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Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma‐aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma‐hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next‐generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4‐guanidinobutanoic acid, and 2‐hydroxyglutaric acid, and prominent elevations of GHB and 4,5‐dihydroxyhexanoic acid (4,5‐DHHA) in SSADHD samples. Remarkably, the intensities of 4,5‐DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5‐DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5‐DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5‐dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology. [ABSTRACT FROM AUTHOR]

We used next‐generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose‐α1‐3‐glucose, and xylose‐α1‐3‐xylose‐α1‐3‐glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose‐α1‐3‐glucose and xylose‐α1‐3‐xylose‐α1‐3‐glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O‐glucosylation. Since many proteins are O‐glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake. [ABSTRACT FROM AUTHOR]

BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC). [ABSTRACT FROM AUTHOR]

Huppke-Brendel syndrome (HBS) is an autosomal recessive disorder caused by SLC33A1 mutations, a gene coding for the acetyl-CoA transporter-1 (AT-1). So far it has been described in nine pediatric and one adult patient. Therapeutic trials with copper histidinate failed to achieve any clinical improvement. Here, we describe the clinical characteristics of two novel patients, one of them diagnosed by gene analysis and his sib postmortally based on clinical characteristics. We demonstrate a therapeutic trial with acetylation therapy, consisting of N-acetylcysteine and ketogenic diet, in one of them. We provide biochemical data on N-acetylated amino acids in cerebrospinal fluid (CSF) and plasma before and after starting this treatment regimen. Our results indicate that ketogenic diet and N-acetylcysteine do not seem to normalize the concentrations of N-acetylated amino acids in CSF or plasma. The overall metabolic pattern shows a trend toward lowered levels of N-acetylated amino acids in CSF and to a lesser extent in plasma. Although there are some assumptions, the function of AT-1 is still not clear and further studies are needed to better understand mechanisms underlying this complex disorder., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Distinguishing isomeric saccharides poses a major challenge for analytical workflows based on (liquid chromatography) mass spectrometry (LC-MS). In recent years, many studies have proposed infrared ion spectroscopy as a possible solution as the orthogonal, spectroscopic characterization of mass-selected ions can often distinguish isomeric species that remain unresolved using conventional MS. However, the high conformational flexibility and extensive hydrogen bonding in saccharides cause their room-temperature fingerprint infrared spectra to have broad features that often lack diagnostic value. Here, we show that room-temperature infrared spectra of ion-complexed saccharides recorded in the previously unexplored far-infrared wavelength range (300-1000 cm -1 ) provide well-resolved and highly diagnostic features. We show that this enables distinction of isomeric saccharides that differ either by their composition of monosaccharide units and/or the orientation of their glycosidic linkages. We demonstrate the utility of this approach from single monosaccharides up to isomeric tetrasaccharides differing only by the configuration of a single glycosidic linkage. Furthermore, through hyphenation with hydrophilic interaction liquid chromatography, we identify oligosaccharide biomarkers in patient body fluid samples, demonstrating a generalized and highly sensitive MS-based method for the identification of saccharides found in complex sample matrices.

Introduction: Current guidelines for clinical biobanking have a strong focus on obtaining, handling, and storage of biospecimens. However, to allow for research tying biomarker analysis to clinical decision making, there should be more focus on collection of data on donor characteristics. Therefore, our aim was to develop a stepwise procedure to define a framework as a tool to help start the data collection process in clinical biobanking., Materials and Methods: The Radboud Biobank (RB) is a central clinical biobanking facility designed in accordance with the standards set by the Parelsnoer Institute, a Dutch national biobank originally initiated with eight different disease cohorts. To organize the information of these cohorts, we used our experience and knowledge in the field of biobanking and translational research to identify research domains and information categories to classify data. We extended this classification system to a stepwise procedure for defining a data collection framework and examined its utility for existing RB biobanks., Results: Our approach resulted in the definition of a three-step procedure: (1) Identification of research domains and relevant questions within the field that may benefit from biobank samples. (2) Identification of information categories and accompanying subcategories that are relevant for answering questions in identified research domains. (3) Reduction to an efficient framework based on essentiality and quality criteria. We showed the utility of the procedure for three existing RB biobanks., Discussion: We developed guidelines for the definition of a framework that supports the standardization of the biobank data collection process. Connecting the biobank database to pertinent information collected from the electronic health record will improve data quality and efficiency for both care and research. This is crucial when using the corresponding biospecimens for scientific research. Further, it also facilitates the combination of different clinical biobanks for a specific disease.