[Development of analytics in newborn screening-from the Guthrie card to genetics]. / Entwicklung der Analytik im Neugeborenen-Screening ­ Von der Guthrie-Karte zur Genetik.

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.

The treatment of biochemical genetic diseases: From substrate reduction to nucleic acid therapies.

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.

Food or medicine? A European regulatory perspective on nutritional therapy products to treat inborn errors of metabolism.

Dietary or nutritional management strategies are the cornerstone of treatment for many inborn errors of metabolism (IEMs). Though a vital part of standard of care, the products prescribed for this are often not formally registered as medication. Instead, they are regulated as food or as food supplements, impacting the level of oversight as well as reimbursed policies. This scoping literature review explores the European regulatory framework relevant to these products and its implications for current clinical practice. Searches of electronic databases (PubMed, InfoCuria) were carried out, supplemented by articles identified by experts, from reference lists, relevant guidelines and case-law by the European Court of Justice. In the European Union (EU), nutritional therapy products are regulated as food supplements, food for special medical purposes (FSMPs) or medication. The requirements and level of oversight increase for each of these categories. Relying on lesser-regulated food products to treat IEMs raises concerns regarding product quality, safety, reimbursement and patient access. In order to ascertain whether a nutritional therapy product functions as medication and thus could be classified as such, we developed a flowchart to assess treatment characteristics (benefit, pharmacological attributes, and safety) with a case-based approach. Evaluating nutritional therapy products might reveal a justifiable need for a pharmaceutical product. A flowchart can facilitate systematically distinguishing products that function medication-like in the management of IEMs. Subsequently, finding and implementing appropriate solutions for these products might help improve the quality, safety and accessibility including reimbursement of treatment for IEMs.

[NEXT-GENERATION SEQUENCING PERFORMED IN PATIENTS RAISING THE SUSPICION OF AN INBORN ERROR OF METABOLISM UNCOVERED A HOMOZYGOUS VARIANT IN YARS1 ALLOWING A NOVEL THERAPEUTIC TRIAL].

INTRODUCTION: Inborn-Errors of Metabolism (IEM) are genetic disorders resulting from mutations in genes encoding proteins involved in biochemical-metabolic pathways. However, some IEMs lack specific biochemical markers. Early incorporation of next-generation-sequencing (NGS) including whole exome sequencing (WES) into the diagnostic algorithm of IEMs herein provided, increases diagnostic accuracy, permits genetic counseling and improves therapeutic options. This is exemplified by diseases affecting aminoacyl-tRNA synthetases (ARSs), enzymes involved in protein translation. Recent studies showed that supplementing amino-acids to cell-culture and patients with ARSs deficiencies resulted in improvement of biochemical and clinical parameters, respectively.

Exercise testing and prescription in patients with inborn errors of muscle energy metabolism.

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies.

Measuring what matters: Why and how to include patient reported outcomes in clinical care and research on inborn errors of metabolism.

Patient reported outcomes (PROs) are generally defined as 'any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else'. A broader definition of PRO also includes 'any information on the outcomes of health care obtained directly from patients without modification by clinicians or other health care professionals'. Following this approach, PROs encompass subjective perceptions of patients on how they function or feel not only in relation to a health condition but also to its treatment as well as concepts such as health-related quality of life (HrQoL), information on the functional status of a patient, signs and symptoms and symptom burden. PRO measurement instruments (PROMs) are mostly questionnaires and inform about what patients can do and how they feel. PROs and PROMs have not yet found unconditional acceptance and wide use in the field of inborn errors of metabolism. This review summarises the importance and usefulness of PROs in research, drug legislation and clinical care and informs about quality standards, development, and potential methodological shortfalls of PROMs. Inclusion of PROs measured with high-quality, well-selected PROMs into clinical care, drug legislation, and research helps to identify unmet needs, improve quality of care, and define outcomes that are meaningful to patients. The field of IEM should open to new methodological approaches such as the definition of core sets of variables including PROs to be systematically assessed in specific metabolic conditions and new collaborations with PRO experts, such as psychologists to facilitate the systematic collection of meaningful data.

A retrospective analysis of MS/MS screening for IEM in high-risk areas.

Inborn errors of metabolism (IEM) can lead to severe motor and neurological developmental disorders and even disability and death in children due to untimely treatment. In this study, we used tandem mass spectrometry (MS/MS) for primary screening and recall of those with positive primary screening for rescreening. Further diagnosis was based on biochemical tests, imaging and clinical presentation as well as accurate genetic testing using multi-gene panel with high-throughput sequencing of 130 IEM-related genes. The screening population was 16,207 newborns born between July 1, 2019, and December 31, 2021. Based on the results, 8 newborns were diagnosed with IEM, constituting a detection rate of 1:2,026. Phenylketonuria was the most common form of IEM. In addition, seven genes associated with IEM were detected in these eight patients. All eight patients received standardized treatment starting in the neonatal period, and the follow-up results showed good growth and development. Therefore, our study suggests that MS/MS rescreening for IEM pathogenic variants in high-risk areas, combined with a sequencing validation strategy, can be highly effective in the early detection of affected children. This strategy, combined with early intervention, can be effective in preventing neonatal morbidity and improving population quality.

Maternal-fetal outcomes of pregnancies in women treated at an inborn errors of metabolism unit.

INTRODUCTION: Intermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-fetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. METHODS: Retrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50 (P25-P75). RESULTS: 24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother's disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31 + 5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. CONCLUSIONS: Pregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and fetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.

Neuroimaging findings of inborn errors of metabolism: urea cycle disorders, aminoacidopathies, and organic acidopathies.

Although there are many types of inborn errors of metabolism (IEMs) affecting the central nervous system, also referred to as neurometabolic disorders, individual cases are rare, and their diagnosis is often challenging. However, early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurological impairment or death. The clinical course of IEMs is very diverse, with some diseases progressing to acute encephalopathy following infection or fasting while others lead to subacute or slowly progressive encephalopathy. The diagnosis of IEMs relies on biochemical and genetic tests, but neuroimaging studies also provide important clues to the correct diagnosis and enable the conditions to be distinguished from other, more common causes of encephalopathy, such as hypoxia-ischemia. Proton magnetic resonance spectroscopy (1H-MRS) is a powerful, non-invasive method of assessing neurological abnormalities at the microscopic level and can measure in vivo brain metabolites. The present review discusses neuroimaging findings, including those of 1H-MRS, of IEMs focusing on intoxication disorders such as urea cycle disorders, aminoacidopathies, and organic acidopathies, which can result in acute life-threatening metabolic decompensation or crisis.

[Pulmonary phenotypes of inborn errors of metabolism]. / Manifestations pulmonaires des maladies héréditaires du métabolisme.

Inborn metabolic diseases or inborn errors of metabolism comprise a large number of rare and heterogeneous genetic diseases categorized in several subgroups depending on their pathophysiologic mechanisms. In this review, we focus on different metabolic diseases with respiratory symptoms in adults: lysosomal glycosphingolipidoses such as acid sphingomyelinase deficiency (Niemann-Pick types A and B disease), Gaucher, Fabry, Pompe diseases and mucopolysaccharidoses in general. We also address classical homocystinuria, which is a monogenic vascular disease, Hermansky-Pudlak syndrome, which is associated with disorders in the lysosomal-related-organelles, and lysinuric protein intolerance, which is due to an amino-acid transporter defect. Presentation and prognosis of these diseases are highly heterogeneous, and respiratory impairment may be central and prognostic. Many are primarily pediatric, and diagnoses are often delivered during childhood. Improved pediatric management has enabled better prognosis and new phenotype of the diseases in the adulthood. Some others can be diagnosed during adulthood. While some diseases call for specific, specialized treatment, all necessitate systematic multidisciplinary management. It is of paramount importance that a pneumologist be familiar with these phenotypes, most of which can benefit from early diagnosis and early therapeutic management with dedicated innovative treatments.

Role of Psychologists in Pediatric Metabolic Disorders.

Metabolic disorders or inborn errors of metabolism (IEMs) can have a wide range of neurodevelopmental and behavioral presentations. These can vary with age and/or management or stressors from common childhood/intercurrent illnesses/procedures/interventions. Collaborative care models such as multidisciplinary metabolic clinics or colocated models with behavioral health clinics and metabolic clinics in the same location can be valuable resources in improving long-term outcomes in patients with IEM. Psychologists' expertise using behavioral interventions, screening, or adaptive/cognitive measures can help with diagnosis, treatment adherence, school performance, family support, community resources, transition to adolescence and young adulthood using health belief concepts to improve outcomes.

Inborn Errors of Metabolism in Dogs: Historical, Metabolic, Genetic, and Clinical Aspects.

Inborn errors of metabolism are genetic disorders caused by a block in a metabolic pathway, affecting both humans and animals. Individually, they are rare diseases, but as a group they are relatively common. As most of them have recessive inheritance, a new case may seem like just a sporadic case. The high degree of inbreeding in dog breeds increases the frequency of heterozygotes in populations, maintaining mutations (variants) in healthy individuals and, consequently, increasing the risk of disease recurrence (homozygotes). General practitioners' familiarization with this subject is a significant factor in identifying new cases, contributing to increased knowledge about inborn errors of metabolism and their control. To help general practitioners, we use a clinical genetics approach covering key genetic, metabolic, diagnostic, and therapeutic aspects, offering an overview that integrates knowledge about these diseases in dogs and humans.

Messenger RNA as a personalized therapy: The moment of truth for rare metabolic diseases.

Inborn errors of metabolism (IEM) encompass a group of monogenic diseases affecting both pediatric and adult populations and currently lack effective treatments. Some IEM such as familial hypercholesterolemia or X-linked protoporphyria are caused by gain of function mutations, while others are characterized by an impaired protein function, causing a metabolic pathway blockage. Pathophysiology classification includes intoxication, storage and energy-related metabolic disorders. Factors specific to each disease trigger acute metabolic decompensations. IEM require prompt and effective care, since therapeutic delay has been associated with the development of fatal events including severe metabolic acidosis, hyperammonemia, cerebral edema, and death. Rapid expression of therapeutic proteins can be achieved hours after the administration of messenger RNAs (mRNA), representing an etiological solution for acute decompensations. mRNA-based therapy relies on modified RNAs with enhanced stability and translatability into therapeutic proteins. The proteins produced in the ribosomes can be targeted to specific intracellular compartments, the cell membrane, or be secreted. Non-immunogenic lipid nanoparticle formulations have been optimized to prevent RNA degradation and to allow safe repetitive administrations depending on the disease physiopathology and clinical status of the patients, thus, mRNA could be also an effective chronic treatment for IEM. Given that the liver plays a key role in most of metabolic pathways or can be used as bioreactor for excretable proteins, this review focuses on the preclinical and clinical evidence that supports the implementation of mRNA technology as a promising personalized strategy for liver metabolic disorders such as acute intermittent porphyria, ornithine transcarbamylase deficiency or glycogen storage disease.

[Practical approach to the diagnosis of inherited metabolic diseases]. / Enfoque práctico en el diagnóstico de los errores congénitos del metabolismo.

Inborn errors of metabolism constitute a growing group of rare diseases with usual neurological impact. Heterogeneous in clinical and biochemical aspects, its diagnosis and treatment are difficult. Advances in its knowledge, in diagnostic methods and in its treatments, highlight the importance of a timely diagnosis, the gateway to access to early medical intervention. The neuropediatrician's suspicion in different clinical situations is very relevant. This article aims to be a practical contribution to facilitate their recognition.

Los errores congénitos del metabolismo constituyen un grupo creciente de enfermedades poco frecuentes con habitual impacto neurológico. Heterogéneas en el aspecto clínico y bioquímico, su diagnóstico y terapéutica son dificultosos. Los avances en su conocimiento, en los métodos diagnósticos y en sus tratamientos, ponen de relevancia lo importante de un diagnóstico oportuno, puerta del acceso a la intervención médica temprana. Es muy relevante la sospecha del neuropediatra ante diferentes situaciones clínicas. El presente artículo pretende ser un aporte práctico para facilitar su reconocimiento.

Neurogenetic and Metabolic Mimics of Common Neonatal Neurological Disorders.

Neurogenetic and metabolic diseases often present in the neonatal period, masquerading as other disorders, most commonly as neonatal encephalopathy and seizures. Advancements in our understanding of inborn errors of metabolism are leading to an increasing number of therapeutic options. Many of these treatments can improve long-term neurodevelopment and seizure control. However, the treatments are frequently condition-specific. A high index of suspicion is required for prompt identification and treatment. When suspected, simultaneous metabolic and molecular testing are recommended along with concurrent treatment.

RNA solutions to treat inborn errors of metabolism.

RNA-based therapies are a new, rapidly growing class of drugs that until a few years ago were being used mainly in research in rare diseases. However, the clinical efficacy of recently approved oligonucleotide drugs and the massive success of COVID-19 RNA vaccines has boosted the interest in this type of molecules of both scientists and industry, as wells as of the lay public. RNA drugs are easy to design and cost effective, with greatly improved pharmacokinetic properties thanks to progress in oligonucleotide chemistry over the years. Depending on the type of strategy employed, RNA therapies offer the versatility to replace, supplement, correct, suppress, or eliminate the expression of a targeted gene. Currently, there are more than a dozen RNA-based drugs approved for clinical use, including some for specific inborn errors of metabolism (IEM), and many other in different stages of development. New initiatives in n-of-1 RNA drug development offer new hope for patients with rare diseases and/or ultra-rare mutations. RNA-based therapeutics include antisense oligonucleotides, aptamers, small interfering RNAs, small activating RNAs, microRNAs, lncRNAs and messenger RNAs. Further research and collaborations in the fields of chemistry, biology and medicine will help to overcome major challenges in their delivery to target tissues. Herein, we review the mechanism of action of the different therapeutic approaches using RNA drugs, focusing on those approved or in clinical trials to treat IEM.

Inborn Errors of Metabolism: Becoming Ready for Rare.

Inborn errors of metabolism (IEMs) are a large group of disorders that can present in any age group and must be considered in the differential diagnosis for a variety of signs and symptoms appearing in infants and children. The rarity and complexity of these conditions often make them difficult to recognize, as they may mimic more common conditions. This review article discusses some of the more commonly presenting IEMs that are important for the general pediatrician to understand when evaluating a sick patient. Many of these diseases are also on the newborn screen, which pediatricians often encounter as first-line providers. Disorders that are discussed in detail herein include disorders of amino acid metabolism, including amino acidopathies and organic acidurias; urea cycle disorders; defects in fatty acid ß-oxidation; disorders of carbohydrate metabolism, including the glycogen storage diseases and galactosemia; and lysosomal storage diseases.

Hematopoietic Stem Cell Transplantation for Children With Inborn Errors of Metabolism: Single Center Experience Over Two Decades.

OBJECTIVE: We present outcome data on hematopoietic stem cell transplantation (HSCT) in children with inborn errors of metabolism (IEM). METHODS: We retrospectively analyzed data on children up to 18 years of age, diagnosed with IEM, who underwent HSCT between January, 2002 and December, 2020. RESULTS: 24 children, (mucopolysaccharidosis - 13, Gaucher disease - 4, X-linked adrenoleukodystrophy - 4, metachromatic leukodystrophy - 2, Krabbe disease - 1) were included. Donors were matched family donors in 24%, matched unrelated donors in 34%, and haploidentical fathers in 42% of the transplants, with engraftment in 91% of children. Overall survival was 72% (55-100%) with a median follow-up of 76.5 (10-120 ) months, and progression-free survival of 68% (MPS-76%, X-ALD -60%, Gaucher disease - 50%, and 100% in MLD and Krabbe disease). CONCLUSION: HSCT is an available curative option, and early age at HSCT prevents end-organ damage.

Haematopoietic stem cell gene therapy in inborn errors of metabolism.

Over the last 30 years, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been adopted as a therapeutic strategy for many inborn errors of metabolism (IEM), due to the ability of donor-derived cells to provide life-long enzyme delivery to deficient tissues and organs. However, (a) the clinical benefit of allo-HSCT is limited to a small number of IEM, (b) patients are left with a substantial residual disease burden and (c) allo-HSCT is still associated with significant short- and long-term toxicities and transplant-related mortality. Haematopoietic stem/progenitor cell gene therapy (HSPC-GT) was established in the 1990s for the treatment of selected monogenic primary immunodeficiencies and over the past few years, its use has been extended to a number of IEM. HSPC-GT is particularly attractive in neurodegenerative IEM, as gene corrected haematopoietic progenitors can deliver supra-physiological enzyme levels to difficult-to-reach areas, such as the brain and the skeleton, with potential increased clinical benefit. Moreover, HSPC-GT is associated with reduced morbidity and mortality compared to allo-HSCT, although this needs to be balanced against the potential risk of insertional mutagenesis. The number of clinical trials in the IEM field is rapidly increasing and some HSPC-GT products recently received market approval. This review describes the development of ex vivo HSPC-GT in a number of IEM, with a focus on recent results from GT clinical trials and risks versus benefits considerations, when compared to established therapeutic strategies, such as allo-HSCT.