The eye as a window to inborn errors of metabolism

Summary: Ocular manifestations in inborn errors of metabolism occur in many diseases and may be associated with any part of all eye components. In a minority of diseases it is possible to attribute the eye symptoms to a single hereditary pathogenetic mechanism. More often the aetiological relationship of the ocular defects to the metabolic disease is unknown. Diverse pathogenetic mechanisms may act via a common pathological pathway inducing ocular damage. The occurrence of eye abnormalities in metabolic disorders suggests that they are associated with direct toxic actions, errors of synthetic pathways or deficient energy metabolism. In this review, metabolic disorders with major abnormalities in the cornea, lens, retina and optic nerve are presented. In all cases, an appropriate combined approach by the ophthalmologist, paediatrician/neurologist, geneticist and clinical biochemist is the only way to diagnostic success. This revised version was published online in August 2006 with corrections to the Cover Date.     

Society for the study of inborn errors of metabolism

Society for the study of inborn errors of metabolism     

Society for the study of inborn errors of metabolism

Society for the study of inborn errors of metabolism     

Sirtuin activation as a therapeutic approach against inborn errors of metabolism

Protein acylation has emerged as a large family of post translational modifications in which an acyl group can alter the function of a wide variety of proteins, especially in response to metabolic stress. The acylation state is regulated through reversible acylation/deacylation. Acylation occurs enzymatically or non-enzymatically, and responds to acyl-CoA levels. Deacylation on the other hand is controlled through the NAD⁺-dependent sirtuin proteins. In several inborn errors of metabolism (IEMs), accumulation of acyl-CoAs, due to defects in amino acid and fatty acid metabolic pathways, can lead to hyperacylation of proteins. This can have a direct effect on protein function and might play a role in pathophysiology. In this review we describe several mouse and cell models for IEM that display high levels of lysine acylation. Furthermore, we discuss how sirtuins serve as a promising therapeutic target to restore acylation state and could treat IEMs. In this context we examine several pharmacological sirtuin activators, such as resveratrol, NAD⁺ precursors and PARP and CD38 inhibitors.     

Applications of mass spectrometry in the study of inborn errors of metabolism

During the twentieth century, and particularly in its last decade, there have been major advances in mass spectrometry (MS). As a result, MS remains one of the most powerful tools for the investigation of genetic metabolic disease. Analysis of organic acids by gas chromatography–mass spectrometry (GC-MS) and analysis of acylcarnitines by tandem mass spectrometry are still leading to the discovery of new disorders. Tandem mass spectrometry is increasingly being used for neonatal screening. New methods for lipid analysis have opened up the fields of inborn errors of cholesterol synthesis, of bile acid synthesis and of leukotriene synthesis. The latest developments in MS allow it to be used for determination of the amino acid sequence and posttranslational modifications of proteins. There are still some major hurdles to be overcome, but soon it should be possible to detect mutant proteins directly rather than by cDNA or genomic DNA analysis. Measurement of which proteins are overexpressed and underexpressed (proteomics) should provide further information on the pathogenesis of complications of inborn errors, e.g. hepatic cirrhosis. The use of stable isotopes in conjunction with MS allows us to probe metabolic pathways. As an example, evidence is presented to support the contention that vitamin E and its oxidation product are catabolized by peroxisomal -oxidation. Mass spectrometry also has a major role in monitoring new forms of treatment for inborn errors.     

Small molecules as therapeutic agents for inborn errors of metabolism

Most inborn errors of metabolism (IEM) remain without effective treatment mainly due to the incapacity of conventional therapeutic approaches to target the neurological symptomatology and to ameliorate the multisystemic involvement frequently observed in these patients. However, in recent years, the therapeutic use of small molecules has emerged as a promising approach for treating this heterogeneous group of disorders. In this review, we focus on the use of therapeutically active small molecules to treat IEM, including readthrough agents, pharmacological chaperones, proteostasis regulators, substrate inhibitors, and autophagy inducers. The small molecules reviewed herein act at different cellular levels, and this knowledge provides new tools to set up innovative treatment approaches for particular IEM. We review the molecular mechanism underlying therapeutic properties of small molecules, methodologies used to screen for these compounds, and their applicability in preclinical and clinical practice.     

Signals on proteins,intracellular targeting and inborn errors of organellar metabolism

Summary Newly synthesized polypeptides contain signals that direct them to the appropriate intracellular organelles and the organelles contain receptors that recognize the signals. Protein synthesis occurs either on free ribosomes or on ribosomes bound to the endoplasmic reticulum. The proteins synthesized on bound ribosomes are co-translationally translocated into the lumen of the endoplasmic reticulum and contain or acquire targeting information for retention in the endoplasmic reticulum or for sorting to lysosomes and other compartments of the secretory and endocytic pathways. Proteins synthesized on free ribosomes remain in the cytosol or contain signals for import into the nucleus, mitochondria or peroxisomes. The nature of the targeting signals and the mechanisms of import are discussed briefly. Examples are given of inborn errors of metabolism caused by incorrect or impaired incorporation of proteins into mitochondria, lysosomes or peroxisomes.     

Modelling inborn errors of metabolism in zebrafish

The majority of human inborn errors of metabolism are fatal multisystem disorders that lack proper treatment and have a poorly understood mechanistic basis. Novel technologies are required to address this issue, and the use of zebrafish to model these diseases is an emerging field. Here we present the published zebrafish models of inborn metabolic diseases, discuss their validity, and review the novel mechanistic insights that they have provided. We also review the available methods for creating and studying zebrafish disease models, advantages and disadvantages of using this model organism, and successful examples of the use of zebrafish for drug discovery and development. Using a zebrafish to model inborn errors of metabolism in vivo, although still in its infancy, shows promise for a deeper understanding of disease pathomechanisms, onset, and progression, and also for the development of specific therapies.     

Severe infectious diseases of childhood as monogenic inborn errors of immunity

This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.This paper reviews the monogenic inborn errors of immunity that have been shown to underlie resistance or vulnerability to human infectious diseases. These studies, first conducted in the 1970s, gained momentum from the mid-1990s onward. The analysis of Mendelian traits was followed by that of non-Mendelian monogenic traits, characterized by incomplete clinical penetrance and variable expressivity.     

Epilepsy and inborn errors of metabolism in children

Epilepsy is a frequent symptom in inborn errors of metabolism, with virtually no specific seizure types or EEG signatures. It is most important to look quickly for those few inborn errors of metabolism in which specific therapies such as supplementation of cofactors or diets can make all the difference. If these investigations remain negative, epilepsy has to be treated with conventional antiepileptic drugs. Still, epilepsy is a potentially treatable symptom of many inborn errors of metabolism, and optimal treatment is of great importance for patients and their families.     

Cultural aspects in the management of inborn errors of metabolism

European Health Care Systems have not yet accommodated both previous and current migration waves. Children from immigrant families, especially children with chronic conditions, are particularly affected from the shortcomings in medical care. One condition, phenylketonuria (PKU), is an inborn error of metabolism (IEM) which results in intellectual disability unless treated with a lifelong phenylalanine (Phe) restricted diet. In our PKU clinic, patients from families who previously had emmigrated from the geographic area of Turkey to Austria, exhibited worse blood Phe control and cognitive development than comparable patients from native Austrian families. Using structured and semi-structured interviews, questionnaires, and illness narratives, we identified language, psychosocial, economic, educational and cultural barriers as factors influencing adherence to treatment. Our findings led us to conclude that access to interpreter services, exploration of the socio-cultural background and of family ecology, as well as bi-directional communication and medical decision making according to the "best interest of the child" principle, may improve outcomes in patients requiring complex treatment and care.     

Sources of propionate in inborn errors of propionate metabolism

Amino acids are widely regarded as the most important sources of propionate in disorders of propionate metabolism. Propionate production was measured in the fasting state by continuous infusion of sodium [1-13C]propionate in three children with methylmalonic acidemia (MMA) and three with propionic acidemia (PA). The contribution of isoleucine, valine, threonine, and methionine catabolism to total propionate production was estimated by extrapolation from the hydroxylation of phenylalanine determined by a continuous-infusion [2H5]phenylalanine technique. The contribution of gut bacterial propionate production was determined by measuring total propionate production before and after treatment with oral metronidazole (10 to 20 mg/kg/d for 1 week). Amino acid catabolism accounted for a mean of 51.7% (range, 24.5% to 66.4%) of total propionate production. The mean decrease in propionate production after metronidazole was 22.2% +/- 8.5 (P less than .02); this percentage is likely to represent the minimum propionate production attributable to gut bacteria. Approximately 30% of total propionate production was unaccounted for, and is likely to arise primarily from odd-chain fatty acid catabolism in the fasting state. These results indicate that sources of propionate other than from protein catabolism are important in disorders of propionate metabolism, and explain the generally disappointing response to dietary protein restriction.     

以癫痫为主要表现的儿童遗传代谢性疾病

目的提高对遗传代谢性疾病所致儿童癫痫的认识。方法采用回顾性方法,对我院以癫痫发作为主诉就诊,经血氨、乳酸、血同型半胱氨酸、尿有机酸气相色谱质谱联用分析、骨髓涂片、脑脊液检查、溶酶体酶活性分析、线粒体基因检测、线粒体酶活性分析确诊的先天代谢性缺陷病26例患儿的临床表现、生化特点以及诊疗情况进行回顾和分析。结果所有患儿均有癫痫发作,以部分性发作、痉挛发作为最常见发作形式,少数患者可有肌阵挛发作。患者多有不同程度的体格或智力运动发育迟滞,年长儿发病的线粒体脑肌病患者发病前智力正常,发病后出现智力运动倒退。脑电图表现以多灶独立性棘波、高度失律、背景慢波为主要表现。患者癫痫发作多难以控制,部分患者对因治疗后癫痫发作明显好转。结论先天代谢性疾病是儿童癫痫的病因之一;临床上应根据患儿发病急缓、生长发育、智力行为等,选择适宜的检查,以早期诊断。除了抗癫痫治疗以外,应根据不同的病因给予病因治疗。