Inborn Errors Of Metabolism Disorders Research Articles

Pre-implantation Genetic Testing in Inherited Metabolic Diseases? Stateof- the-art and current challenges.

Inborn errors of metabolism (IEM) are genetic diseases involving congenital disorders of enzyme activities. Most follow Mendelian autosomal recessive inheritance and few follow mitochondrial inheritance. In many cases, after the birth of an affected child parents discover that have been the carriers for the condition and worry about the risk of recurrence in future offspring. Preimplantation genetic testing (PGT) can analyze embryos before their transfer to the uterus and prevent the transmission of hereditary conditions to descendants, however this procedure is of limited value in mtDNA conditions. The list of diseases currently approved for PGT were reviewed. The process for eligibility, was as for the Comissão Nacional Procriação Medicamente Assistida (CNPMA), of Portugal (PT). Review of international practices for Assisted Reproductive Techniques (ART) in IEM was carried out. As of 07.2022, 23 IEM diseases associated with deleterious variants in nDNA were approved for PGT in PT. Couples at risk for conditions not included in the list can solicit an evaluation from an expert committee, after a medical genetics consultation. To qualify for approval, diseases must cause significant suffering and/or premature death. Due to a greater number of solicitations many more IEM conditions have been approved for PGT across the world. ART for mtDNA is not available in PT. International expert centers include PGT for specific well documented variants and mitochondrial donation. PGT is a reliable approach to reduce the risk of transmission of a genetic condition to the offspring. The list of IEM disorders currently accepted for this technique in Portugal are small, but it is expanding, as many more diseases fit the necessary criteria. While appealing in theory, low success rates coupled with limited availability can be discouraging for patients. Genetic counselling is of paramount importance after the diagnosis of IEM diseases. It is important for both clinicians and patients to be made aware of the available reproductive options and their limitations.

Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology.

Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease.

Advances in Self‐Assembly of Metabolite Nanostructures: Physiology, Pathology and Nanotechnology

AbstractMetabolites are immensely important for the routine function of every cell and take part in numerous physiological processes. Yet, in excess amounts, metabolites can self‐assemble, giving rise to cytotoxic amyloid‐like structures. Such structures may underlie some of the pathological effects associated with inborn error of metabolism disorders characterized by metabolite accumulation due to genetic mutations. Furthermore, such assemblies may have a role in neurodegenerative disorders due to abnormal accumulation. On the other hand, metabolites were shown to form functional assemblies in various organisms. Interestingly, various proteins and peptides showing amyloidal properties also have physiological roles and have been used for the fabrication of functional nanomaterials. Following this notion, metabolite self‐assembly could also be utilized due to several advantages including exceptional biocompatibility, inexpensive production, facile modeling and biodegradability in vivo. Co‐assembly of metabolites resulting in high rigidity can be further used in different biomedical and nanotechnological applications. Metal‐coordinated metabolite assemblies can be used as electrocatalysts in energy harvesting applications. Consequently, the study of metabolite self‐assemblies is not only crucial in order to understand their role in normal physiology and in pathology, but can also uncover a new route in exploring the fabrication of organic, biocompatible structures for material sciences and various technological applications.

Clinical metabolomics for inborn errors of metabolism.

Metabolism is a highly regulated process that provides nutrients to cells and essential building blocks for the synthesis of protein, DNA and other macromolecules. In healthy biological systems, metabolism maintains a steady state in which the concentrations of metabolites are relatively constant yet are subject to metabolic demands and environmental stimuli. Rare genetic disorders, such as inborn errors of metabolism (IEM), cause defects in regulatory enzymes or proteins leading to metabolic pathway disruption and metabolite accumulation or deficiency. Traditionally, the laboratory diagnosis of IEMs has been limited to analytical methods that target specific metabolites such as amino acids and acyl carnitines. This approach is effective as a screening method for the most common IEM disorders but lacks the comprehensive coverage of metabolites that is necessary to identify rare disorders that present with nonspecific clinical symptoms. Fortunately, advancements in technology and data analytics has introduced a new field of study called metabolomics which has allowed scientists to perform comprehensive metabolite profiling of biological systems to provide insight into mechanism of action and gene function. Since metabolomics seeks to measure all small molecule metabolites in a biological specimen, it provides an innovative approach to evaluating disease in patients with rare genetic disorders. In this review we provide insight into the appropriate application of metabolomics in clinical settings. We discuss the advantages and limitations of the method and provide details related to the technology, data analytics and statistical modeling required for metabolomic profiling of patients with IEMs.

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective

Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60–80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.

Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy.

First described almost two decades ago, the pioneering yeast models of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases, have become well-established research tools, providing both basic mechanistic insights as well as a platform for the development of therapeutic agents. These maladies are associated with the formation of aggregative amyloid protein structures showing common characteristics, such as the assembly of soluble oligomeric species, binding of indicative dyes, and apoptotic cytotoxicity. The canonical yeast models have recently been expanded by the establishment of a model for type II diabetes, a non-neurological amyloid-associated disease. While these model systems require the exogenous expression of mammalian proteins in yeast, an additional amyloid-associated disease model, comprising solely mutations of endogenous yeast genes, has been recently described. Mutated in the adenine salvage pathway, this yeast model exhibits adenine accumulation, thereby recapitulating adenine inborn error of metabolism disorders. Moreover, in line with the recent extension of the amyloid hypothesis to include metabolite amyloids, in addition to protein-associated ones, the intracellular assembly of adenine amyloid-like structures has been demonstrated using this yeast model. In this review, we describe currently available yeast models of diverse amyloid-associated disorders, as well as their impact on our understanding of disease mechanisms and contribution to future potential drug development.

Fibril formation and therapeutic targeting of amyloid-like structures in a yeast model of adenine accumulation

The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. However, a direct demonstration of the assembly of metabolite amyloid-like structures has so far been provided only in vitro. Here, we established an in vivo model of adenine self-assembly in yeast, in which toxicity is associated with intracellular accumulation of the metabolite. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.

The role of integrated behavioral health in caring for patients with metabolic disorders.

This review of integrated behavioral health (IBH) provides a background on IBH models, and the benefits of IBH in pediatric practice with an emphasis on how IBH specialists can collaborate with families and clinicians. An overview of intellectual disability (ID) and psychiatric disorders focused on disorders of inborn errors of metabolism (IEM) highlights issues in assessment and monitoring of these patients with implications for clinical practice and the role of IBH in caring for patients with IEM disorders.

Intrinsic Fluorescence of Metabolite Amyloids Allows Label-Free Monitoring of Their Formation and Dynamics in Live Cells.

The formation of apoptosis-inducing amyloidal structures by metabolites has significantly extended the "amyloid hypothesis" to include non-proteinaceous, single metabolite building blocks. However, detection of metabolite assemblies is restricted compared to their larger protein-based counterparts owing to the hindrance of external labelling and limited immunohistochemical detection tools. Herein, we present the detection of the formation, dynamics, and cellular distribution of metabolite amyloid-like structures and provide mechanistic insights into the generation of supramolecular chromophores. Moreover, the intrinsic fluorescence properties allow the detection of metabolite assemblies in living cells without the use of external dyes. Altogether, this intrinsic fluorescence of metabolite assemblies further verifies their amyloidal nature, while providing an important tool for further investigation of their pathological role in inborn error of metabolism disorders.

Intrinsic Fluorescence of Metabolite Amyloids Allows Label‐Free Monitoring of Their Formation and Dynamics in Live Cells

AbstractThe formation of apoptosis‐inducing amyloidal structures by metabolites has significantly extended the “amyloid hypothesis” to include non‐proteinaceous, single metabolite building blocks. However, detection of metabolite assemblies is restricted compared to their larger protein‐based counterparts owing to the hindrance of external labelling and limited immunohistochemical detection tools. Herein, we present the detection of the formation, dynamics, and cellular distribution of metabolite amyloid‐like structures and provide mechanistic insights into the generation of supramolecular chromophores. Moreover, the intrinsic fluorescence properties allow the detection of metabolite assemblies in living cells without the use of external dyes. Altogether, this intrinsic fluorescence of metabolite assemblies further verifies their amyloidal nature, while providing an important tool for further investigation of their pathological role in inborn error of metabolism disorders.

Seeding of proteins into amyloid structures by metabolite assemblies may clarify certain unexplained epidemiological associations.

The accumulation of various metabolites appears to be associated with diverse human diseases. However, the aetiological link between metabolic alteration and the observed diseases is still elusive. This includes the correlation between the abnormally high levels of homocysteine and quinolinic acid in Alzheimer's disease, as well as the accumulation of oncometabolites in malignant processes. Here, we suggest and discuss a possible mechanistic insight into metabolite accumulation in conditions such as neurodegenerative diseases and cancer. Our hypothesis is based on the demonstrated ability of metabolites to form amyloid-like structures in inborn error of metabolism disorders and the potential of such metabolite amyloids to promote protein aggregation. This notion can provide a new paradigm for neurodegeneration and cancer, as both conditions were linked to loss of function due to protein aggregation. Similar to the well-established observation of amyloid formation in many degenerative disorders, the formation of amyloids by tumour-suppressor proteins, including p53, was demonstrated in malignant states. Moreover, this new paradigm could fill the gap in understanding the high occurrence of specific types of cancer among genetic error of metabolism patients. This hypothesis offers a fresh view on the aetiology of some of the most abundant human maladies and may redirect the efforts towards new therapeutic developments.

Inborn errors of metabolism associated with hyperglycaemic ketoacidosis and diabetes mellitus: narrative review.

Inborn errors of metabolism (IEM) are heterogeneous group of disorders that might present in the clinics or emergency departments in different phenotypes, and one of these is a diabetes scenario. Diabetes is the most common endocrine disorder among children. The mechanism of how IEM could lead to diabetes is unclear; however, the postulated pathogenesis consists of three mechanisms: 1) accumulation of toxic substance in the gland, ruining structure and normal functionality, 2) disturbing energy availability required for hormone synthesis and 3) defect of complex molecules. The differential diagnosis of IEM associated with hyperglycaemic ketoacidosis and diabetes include: organic acidemias specifically propionic acidemia, methylmalonic acidemia, isovaleric acidemia, hereditary hemochromatosis, aceruloplasminemia, holocarboxylase synthetase deficiency, β-ketothiolase deficiency and finally, cystinosis, Rogers syndrome (thiamine-responsive megaloblastic anaemia) and congenital disorders of glycosylation type Ia. Clinical approach will help in ready diagnosis and treatment for IEM disorders in early detection of diabetes. In this review, we will discuss the differential diagnosis, clinical features and diagnostic approaches of IEM presenting as hyperglycaemic ketoacidosis and diabetes.

Metabolite amyloids: a new paradigm for inborn error of metabolism disorders.

The formation of ordered amyloid assemblies is associated with major human degenerative disorders, including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. Amyloid fibrils are elongated nanoscale structures that bind to specific dyes (including thioflavin T and Congo red). Amyloid fibrillar assemblies or their early intermediates are known to induce apoptotic cytotoxic effect. Until recently, amyloid fiber formation was observed only with proteins and peptides. We reported in 2012 that a single amino acid, phenylalanine, could also form typical amyloid fibrils with the same morphology, dye-binding specificity, and electron diffraction pattern as protein amyloids. X-ray crystallography demonstrated the formation of supramolecular β-sheet-like organization by phenylalanine at its zwitterionic form. Metabolite amyloids had pronounced cytotoxicity that could be depleted by treatment with antibodies raised against the phenylalanine structures. We suggested that the observed amyloid formation could explain some of the symptoms observed in phenylketonuria (PKU) upon the accumulation of phenylalanine. Follow-up studies by other groups revealed the ability of phenylalanine amyloids to bind to membranes, as observed with protein amyloids. Furthermore, the doxycycline amyloid formation inhibitor was shown to also affect the formation of phenylalanine amyloids. In 2015, it was reported that other metabolites involved in metabolic disorders, including adenine, uracil, tyrosine, and orotic acid, could form amyloid-like assemblies. It was further demonstrated that the assemblies induce apoptotic cell death. Taken together, we suggest a new hypothesis to understand the etiology of degenerative processes observed in inborn error of metabolism disorders and indicate new avenues for treatment.

Patterns of inborn errors of metabolism: A 12 year single-center hospital-based study in Libya.

Background: Inborn errors of metabolism (IEM) are mostly transmitted as autosomal recessive disorders and are therefore more frequent in countries with high consanguinity rates such as in the Arab world. Objective: To study the socio-demographic characteristics and the clinical presentation of IEM in Libyan children and to shed light on our experience in dealing with these disorders. Methods: This is a descriptive case series hospital-based study of 107 children attending the Metabolic Unit at El-Khadra Teaching Hospital (MUKH) in Tripoli, Libya. The study took place between January 2001 and December 2012. Information was collected from caregivers and from all available hospital records on the following variables: age, sex, birth order, place of residence, age at onset, presenting complaints and family history of the same illness. Results: During the 12-year study period, there were 55,422 live births at El-Khadra Teaching Hospital and 107 children were diagnosed with 46 different metabolic disorders. A significantly high consanguinity rate was observed (86.9%) among parents of the affected children. Family history of previous affected children was noted in 63.5% of cases. Male to female ratio was 1.18:1. The most frequent IEM cases were amino acids disorders (25%), carbohydrate disorders (14.9%), lysosomal storage diseases (14%), organic aciduria and energy metabolic defects (9.3% each). The main clinical presentations were jaundice, hepatomegaly and seizures. Most children presented between one and six months of age (43.4%); whereas the median age at diagnosis was eight months. Thirty-eight children (35.5%) were born at El-Khadra Hospital with IEM giving a birth prevalence of 1:1458 live births, (1:6158 for aminoaciduria and 1:6927 for carbohydrate disorders). Conclusion: IEM disorders are common in Libya. Efforts to enhance awareness among pediatricians and primary healthcare providers should be supported and encouraged as many diseases are still undiagnosed. It is very important to consider IEM among all children when they present any worrying or suspicious symptoms or signs which do not respond to conventional treatment. Although our findings are preliminary, and probably the first to be conducted in Libya, they suggest ideas for decision makers to plan services including newborn screening programs and country-wide research of IEM diseases.

Hot Topics in Metabolism

New developments for several inborn errors of metabolism disorders detected by newborn screen are explored—phenylketonuria, liver transplant for urea cycle disorders, maple syrup urine disease, methylmalonic acidemia/propionic acidemia, and galactosemia. Phenylketonuria advancements discussed include medical foods, low protein foods, large neutral amino acid therapy, Kuvan, and pegylated recombinant phenylalanine ammonia lyase. Clinical and quality of life outcomes of liver transplantations for urea cycle disorders and maple syrup urine disease are described. The recent developments and controversies of liver transplants in methylmalonic acidemia/propionic acidemia are explored. Lastly, feeding complications and dietary restrictions in galactosemia are reviewed.

Identification of Mutations Underlying 20 Inborn Errors of Metabolism in the United Arab Emirates Population

Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders.

A database for inborn errors of metabolism in the Indian state of Andhra Pradesh.

A Database for Inborn Errors of Metabolism (IEM) in the Indian State of Andhra Pradesh (DIEMISAP), is a continuously updated literature depository containing the extensive information on the regional prevalence and heterogeneity of Inborn Errors of metabolism. We report the construction of a database, a flat file and secondary data resource developed using Microsoft Front Page as the core engine. The database contains 18 summaries regarding 43 IEM disorders reported in the AP population, both in general and region wise, with references and links to the IEM disorder databases available on web and institutes involved in IEM research, in India. Summaries can be accessed from the reference given against an alphabetically arranged list of IEM disorders. The DIEMISAP is a useful user friendly and extendable online resource for information on prevalence of IEM in AP. http://biochem.uohyd.ernet.in.