We propose a nosology for inborn errors of metabolism that builds on their recent redefinition.
We established a strict definition of criteria to develop a self-consistent schema for inclusion of a ...disorder into the nosology.
We identified 1015 well-characterized inborn errors of metabolism described in the literature. In addition, there are 111 less well-characterized conditions that may be inborn errors but do not meet strict criteria for inclusion in the current nosology.
We provide a master list of all currently recognized inborn errors of metabolism grouped according to their pathophysiological basis, with the hope of setting a standard against which new errors should be defined, as well as to promote awareness and foster collaboration in the area. With the rapid advances in the field of genetics in recent years, it is likely that this nosology will need to be updated in the near future, a process that will benefit from broader input and collaboration of experts in the field to improve future versions of the proposed classification.
NAD+ homeostasis in human health and disease Zapata‐Pérez, Rubén; Wanders, Ronald J A; Karnebeek, Clara D M ...
EMBO molecular medicine,
07 July 2021, Letnik:
13, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Depletion of nicotinamide adenine dinucleotide (NAD+), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in ...humans. Primary deficiencies of NAD+ homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD+ homeostasis, such as increased NAD+ consumption or dietary deficiency of its vitamin B3 precursors. NAD+ depletion can manifest in a wide variety of pathological phenotypes, ranging from rare inherited defects, characterized by congenital malformations, retinal degeneration, and/or encephalopathy, to more common multifactorial, often age‐related, diseases. Here, we discuss NAD+ biochemistry and metabolism and provide an overview of the etiology and pathological consequences of alterations of the NAD+ metabolism in humans. Finally, we discuss the state of the art of the potential therapeutic implications of NAD+ repletion for boosting health as well as treating rare and common diseases, and the possibilities to achieve this by means of the different NAD+‐enhancing agents.
This comprehensive review discusses pathological consequences of NAD+ metabolism alterations and the therapeutic potential of NAD+ enhancers.
This study describes the cost trajectory of the standard diagnostic care pathway for children with suspected genetic disorders in British Columbia, Canada.
Average annual per-patient costs were ...estimated using medical records review and a caregiver survey for a cohort of 498 children referred to BC Children's and Women's Hospitals (C&W) with unexplained intellectual disability (the TIDE-BC study) and families enrolled in the CAUSES study, which offered diagnostic genome-wide sequencing (GWS; exome and genome sequencing) to 500 families of children with suspected genetic disorders.
Direct costs peaked in the first year of patients' diagnostic odyssey, with an average of C$2257 per patient (95% confidence interval CI C$2074, C$2441) for diagnostic testing and C$631 (95% CI C$543, C$727) for specialist consultations at C&W. In subsequent years, direct costs accrued at a constant rate, with an estimated annual per-patient cost of C$511 (95% CI C$473, C$551) for diagnostic testing and C$334 (95% CI C$295, C$369) for consultations at C&W. Travel costs and caregiver productivity loss associated with attending diagnosis-related physician appointments averaged C$1907/family/year.
The continuing long-term accrual of costs by undiagnosed patients suggests that economic evaluations of diagnostic GWS services should use longer time horizons than have typically been used.
Intellectual disability (‘developmental delay’ at age<5years) affects 2.5% of population worldwide. Recommendations to investigate genetic causes of intellectual disability are based on frequencies ...of single conditions and on the yield of diagnostic methods, rather than availability of causal therapy. Inborn errors of metabolism constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. To identify all currently treatable inborn errors of metabolism presenting with predominantly intellectual disability, we performed a systematic literature review.
We applied Cochrane Collaboration guidelines in formulation of PICO and definitions, and searched in Pubmed (1960–2011) and relevant (online) textbooks to identify ‘all inborn errors of metabolism presenting with intellectual disability as major feature’. We assessed levels of evidence of treatments and characterised the effect of treatments on IQ/development and related outcomes.
We identified a total of 81 ‘treatable inborn errors of metabolism’ presenting with intellectual disability as a major feature, including disorders of amino acids (n=12), cholesterol and bile acid (n=2), creatine (n=3), fatty aldehydes (n=1); glucose homeostasis and transport (n=2); hyperhomocysteinemia (n=7); lysosomes (n=12), metals (n=3), mitochondria (n=2), neurotransmission (n=7); organic acids (n=19), peroxisomes (n=1), pyrimidines (n=2), urea cycle (n=7), and vitamins/co-factors (n=8). 62% (n=50) of all disorders are identified by metabolic screening tests in blood (plasma amino acids, homocysteine) and urine (creatine metabolites, glycosaminoglycans, oligosaccharides, organic acids, pyrimidines). For the remaining disorders (n=31) a ‘single test per single disease’ approach including primary molecular analysis is required. Therapeutic modalities include: sick-day management, diet, co-factor/vitamin supplements, substrate inhibition, stemcell transplant, gene therapy. Therapeutic effects include improvement and/or stabilisation of psychomotor/cognitive development, behaviour/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=45), Level 4–5 (n=27). In clinical practice more than 60% of treatments with evidence level 4–5 is internationally accepted as ‘standard of care’.
This literature review generated the evidence to prioritise treatability in the diagnostic evaluation of intellectual disability. Our results were translated into digital information tools for the clinician (www.treatable-id.org), which are part of a diagnostic protocol, currently implemented for evaluation of effectiveness in our institution. Treatments for these disorders are relatively accessible, affordable and with acceptable side-effects. Evidence for the majority of the therapies is limited however; international collaborations, patient registries, and novel trial methodologies are key in turning the tide for rare diseases such as these.
► Our review identified 81 metabolic diseases causing intellectual disability. ► Diagnosis is established via screening tests and digital tools www.treatable-id.org. ► Therapeutic modalities (n=91) are generally affordable, accessible, and safe. ► Effects include improved primary (cognition / development) and secondary outcomes. ► Evidence is limited, but often therapies are effective and ‘standard of care’.
The implementation of whole-exome sequencing in clinical diagnostics has generated a need for functional evaluation of genetic variants. In the field of inborn errors of metabolism (IEM), a diverse ...spectrum of targeted biochemical assays is employed to analyze a limited amount of metabolites. We now present a single-platform, high-resolution liquid chromatography quadrupole time of flight (LC-QTOF) method that can be applied for holistic metabolic profiling in plasma of individual IEM-suspected patients. This method, which we termed “next-generation metabolic screening” (NGMS), can detect >10,000 features in each sample. In the NGMS workflow, features identified in patient and control samples are aligned using the “various forms of chromatography mass spectrometry (XCMS)” software package. Subsequently, all features are annotated using the Human Metabolome Database, and statistical testing is performed to identify significantly perturbed metabolite concentrations in a patient sample compared with controls. We propose three main modalities to analyze complex, untargeted metabolomics data. First, a targeted evaluation can be done based on identified genetic variants of uncertain significance in metabolic pathways. Second, we developed a panel of IEM-related metabolites to filter untargeted metabolomics data. Based on this IEM-panel approach, we provided the correct diagnosis for 42 of 46 IEMs. As a last modality, metabolomics data can be analyzed in an untargeted setting, which we term “open the metabolome” analysis. This approach identifies potential novel biomarkers in known IEMs and leads to identification of biomarkers for as yet unknown IEMs. We are convinced that NGMS is the way forward in laboratory diagnostics of IEMs.
The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay ...and intellectual disability (collectively 'treatable IDs'). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation.
Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classification of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features.
Our review identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case-control studies) for 19% and 4-5 (case-report, expert opinion) for 81% of treatments. Reported effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%.
The number of treatable IDs identified by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.
Inborn disorders of the malate aspartate shuttle Broeks, Melissa H.; Karnebeek, Clara D. M.; Wanders, Ronald J. A. ...
Journal of inherited metabolic disease,
July 2021, Letnik:
44, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two ...isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to the electron carrier NADH. By shuttling NADH across the mitochondrial membrane in the form of a reduced metabolite (malate), the MAS plays an important role in mitochondrial respiration. In addition, the MAS maintains the cytosolic NAD+/NADH redox balance, by using redox reactions for the transfer of electrons. This explains why the MAS is also important in sustaining cytosolic redox‐dependent metabolic pathways, such as glycolysis and serine biosynthesis. The current review provides insights into the clinical and biochemical characteristics of MAS deficiencies. To date, five out of seven potential MAS deficiencies have been reported. Most of them present with a clinical phenotype of infantile epileptic encephalopathy. Although not specific, biochemical characteristics include high lactate, high glycerol 3‐phosphate, a disturbed redox balance, TCA abnormalities, high ammonia, and low serine, which may be helpful in reaching a diagnosis in patients with an infantile epileptic encephalopathy. Current implications for treatment include a ketogenic diet, as well as serine and vitamin B6 supplementation.
Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks ...for hepatocellular carcinoma. An effective medical treatment with 2-2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.
Untargeted liquid chromatography–mass spectrometry (LC–MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The ...long-standing “grand challenge” in the utilization of this approach is metabolite identificationconfidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC–MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of α-aminoadipic semialdehyde (α-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While α-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics–IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.
Abstract Background Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive epileptic encephalopathy caused by Antiquitin (ATQ, ALDH7A1 ) deficiency. Despite adequate seizure control, 75% ...of patients suffer intellectual developmental disability. ATQ deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde (α-AASA) / pyrroline 6’ carboxylate (P6C) and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurologic manifestations and metabolic / biochemical findings have been reported. Methods and Results Here we present a phenotypic spectrum of ATQ deficiency, based on a literature review (2006-2015) of all reports (n=49) describing the clinical presentation of confirmed patients (n>200), and a further 6 case vignettes. Possible presentations include perinatal asphyxia, neonatal withdrawal syndrome, sepsis, enterocolitis, hypoglycaemia, neuro-imaging abnormalities (corpus callosum and cerebellar abnormalities, haemorrhage, white matter lesions), biochemical abnormalities (lactic acidosis, electrolyte disturbances, neurotransmitter abnormalities) and seizure response to pyridoxine, pyridoxal-phosphate, and folinic acid dietary interventions. Discussion The phenotypic spectrum of pyridoxine-dependent epilepsy is wide, including a myriad of neurological and systemic symptoms. Its hallmark feature is seizures during the first year of life, which are either partially or not amenable to anti-seizure medications. Given its amenability to treatment with lysine lowering strategies in addition to pyridoxine supplementation for optimal seizure control and developmental outcomes, early diagnosis of PDE is essential. All infants presenting with unexplained seizures should be screened for ATQ deficiency by determination of α-AASA / P6C (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis.