Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient

Background: Primary hyperoxaluria type 1 (PH1) is a multisystemic metabolic disorder caused by an excessive production of oxalate by the liver. The majority of patients presenting in early infancy have end-stage renal disease (ESRD). While awaiting the results of sRNAi trials, the current standard treatment is combined liver-kidney transplantation. Recently, Stiripentol has been reported as a promising drug in the treatment of primary hyperoxaluria by reducing urinary oxalate (UOx). Stiripentol is an anti-convulsive drug used in the treatment of children suffering from Dravet syndrome. It causes blockage of the last step in oxalate production by inhibition of hepatic lactate dehydrogenase 5 (LDH5). Case: We administered Stiripentol as compassionate use in an anuric infant with dialysis-dependent PH1 over a period of 4 months. Although achieving plasma concentrations of Stiripentol that were recently reported to lower UOx excretion, we did not observe significant reduction to plasma oxalate concentrations (POx). Conclusion: We conclude that Stiripentol may not be useful to reduce POx in PH patients with advanced chronic kidney disease (CKD), but larger studies are needed to confirm this finding

Single-Pass Albumin Dialysis in the Treatment of Children with Liver Failure

Background and Aims: Acute and acute on chronic liver failure are life-threatening conditions, and bridging to transplantation is complicated by a paucity of suitable organs for children. While different modalities of extracorporeal liver support exist, their use in children is complicated by a large extracorporeal volume, and data on their use in children is limited. The aim of this analysis was to investigate the efficacy and safety of single-pass albumin dialysis (SPAD) in children with liver failure. Methods: Retrospective medical chart review of pediatric patients with liver failure treated with SPAD. The decrease in hepatic encephalopathy (HE) and the serum levels of bilirubin and ammonia were measured to determine efficacy. Adverse events were documented to assess safety. Results: Nineteen pediatric patients with a median age of 25.5 months and a median body weight of 11.9 kg were treated with SPAD between January 2011 and March 2018. Total bilirubin (p < 0.001) and ammonia (p = 0.02) significantly decreased after treatment with SPAD. As clinical outcome parameter, HE significantly improved (p = 0.001). Twelve patients were bridged successfully to liver transplantation. In all patients, 71 SPAD sessions were run. Clotting in the dialysis circuit was observed in 49% of all sessions. Heparin and citrate were used for anticoagulation and were significantly superior to dialysis without any anticoagulation (p= 0.03). Transfusion of packed blood cells (57%) and catecholamine therapy (49%) were frequently necessary. Conclusions: Treatment with SPAD was effective in detoxification, as measured by significant improvement of HE and clearance from surrogate laboratory parameters

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Monitoring CSF Proteome Alterations in Amyotrophic Lateral Sclerosis: Obstacles and Perspectives in Translating a Novel Marker Panel to the Clinic

<div><h3>Background</h3><p>Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials.</p> <h3>Methods and Findings</h3><p>CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay.</p> <h3>Conclusions</h3><p>ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be readily used to complement current ALS diagnostics and might also provide new insights into the pathomechanisms of this disease in the future.</p> </div

Structural features of phenol derivatives determining potency for activation of chloride currents via α(1) homomeric and α(1)β heteromeric glycine receptors

1. Phenol derivatives constitute a family of neuroactive compounds. The aim of our study was to identify structural features that determine their modulatory effects at glycine receptors. 2. We investigated the effects of four methylated phenol derivatives and two halogenated analogues on chloride inward currents via rat α(1) and α(1)β glycine receptors, heterologously expressed in HEK 293. 3. All compounds potentiated the effect of a submaximal glycine concentration in both α(1) homomeric and α(1)β glycine receptors. While the degree of maximum potentiation of the glycine 10 μM effect in α(1)β receptors was not different between the compounds, the halogenated compounds achieved half-maximum potentiating effects in the low μM range – at more than 20-fold lower concentrations compared with their nonhalogenated analogues (P<0.0001). The coactivating effect was over-ridden by inhibitory effects at concentrations >300 μM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC(50) for coactivation. 4. Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 μM) directly activated both α(1) and α(1)β receptors up to 30% of the maximum response evoked by 1000 μM glycine. 5. These results show that halogenation in the para position is a crucial structural feature for the potency of a phenolic compound to positively modulate glycine receptor function, while direct activation is only seen with high concentrations of compounds that carry at least two methyl groups. The presence of the β subunit is not required for both effects

ROC plot analysis with area under the curve of CSF classification of ALS/non-ALS spectra.

<p>The Random Forest and decision tree predictor assign a score between 0 ( = non-ALS) and 1 ( = ALS) to all spectra. A CSF sample that shows a higher score than a predefined cut-off is classified as an ALS sample. The ROC plot curve shows the sensitivity against the specificity for different cut-offs. The curves are color-coded according to the level of the cut-off. The results shown are for the Random Forest with the optimized set of 38 peaks.</p