolismo , Transtornos dos Movimentos , Humanos , Coreia/diagnóstico , Atetose/complicações , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Transtornos dos Movimentos/complicações
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(11): 1377-1381, 2023 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-37906145

RESUMO

OBJECTIVE: To explore the clinical features and genetic basis for a child with 3-methylglutaconic aciduria type VII. METHODS: A child who was diagnosed at the Gansu Provincial Maternity and Child Health Care Hospital on August 9, 2019 was selected as the study subject. Clinical data of the child, including urine gas chromatography and mass spectrometry, were collected. The child and her parents were subjected to whole exome sequencing. RESULTS: The child, a female neonate, had presented mainly with intermittent skin cyanosis, convulsions, hypomagnesemia, apnea, neutropenia after birth. Her urine 3-methylpentenedioic acid has increased to 17.53 µmol/L. DNA sequencing revealed that she has harbored compound heterozygous variants of the CLPB gene, namely c.1016delT (p.L339Rfs*5) and c.1087A>G (p.R363G), which were respectively inherited from her mother and father. Both variants were unreported previously. Based on the standards from the American College of Medical Genetics and Genomics (ACMG), the variants were respectively predicted to be pathogenic and likely pathogenic. CONCLUSION: The child was diagnosed with 3-methylglutenedioic aciduria type VII. Discovery of the c.1016delT and c.1087A>G variants has enriched the mutational spectrum of the CLPB gene.


Assuntos
Erros Inatos do Metabolismo , Neutropenia , Feminino , Humanos , Recém-Nascido , Gravidez , Sequência de Bases , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/diagnóstico , Mutação , Neutropenia/genética , Análise de Sequência de DNA
18.
JAMA ; 330(15): 1423-1424, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37732817

RESUMO

In this Viewpoint, Lasker Award winner Piet Borst looks back over a 50-year career in scientific research, including work with trypanosomatids, mechanisms of drug resistance in cancer cells, and inborn errors of metabolism.


Assuntos
Distinções e Prêmios , Pesquisa Biomédica , Animais , Humanos , Pesquisa Biomédica/história , História do Século XX , História do Século XXI , Medicina , Erros Inatos do Metabolismo , Neoplasias/terapia , Países Baixos , Parasitos
19.
Mol Genet Metab ; 140(3): 107693, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37716025

RESUMO

Newborn screening (NBS) began a revolution in the management of biochemical genetic diseases, greatly increasing the number of patients for whom dietary therapy would be beneficial in preventing complications in phenylketonuria as well as in a few similar disorders. The advent of next generation sequencing and expansion of NBS have markedly increased the number of biochemical genetic diseases as well as the number of patients identified each year. With the avalanche of new and proposed therapies, a second wave of options for the treatment of biochemical genetic disorders has emerged. These therapies range from simple substrate reduction to enzyme replacement, and now ex vivo gene therapy with autologous cell transplantation. In some instances, it may be optimal to introduce nucleic acid therapy during the prenatal period to avoid fetopathy. However, as with any new therapy, complications may occur. It is important for physicians and other caregivers, along with ethicists, to determine what new therapies might be beneficial to the patient, and which therapies have to be avoided for those individuals who have less severe problems and for which standard treatments are available. The purpose of this review is to discuss the "Standard" treatment plans that have been in place for many years and to identify the newest and upcoming therapies, to assist the physician and other healthcare workers in making the right decisions regarding the initiation of both the "Standard" and new therapies. We have utilized several diseases to illustrate the applications of these different modalities and discussed for which disorders they may be suitable. The future is bright, but optimal care of the patient, including and especially the newborn infant, requires a deep knowledge of the disease process and careful consideration of the necessary treatment plan, not just based on the different genetic defects but also with regards to different variants within a gene itself.


Assuntos
Erros Inatos do Metabolismo , Fenilcetonúrias , Recém-Nascido , Lactente , Gravidez , Feminino , Humanos , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia , Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal , Fenilcetonúrias/genética , Fenilcetonúrias/terapia , Biologia Molecular , Sequenciamento de Nucleotídeos em Larga Escala
20.
Nutrients ; 15(18)2023 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-37764685

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD) is distinguished by the buildup of excessive liver fat unrelated to alcohol consumption. However, the role of alcohol consumption on disease progression is debatable. Recently, alcohol flushing syndrome in Asian populations has gained interest, and its role in the risk of developing MASLD is unknown. Therefore, in this cross-sectional study, we investigated the association between alcohol consumption and MASLD in Korean men, considering their alcohol flushing response and utilizing the lipid accumulation product (LAP) score. Data from the Korean National Health and Nutrition Examination Survey (2019-2021) were analyzed. Participants were categorized into non-or-infrequent drinkers and light-to-heavy drinkers and further sub-classified based on alcohol flushing response as non-flushers and flushers. Multivariate logistic regression analysis showed a significant association between alcohol consumption and MASLD risk in both non-flushers (aHR 1.90, 95% CI 1.51-2.40, p < 0.001) and flushers (aHR 2.35, 95% CI 1.94-2.84, p < 0.001) after adjusting for potential confounding factors such as age, exercise, smoking, body mass index, systolic blood pressure, total cholesterol, and fasting plasma glucose. There was a significant interaction between alcohol consumption and alcohol flushing response for MASLD risk (p for interaction < 0.001). These findings emphasize the importance of alcohol flushing as a potential indicator of MASLD risk in Korean men and highlight the need for further research to understand the underlying mechanisms and develop targeted preventive strategies.


Assuntos
Transtornos Relacionados ao Uso de Álcool , Fígado Gorduroso , Doenças Metabólicas , Erros Inatos do Metabolismo , Masculino , Humanos , Estudos Transversais , Inquéritos Nutricionais , Consumo de Bebidas Alcoólicas/efeitos adversos , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/etiologia , República da Coreia/epidemiologia
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