Impact of newborn screening for fatty acid oxidation disorders on neurological outcome: A Belgian retrospective and multicentric study.

Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.

New Pathophysiological Insights from Serum Proteome Profiling in Equine Atypical Myopathy.

Equine atypical myopathy (AM) is a severe environmental intoxication linked to the ingestion of protoxins contained in seeds and seedlings of the sycamore maple (Acer pseudoplatanus) in Europe. The toxic metabolites cause a frequently fatal rhabdomyolysis syndrome in grazing horses. Since these toxic metabolites can also be present in cograzing horses, it is still unclear as to why, in a similar environmental context, some horses show signs of AM, whereas others remain clinically healthy. Label-free proteomic analyses on the serum of 26 diseased AM, 23 cograzers, and 11 control horses were performed to provide insights into biological processes and pathways. A total of 43 and 44 differentially abundant proteins between "AM vs cograzing horses" and "AM vs control horses" were found. Disease-linked changes in the proteome of different groups were found to correlate with detected amounts of toxins, and principal component analyses were performed to identify the 29 proteins representing a robust AM signature. Among the pathway-specific changes, the glycolysis/gluconeogenesis pathway, the coagulation/complement cascade, and the biosynthesis of amino acids were affected. Sycamore maple poisoning results in a combination of inflammation, oxidative stress, and impaired lipid metabolism, which is trying to be counteracted by enhanced glycolysis.

Large-scale study of blood markers in equine atypical myopathy reveals subclinical poisoning and advances in diagnostic and prognostic criteria.

Equine atypical myopathy (AM) is a severe rhabdomyolysis syndrome primarily caused by hypoglycin A (HGA) and methylenecyclopropylglycine protoxins. This study aimed to refine diagnostic and prognostic criteria for AM while exploring apparently healthy cograzers. Blood samples from 263 horses, including AM cases (n= 95), cograzers (n= 73), colic horses (n= 19), and controls (n= 76), were analyzed for HGA, its toxic metabolite, and acylcarnitines profile. Diseased horses exhibited alterations in acylcarnitines that strongly distinguished them from controls and colic horses. Regression analyses identified distinct acylcarnitines profiles among groups, with cograzers showing intermediate alterations. Age and gelding status emerged as protective factors against AM. Furthermore, serum acylcarnitines profiling was valuable in predicting AM survival, with isovaleryl-/2-methylbutyrylcarnitine (i.e., C5 acylcarnitine) showing promise as both a diagnostic and prognostic marker. Subclinical alterations in cograzers underscore a novel aspect: the presence of subclinical cases of AM.

Determining the characteristics of genetic disorders that predict inclusion in newborn genomic sequencing programs.

Over 30 international research studies and commercial laboratories are exploring the use of genomic sequencing to screen apparently healthy newborns for genetic disorders. These programs have individualized processes for determining which genes and genetic disorders are queried and reported in newborns. We compared lists of genes from 26 research and commercial newborn screening programs and found substantial heterogeneity among the genes included. A total of 1,750 genes were included in at least one newborn genome sequencing program, but only 74 genes were included on >80% of gene lists, 16 of which are not associated with conditions on the Recommended Uniform Screening Panel. We used a linear regression model to explore factors related to the inclusion of individual genes across programs, finding that a high evidence base as well as treatment efficacy were two of the most important factors for inclusion. We applied a machine learning model to predict how suitable a gene is for newborn sequencing. As knowledge about and treatments for genetic disorders expand, this model provides a dynamic tool to reassess genes for newborn screening implementation. This study highlights the complex landscape of gene list curation among genomic newborn screening programs and proposes an empirical path forward for determining the genes and disorders of highest priority for newborn screening programs.

270th ENMC International Workshop: Consensus for SMN2 genetic analysis in SMA patients 10-12 March, 2023, Hoofddorp, the Netherlands.

The 270th ENMC workshop aimed to develop a common procedure to optimize the reliability of SMN2 gene copy number determination and to reinforce collaborative networks between molecular scientists and clinicians. The workshop involved neuromuscular and clinical experts and representatives of patient advocacy groups and industry. SMN2 copy number is currently one of the main determinants for therapeutic decision in SMA patients: participants discussed the issues that laboratories may encounter in this molecular test and the cruciality of the accurate determination, due the implications as prognostic factor in symptomatic patients and in individuals identified through newborn screening programmes. At the end of the workshop, the attendees defined a set of recommendations divided into four topics: SMA molecular prognosis assessment, newborn screening for SMA, SMN2 copies and treatments, and modifiers and biomarkers. Moreover, the group draw up a series of recommendations for the companies manufacturing laboratory kits, that will help to minimize the risk of errors, regardless of the laboratories' expertise.

Untargeted Metabolomics Profiling Reveals Exercise Intensity-Dependent Alterations in Thoroughbred Racehorses' Plasma after Routine Conditioning Sessions.

Thoroughbred (TB) racehorses undergo rigorous conditioning programs to optimize their physical and mental capabilities through varied exercise sessions. While conventional investigations focus on limited hematological and biochemical parameters, this field study employed untargeted metabolomics to comprehensively assess metabolic responses triggered by exercise sessions routinely used in TB conditioning. Blood samples were collected pre- and post-exercise from ten racehorses, divided into two groups based on exercise intensity: high intensity (n = 6, gallop at ± 13.38 m/s, 1400 m) and moderate intensity (n = 4, soft canter at ± 7.63 m/s, 2500 m). Intensity was evaluated through monitoring of the speed, heart rate, and lactatemia. Resting and 30 min post-exercise plasma samples were analyzed using ultraperformance liquid chromatography coupled with high-resolution mass spectrometry. Unsupervised principal component analysis revealed exercise-induced metabolome changes, with high-intensity exercise inducing greater alterations. Following high-intensity exercise, 54 metabolites related to amino acid, fatty acid, nucleic acid, and vitamin metabolism were altered versus 23 metabolites, primarily linked to fatty acid and amino acid metabolism, following moderate-intensity exercise. Metabolomics confirmed energy metabolism changes reported by traditional biochemistry studies and highlighted the involvement of lipid and amino acid metabolism during routine exercise and recovery, aspects that had previously been overlooked in TB racehorses.

Cribado neonatal de la atrofia muscular espinal: el momento es ahora / Neonatal screening for spinal muscular atrophy: the time is now

La atrofia muscular espinal (AME) es la enfermedad neurodegenerativa más común en la infancia. La aprobación reciente de nuevas terapias efectivas ha justificado la implementación desde hace dos años de un programa piloto de cribado neonatal en la Federación Valonia Bruselas (FWB).Se describe el procedimiento de cribado neonatal utilizado actualmente para detección para la AME en recién nacidos en el sur de Bélgica. El coste del cribado es de 3,10 € por niño. Si se mantiene esta configuración, representa un coste anual de 181 000 € (por aproximadamente 60 000 nacimientos anuales en FWB).En el contexto de contar con un método de cribado neonatal fiable, con un coste económico moderado y la posibilidad de un tratamiento inmediato viable, los autores recomiendan la inclusión y financiación del despistaje de la atrofia muscular espinal en la lista de enfermedades incluidas oficialmente en el marco del cribado neonatal. (AU)

Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. The recent approval of new effective therapies has justified the implementation of a pilot neonatal screening program in the Federation Wallonia Brussels (FWB).The neonatal screening procedure currently used for screening for SMA in newborns in southern Belgium is described. The cost of screening is € 3.10 per child. If this configuration is maintained, it represents an annual cost of € 181,000 (for approximately 60,000 annual births in FWB).In the context of having a reliable neonatal screening method, with a moderate economic cost and the possibility of a viable immediate treatment, the authors recommend the inclusion and financing of the screening for the spinal muscular atrophy in the list of diseases officially included in the framework of the neonatal screening program. (AU)

Falsos positivos de C5-carnitina elevada en cribado neonatal: ¿a qué son debidos? / C5-carnitine false positive results in newborn screening: What is the cause?

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