Treatment Of Inborn Errors Of Metabolism Research Articles

Inborn Errors of Metabolism Screening in Neonates: Current Perspective with Diagnosis and Therapy.

Inborn errors of metabolism (IEMs) are rare hereditary or acquired disorders resulting from an enzymatic deformity in biochemical and metabolic pathways influencing proteins, fats, carbohydrate metabolism, or hampered some organelle function. Even though individual IEMs are uncommon, together, they represent a diverse class of genetic diseases, with new issues and disease mechanisms being portrayed consistently. IEM includes the extraordinary multifaceted nature of the fundamental pathophysiology, biochemical diagnosis, molecular level investigation, and complex therapeutic choices. However, due to the molecular, biochemical, and clinical heterogeneity of IEM, screening alone will not detect and diagnose all illnesses included in newborn screening programs. Early diagnosis prevents the emergence of severe clinical symptoms in the majority of IEM cases, lowering morbidity and death. The appearance of IEM disease can vary from neonates to adult people, with the more serious conditions showing up in juvenile stages along with significant morbidity as well as mortality. Advances in understanding the physiological, biochemical, and molecular etiologies of numerous IEMs by means of modalities, for instance, the latest molecular-genetic technologies, genome engineering knowledge, entire exome sequencing, and metabolomics, have prompted remarkable advancement in detection and treatment in modern times. In this review, we analyze the biochemical basis of IEMs, clinical manifestations, the present status of screening, ongoing advances, and efficiency of diagnosis in treatment for IEMs, along with prospects for further exploration as well as innovation.

MR Neuroimaging in Pediatric Inborn Errors of Metabolism.

Inborn errors of metabolism (IEM) are a group of disorders due to functional defects in one or more metabolic pathways that can cause considerable morbidity and death if not diagnosed early. While individually rare, the estimated global prevalence of IEMs comprises a substantial number of neonatal and infantile disorders affecting the central nervous system. Clinical manifestations of IEMs may be nonspecific. Newborn metabolic screens do not capture all IEMs, and likewise, genetic testing may not always detect pathogenic variants. Neuroimaging is a critical component of the work-up, given that imaging sometimes occurs before prenatal screen results are available, which may allow for recognition of imaging patterns that lead to early diagnosis and treatment of IEMs. This review will demonstrate the role of magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) in the evaluation of IEMs. The focus will be on scenarios where MRI and 1H MRS are suggestive of or diagnostic for IEMs, or alternatively, refute the diagnosis.

Medical Foods for Inborn Errors of Metabolism: History, Current Status, and Critical Need.

Successful intervention for inborn errors of metabolism (IEMs) is a triumph of modern medicine. For many of these conditions, medical foods are the cornerstone of therapy and the only effective interventions preventing disability or death. Medical foods are designed for patients with limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foods or nutrients, whereby dietary management cannot be achieved by modification of the normal diet alone. In the United States today, access to medical foods is not ensured for many individuals who are affected despite their proven efficacy in the treatment of IEMs, their universal use as the mainstay of IEM management, the endorsement of their use by professional medical organizations, and the obvious desire of families for effective care. Medical foods are not sufficiently covered by many health insurance plans in the United States and, without insurance coverage, many families cannot afford their high cost. In this review, we outline the history of medical foods, define their medical necessity, discuss the barriers to access and reimbursement resulting from the regulatory status of medical foods, and summarize previous efforts to improve access. The Advisory Committee on Heritable Disorders in Newborns and Children asserts that it is time to provide stable and affordable access to the effective management required for optimal outcomes through the life span of patients affected with IEMs. Medical foods as defined by the US Food and Drug Administration should be covered as required medical benefits for persons of all ages diagnosed with an IEM.

Metabolic Disorders

Inborn errors of metabolism (IEM) are individually rare but have a collective incidence of approximately one in 1000. Most IEM can manifest with neurologic symptoms. It is crucial for the pediatric neurologist to be familiar with the evaluation and management of these disorders because many are amenable to specific treatments. This review provides a category-based approach to the diagnosis and treatment of IEM organized by metabolic pathway and organelle. Categories include disorders of mitochondrial fatty acid oxidation and carnitine metabolism, urea cycle disorders, organic acidemias, aminoacidopathies, lysosomal disorders, peroxisomal disorders, vitamin- and diet-responsive metabolic epilepsies, and neurotransmitter disorders. Multiple summary tables for quick reference are provided. Figures show mitochondrial β-oxidation and carnitine cycle; urea cycle; T2-weighted magnetic resonance images (MRI) of ornithine transcarbamylase deficiency presenting with hyperammonemic encephalopathy, propionic academia, methylmalonic academia, glutaric acidemia type 1, ethylmalonic encephalopathy, mitochondrial complex 1 deficiency, pyruvate dehydrogenase complex E3 deficiency, untreated biotin-thiamine-responsive basal ganglia disease, homocysteinemia and low plasma methionine (suspected remethylation defect), attenuated Krabbe disease, Hunter syndrome, and GM1-gangliosidosis; branched-chain amino acid catabolic pathway; lysine, hydroxylysine, and tryptophan catabolic pathway; intracellular cobalamin metabolism; metabolism of homocysteine; diffusion-weighted imaging of maple syrup urine disease, nonketotic hyperglycinemia, and poorly controlled phenylketonuria; sphingolipid metabolic pathway; skeletal surveys of Hurler syndrome demonstrating features of dysostosis multiplex and rhizomelic chondrodysplasia punctata type 1; MRI of Salla disease; peroxisomal oxidation reactions, and the biogenic amine biosynthetic pathway. Tables list fatty acid oxidation and carnitine disorders, metabolic myopathies presenting with recurrent rhabdomyolysis, urea cycle disorders, organic acidemias, IEM associated with abnormal head size, cobalamin disorders, aminoacidopathies, IEM associated with abnormal odor, lysosomal disorders, lysosomal disease Symptom categories (Not mutually exclusive), peroxisomal disorders, IEM associated with brain malformations, vitamin- and diet-responsive epilepsies, neurotransmitter disorders, and IEM associated with brain mineralization. This review contains 26 highly rendered figures, 15 tables, and 71 references. Key words: Inborn errors of metabolism, organic acidemia, cobalamin disorders, aminoacidopathy, lysosomal disorders

MG-135 Metabolic diet app suite: Digital medicine to support families with inborn errors of metabolism

Background Diets for inborn errors of metabolism (IEMs) are known to be burdensome, with lack of nutrient information often leading to compliancy issues, one-sided nutrition and frustration for children and families. Digital technologies provide the opportunity to develop Metabolic Diet Applications for handheld devices which can help families overcome these problems. Objective We aimed to develop Applications comprising nutrient information with options for tracking and exporting food records, to facilitate therapeutic compliance for IEM patients on diets. Methods and results Using Metabolic Pro Database we designed the 1st ever Metabolic Diet Apps Suite tailored to more than 15 different IEMs. Login to the App is personal. Features of each App include: relevant nutrient listing per food item, calculation tracking of food/nutrient intake, summary of food records with graphs, own recipes, and the possibility to export the food records as PDFs. We have performed a study on user friendliness; data was used to improve the Apps, to be launched summer 2014. Discussion The Metabolic Diet App suite enhances personalised treatment of IEMs via digital medicine. Especially for adolescents the Apps will be attractive tools, allowing them to better understand and control their disease. Change in adherence will be evaluated.

Treatment of inborn errors of metabolism.

Inborn errors of metabolism (IEM), though individually rare are collectively common. Average incidence of 50+ common IEMs is considered to be approx 1 in 1,000 live births. With annual birth rate of approximately 25 million babies in India, we can expect at least 25,000 babies being born with IEM in India and hence it is a significant burden to the families and societies. Over the last 3 decades many new and effective therapies have emerged for the management and treatment of IEMs. As of today approximately 70 different forms of therapeutic agents are available to help people suffering from IEM. Besides these we have various forms of transplants–liver cell transplants, liver transplant (both ALT and OLT), bone marrow or HSCT and kidney transplant now easily available at various parts of India. Amongst hundreds of IEM, certain disorders are common and treatable with simple forms of therapeutic agents. Urea Cycle Disorders and Organic Acidemias are top on the list. Every pediatrician and neonatologist must be aware of emergency management of these two group of disorders as they may present at any age especially in the 1st decade and more so in infancy. Both of these groups of disorders may present with hyperammonemia as their first manifestations and needs to be treated with easily available medications as oral form of Sodium Benzoate (250–500 mg/kg/day in 2-3 divided doses), low protein diet or temporary stoppage of protein intake till acute crisis is under control. For UCDs one can use arginine (granules or powder) hydrochloride or base–250 mg/kg/day in 2-3 divided doses except for Arginase deficiency. For disorders like CPS and NAGS deficiency Carbaglu of Carbamylglutamate or N Acetyl Glutamate can also be used in the dose of 100–300 mg/kg/day. Now a days it is also recommended for treatment of certain organic acidemias e.g. propionic acidemia. Other products like Sodium Phenyl butyrate or injectable forms of Arginine (10%) or Sodium Benzoate+Sodium Phenylbutyrate) are not available in India and are very costly for an average Indian patient. Once acute crisis is managed, special diets with low protein are successful in managing most of the UCDs. For Organic acidemias like Propionic acidemia, Methyl malonic Acidemia and Isovaleric acidemia, L-Carnitine in the dose of 100–300 mg/kg/day must be used. Injectable form of L-Carnitine is also available for emergency management. Correction of acidosis is very important along with supplementation of adequate amount of dextrose. One can use Dextrose-Insulin drip in emergency. Besides these, other medications like Betaine, NTBC, Dextromethrophane, Diazoxide, certain vitamins e.g. Biotin, Vit-B12, Thiamine, Riboflavin, Folic acid, Folinic acid, Pyridoxine, Pyridoxal–5-Phosphate, Vit C, certain aminoacids like Glycine, Ornithine, Citrulline etc are also available for the management of various types of IEMs. Of late many enzymes are available for enzyme replacement therapies of LSDs e.g. Gaucher, Pompe, Fabry’s Disease, MPS I, II and VI.

Senate Bill 311

Inborn errors of metabolism (IEMs) are heritable disorders in the biochemical processes of metabolism that occur in approximately 1 in every 1500 live births. The lifelong disorder is treatable through the use of medical foods, specially formulated foods that contain the nutritional content, and dietary restrictions customized to each type of disorder. Without treatment, the buildup of toxic substances in the blood would lead to progressive brain damage, mental retardation, and death. There are approximately 700 different types of IEMs, but today, only 30 are detectable through newborn screening. Each state has mandates to screen for such disorders at birth; however, there are no federal mandates to provide treatment for IEMs. Some states require health insurance companies to cover the costs of these expensive medical foods as treatment, but coverage is insufficient and often expires at adolescence. Senate Bill 311 (S.311), the Medical Foods Equity Act of 2011, proposes to provide coverage of medically necessary foods and other treatment costs under federal health programs and private health insurance. This bill would create uniform access to treatment for all individuals diagnosed with an IEM and reduce the financial burden on families. S.311 would also create a cost–benefit effect in which continuous treatment of IEMs would diminish the risks of developing mental retardation, a disorder that costs significantly more to treat through federal and private health care.

Recent Patents in Diagnosis and Treatment for Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) is a group of around 500 diseases, characterized by function alteration in proteins or enzymes involving the intermediary metabolism of carbohydrates, amino acids, and lipids, among others. Since their discovery at the beginning of the last century, IEM have made important contributions to different fields of biochemistry and medicine. In this paper, a review of the recent patents for the diagnosis and treatment of IEM will be presented. During the last years significant achievements have been done for their diagnosis, including the use of tandem mass spectrometry for the identification of an important number of disorders and the use of genetic and immunological techniques, which have allowed the development of reliable diagnosis tests. Also, important progresses has been done in therapeutic strategies, most of them based on the use of recombinant DNA technology, such as enzyme and gene therapies, and the use of small molecules for chaperone and substrate reduction therapies. Improvements in classical treatments, like nutritional management, have also contributed in the generation of new therapeutic strategies for these patients. Keywords: Inborn errors of metabolism, tandem mass spectrometry, enzyme replacement therapy, gene therapy, nutritional management

A comparison of disease and gene frequencies of inborn errors of metabolism among different ethnic groups in the West Midlands, UK.

OBJECTIVE: To assess birth and gene frequencies of specific autosomal recessively inborn errors of metabolism (IEM) within different ethnic groups. DESIGN: Retrospective study in a regional centre for investigation and...