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We describe a neonate and a 14-month-old child presenting with seizures that were not (completely) controlled with antiepileptic medications. There were no signs of infection, and electrolytes and neuroimaging were normal. In the neonate, pyridoxine was administered followed by cessation of seizures, and a diagnosis of pyridoxine-dependent epilepsy (PDE-ALDH7A1, a neurometabolic disorder of lysine metabolism) was genetically confirmed. The 14-month-old child received a genetic diagnosis of PDE-ALDH7A1 after abnormalities in the metabolic investigations. Both children were treated with pyridoxine and adjunct lysine reduction therapy (LRT). Seizures were controlled completely, but both children are developmentally delayed. During her second pregnancy, the mother of the neonate was started on pyridoxine treatment because of the risk of PDE-ALDH7A1. After delivery, pyridoxine treatment was continued in the neonate, who did not show any clinical symptoms. Molecular analysis identified the familial variants consistent with the diagnosis of PDE-ALDH7A1. Adjunct LRT was initiated. This child has never experienced seizures, and development has been completely normal thus far (age 2.9 years), despite the shared genotype with their sibling with developmental delays (DDs). In conclusion, in neonates, infants, and children presenting with seizures of unknown origin with partial or no response to common antiepileptic medications, the diagnosis of PDE-ALDH7A1 or other pyridoxine-responsive genetic epilepsies should be considered, prompting a trial of pyridoxine as “diagnostic therapeuticum.” The digital applicationTreatable-ID(treatable-id.org) can support clinicians in the early diagnosis of treatable conditions in patients presenting with DD/intellectual disability of unknown cause.

Contains fulltext : 248229.pdf (Publisher’s version ) (Closed access) BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. METHODS: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. RESULTS: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. CONCLUSION: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. TAKE- HOME MESSAGE: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome.

Purpose: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities.Methods: In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments.Results: Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (PLARS and PFARSB), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2–2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency.Conclusion: For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.

BackgroundThe 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.MethodsTwo 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.ResultsOur 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%.ConclusionThe 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.

Pyridoxine-dependent epilepsy due to mutations in ALDH7A1 (PDH-ALDH7A1) is a highly treatable developmental and epileptic encephalopathy. Pharmacologic doses of pyridoxine are associated with dramatic clinical seizure improvement, and most patients achieve adequate seizure control with pyridoxine alone. Unfortunately, some patients with PDE-ALDH7A1 have died prior to when the diagnosis was made and subsequent treatment with pyridoxine could be implemented, highlighting the importance of a timely diagnosis. Although critical for seizure control, pyridoxine treatment alone is not sufficient for normal outcomes as most patients suffer intellectual and developmental delay. Adjunct lysine reduction therapies are associated with significant developmental improvements, although these treatments have limited efficacy if delayed after the first few months of life. Recently two biomarkers were identified that overcome previous technical hurdles for newborn screening. Herein we provide commentary that PDE-ALDH7A1 meets both current and historic criteria for newborn screening, and that a neonatal diagnosis and treatment can both reduce mortality from uncontrolled seizures and significantly improve the cognitive delay that is pervasive in this treatable disorder.

Contains fulltext : 283153.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 237516.pdf (Publisher’s version ) (Open Access) 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).

Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5’-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Using a combination of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we have been able to discover novel biomarkers for PDE-ALDH7A1: 2S,6S-and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) and 6-oxopiperidine-2-carboxylic acid (6-oxoPIP). We demonstrate the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we show that 2-OPP accumulates in brain tissue of patients and Aldh7a1 knock-out mice, and induces epilepsy-like behavior in a zebrafish model system. 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.

PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) with only symptomatic therapy. Some CDG have been successfully treated with D-galactose. We performed an open-label pilot trial with D-galactose in 9 PMM2-CDG patients. Overall, there was no significant improvement but some milder patients did show positive clinical changes; also there was a trend toward improved glycosylation. Larger placebo-controlled studies are required to determine whether D-galactose could be used as supportive treatment in PMM2-CDG patients.Trial registration ClinicalTrials.gov Identifier: NCT02955264. Registered 4 November 2016, https://clinicaltrials.gov/ct2/show/NCT02955264

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of alpha-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.

Contains fulltext : 237469.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. METHODS: Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. RESULTS: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ > 85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5′ untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.

Item does not contain fulltext BACKGROUND: Studies on the outcome of ileocecal resection in pediatric Crohn's disease (CD) have a limited follow-up and fail to assign predictors of adverse outcomes. Therefore, we aimed to investigate (I) the complication and disease recurrence rates and (II) identify risk factors for these adverse outcomes after ileocecal resection for pediatric CD. METHODS: This is a retrospective cohort analysis of all children (

Objective—To evaluate a point-of-care coagulation analyzer (PCCA) in dogs with coagulopathies and healthy dogs. Animals—27 healthy and 32 diseased dogs with and without evidence of bleeding. Procedure—Prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT) were determined, using a PCCA and standard methods. Results—Using the PCCA, mean (± SD) PT of citrated whole blood (CWB) from healthy dogs was 14.5 ± 1.2 seconds, whereas PT of nonanticoagulated whole blood (NAWB) was 10.4 ± 0.5 seconds. Activated partial thromboplastin time using CWB was 86.4 ± 6.9 seconds, whereas aPTT was 71.2 ± 6.7 seconds using NAWB. Reference ranges for PT and aPTT using CWB were 12.2 to 16.8 seconds and 72.5 to 100.3 seconds, respectively. Activated clotting time in NAWB was 71 ± 11.8 seconds. Agreement with standard PT and aPTT methods using citrated plasma was good (overall agreement was 93% for PT and 87.5% for aPTT in CWB). Comparing CWB by the PCCA and conventional coagulation methods using citrated plasma, sensitivity and specificity were 85.7 and 95.5% for PT and 100 and 82.9% for aPTT, respectively. Overall agreement between the PCCA using NAWB and the clinical laboratory was 73% for PT and 88% for aPTT. Using NAWB for the PCCA and citrated plasma for conventional methods, sensitivity and specificity was 85.7 and 68.4% for PT and 86.7 and 88.9% for aPTT, respectively. Conclusions and Clinical Relevance—The PCCA detected intrinsic, extrinsic, and common pathway abnormalities in a similar fashion to clinical laboratory tests. (Am J Vet Res 2001;62:1455–1460)

The ultimate goal of this work is to accurately predict the resonance frequencies of large (on the order of 10 cm radius) encapsulated bubbles used in an underwater noise abatement system, and also to investigate ways to enhance the system's efficacy over the use of air-filled bubbles alone. Toward that end, a closed water-filled tank was developed for the purpose of measuring the resonance frequency and damping of single large tethered encapsulated bubbles. The tank was designed to be operated in the long wavelength limit for frequencies below the lowest tank resonance, which was near 350 Hz, using the method described by Leighton, et al. [J. Acoust. Soc. Am.112, 1366-1376 (2002)]. Individual bubble resonance frequencies and quality factors were measured for encapsulated bubbles of various sizes. The effects of the encapsulating material and wall thickness were investigated, along with the effects of alternative fill gases and internal heat transfer materials. The experimental results were compared with an existing predictive model [J. Acoust. Soc. Am. 97, 1510-1521 (1995)] of bubble resonance and damping.

Case Description—A 9-month-old domestic shorthair cat was evaluated after being struck by a car. Clinical Findings—The cat had a fractured tibia and avulsion of the tail base. Motor and deep pain sensation were absent from the tail. The fractured tibia was repaired 2 days after the trauma. On the third day, the cat developed tachypnea, dyspnea, high serum urea nitrogen and total bilirubin concentrations, epistaxis, persistent hypotension, and oliguria. The cat recovered with supportive care but developed extensive necrosis of the skin on the dorsum by 9 days after the initial trauma. Treatment and Outcome—The skin was debrided from the caudal portion of the scapula to the anus and down each pelvic limb to the level of the distal portion of the femur. The tail was amputated. Wet-to-dry bandages were applied to the wound for 3 days. Approximately 50% of the wound underwent delayed primary closure, and the remainder was managed with vacuum-assisted closure. A healthy granulation bed was quickly established. Vacuum-assisted closure was also applied after graft application. Graft acceptance was 100%, and use of the vacuum-assisted closure bandage was not associated with the complications associated with the traditional bandage. Clinical Relevance—Vacuum-assisted closure is a useful, easily applicable technique for open and grafted wounds, even when wounds are in challenging anatomic locations.

This paper investigates the near-resonance acoustical properties of submerged air-filled resonators intended for use in an underwater noise abatement system. These resonators are a potential alternative to encapsulated bubbles. The resonators are similar to Helmholtz resonators in shape and design, but without a neck, consisting of underwater inverted air-filled cavities with rigid walls. A finite element model was developed to investigate the acoustic behavior of the resonators near their resonance frequencies, and based on the results of the model, physical realizations of the resonators were designed and fabricated for testing. Experiments were performed with the resonators in a closed water-filled tank operated in the long wavelength limit [J. Acoust. Soc. Am. 132, 2039 (2012)], where their resonance frequencies and Q-factors were measured using the technique described by Leighton et al., [J. Acoust. Soc. Am. 112, 1366–1376 (2002)]. Comparison between the results from the measurements and modeling will be discussed. [Work supported by Shell Global Solutions.]

Respiratory distress is a very common presenting complaint in emergency practice. It is essential that the clinician rapidly determine the underlying cause of the clinical signs using physical examination findings and nonstressful diagnostic tests. Oxygen therapy will often stabilize a patient, allowing for a more complete physical examination and diagnostics, including thoracocentesis, thoracic radiographs, and blood collection for laboratory analysis. The disease processes that cause respiratory distress can be grouped according to anatomic location: the airways, pulmonary parenchyma, pleural space, or thoracic wall. The choice of diagnostic and therapeutic techniques will be dependent on the suspected anatomic origin of disease. Techniques useful in diagnosing airway disorders include oral examination, cervical and thoracic radiographs, fluoroscopy, and bronchoscopy. Therapeutic techniques include intubation and tracheostomy. For parenchymal disease, thoracic radiographs, echocardiography, ultrasound of the thorax, and transtracheal or endotracheal wash can be useful. When the disease process is in the pleural space, thoracocentesis can be both diagnostic and therapeutic. Chest tube placement may be necessary for continuous removal of air or fluid from the pleural space. Monitoring of the respiratory patient can involve serial physical examination, pulse oximetry, and arterial blood gas analysis. It is essential to minimize stress on patients with respiratory distress because decompensation can occur easily, leading to respiratory arrest.