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.

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.

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.

Mid-Term Evolution of the Serum Acylcarnitine Profile in Critically Ill Survivors: A Metabolic Insight into Survivorship.

It is unknown if the abnormal acylcarnitine (AC) profile observed early after discharge of a prolonged stay in an intensive care unit (ICU) would persist over time. This prospective observational study aimed to describe the mid-term AC profile evolution in survivors of a prolonged ICU stay (≥7 days). Adults enrolled in our post-ICU follow-up program and who attended the consultation 3 months (M3) after discharge were included. Serum AC concentrations were assessed within 7 days following ICU discharge (T0) and at M3. A total of 64 survivors were analyzed after an ICU stay of 15 (9-24) days. Free carnitine (C0) concentration decreased from 45.89 (35.80-127.5) to 28.73 (20.31-38.93) µmol/L (p < 0.001). C0 deficiency was not observed at T0 but in 7/64 (11%) survivors at M3. The total AC/C0 ratio (normal ≤ 0.4) was 0.33 (0.24-0.39) at T0 and reached 0.39 (0.30-0.56) at M3 (p = 0.001). A ratio >0.4 was observed in 16/64 (25%) at T0 and in 32/64 (50%) at M3 (p = 0.006). The short-chain ACs decreased from 1.310 (0.927-1.829) at T0 to 0.945 (0.709-1.127) µmol/L at M3 (p < 0.001). In parallel, the urea/creatinine ratio and the Sarcopenic Index, respectively, decreased and increased between T0 and M3. This AC profile is suspected to signal a mitochondrial dysfunction and was, especially for short-chain ACs, a marker of protein catabolism.

Tissue Specific Distribution and Activation of Sapindaceae Toxins in Horses Suffering from Atypical Myopathy.

Equine atypical myopathy is caused by hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG), the known protoxins of sycamore maple (Acer pseudoplatanus). Various tissues from five atypical myopathy cases were analyzed but only HGA was found. Whether deamination of MCPrG has already occurred in the intestine as the first stage of metabolization has not been investigated. Activation of the protoxins to methylenecyclopropylacetyl (MCPA)-CoA and methylenecyclopropylformyl (MCPF)-CoA, respectively, occurred mainly in the skeletal muscles, as evidenced by very high concentrations of MCPA-carnitine and MCPF-carnitine in this tissue. Inhibition of the acyl-CoA dehydrogenases of short- and medium-chain as well as branched-chain fatty acids by the toxins led to a strong increase in the corresponding acylcarnitines, again preferentially in skeletal muscles. An accumulation of the long-chain acylcarnitines beyond the level of the control samples could not be detected in the tissues. As a high amount of HGA was always found unmetabolized in the organs, we speculate that targeting the interruption of further metabolization might be a way to stop the progression of intoxication. Inhibition of the mitochondrial branched-chain amino acid aminotransferase, i.e., the first enzyme responsible for the activation of sycamore maple protoxins, could be a therapeutic approach.

Newborn screening for sickle cell disease in Kisangani, Democratic Republic of the Congo: an update.

BACKGROUND: Neonatal screening is the first action necessary to identify children with sickle cell disease (SCD) and thus ensure their care. Using rapid tests to give an immediate result to families is a new resilient approach of great interest. These two aspects are essential for establishing an adequate health policy for this disease. This study was undertaken in Kisangani to update the current incidence of neonatal SCD. METHODS: Heel prick blood samples of 1432 babies born from different racial groups of parents living in Kisangani were collected at birth and screened using a point of care test, i.e. the HemoTypeSCTM. RESULTS: The incidence at birth was 2.2% (n = 31; 95% CI: [1.5%-3.1%]) for HbSS homozygosity and 21% (n = 303; 95% CI: [19%-23%]) for HbAS heterozygosity. Compared to a previous study in 2010; the incidence at the birth of the HbSS form has doubled, while that of the heterozygous form HbAS remained almost unchanged. The inter-ethnic incidence of HbSS among the five top-represented ethnic groups was significant (<0.001). CONCLUSION: The prevalence of homozygote form has doubled compared to the 0.96% reported in 2010. Setting up a neonatal screening program and an awareness unit is necessary to assess the need for care services correctly.

Serum Acylcarnitines Profile in Critically Ill Survivors According to Illness Severity and ICU Length of Stay: An Observational Study.

The acylcarnitine (AC) profile has been shown to be altered in survivors of a prolonged stay in intensive care unit (ICU), with higher short-chain derivates compared to reference ranges. The present study aimed at describing the AC profile of patients surviving a short ICU stay versus patients surviving a >7-day multiple organ dysfunction. Patients discharged from ICU after an elective and non-complicated cardiac surgery (CS) were recruited. For each CS, one to two adults, matched for gender and age, were recruited among patients enrolled in our post-ICU follow-up program after an ICU stay ≥7 days (PS). In both groups, the AC profile was determined during the week following ICU discharge. A total of 50 CS patients (SAPS II 23 (18-27)) survived an ICU stay of 2 (2-3) days and were matched to 85 PS patients (SAPS II 36 (28-51), p < 0.001) who survived an ICU stay of 11 (8-15.5) days. No carnitine deficiency was observed in either group. Their total AC/C0 ratio was similar: 0.355 (0.268-0.415) and 0.358 (0.289-0.417), respectively (p = 0.391). A ratio >0.4 representing a disturbed mitochondrial metabolism was observed in 26/85 (30.6%) PS patients and in 15/50 (30%) CS patients (p > 0.999). The long-chain ACs were elevated in both groups, with a greater increase in the CS group. The short-chain ACs were higher in the PS group: 1.520 (1.178-1.974) vs. 1.185 (0.932-1.895) µmol/L (p < 0.001). The role of the AC profile as potential marker of catabolism and/or mitochondrial dysfunction during the critical illness trajectory should be further investigated.

Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry.

BACKGROUND: Expanded newborn screening using tandem mass spectrometry (MS/MS) for inborn errors of metabolism (IEM), such as organic acidemias (OAs), fatty acid oxidation disorders (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in Africa. With this study, we aim to establish the disease spectrum and frequency of inborn errors of OAs, FAODs, and AAs in Morocco. METHODS: Selective screening was performed among infants and children suspected to be affected with IEM between 2016 and 2021. Amino acids and acylcarnitines spotted on filter paper were analyzed using MS/MS. RESULTS: Out of 1178 patients with a clinical suspicion, 137 (11.62%) were diagnosed with IEM, of which 121 (88.3%) patients suffered from amino acids disorders, 11 (8%) were affected by FAOD, and 5 (3.7%) by an OA. CONCLUSIONS: This study shows that various types of IEM are also present in Morocco. Furthermore, MS/MS is an indispensable tool for early diagnosis and management of this group of disorders.

Rapid Whole Genome Sequencing Diagnoses and Guides Treatment in Critically Ill Children in Belgium in Less than 40 Hours.

Rapid Whole Genome Sequencing (rWGS) represents a valuable exploration in critically ill pediatric patients. Early diagnosis allows care to be adjusted. We evaluated the feasibility, turnaround time (TAT), yield, and utility of rWGS in Belgium. Twenty-one unrelated critically ill patients were recruited from the neonatal intensive care units, the pediatric intensive care unit, and the neuropediatric unit, and offered rWGS as a first tier test. Libraries were prepared in the laboratory of human genetics of the University of Liège using Illumina DNA PCR-free protocol. Sequencing was performed on a NovaSeq 6000 in trio for 19 and in duo for two probands. The TAT was calculated from the sample reception to the validation of results. Clinical utility data were provided by treating physicians. A definite diagnosis was reached in twelve (57.5%) patients in 39.80 h on average (range: 37.05-43.7). An unsuspected diagnosis was identified in seven patients. rWGS guided care adjustments in diagnosed patients, including a gene therapy, an off-label drug trial and two condition-specific treatments. We successfully implemented the fastest rWGS platform in Europe and obtained one of the highest rWGS yields. This study establishes the path for a nationwide semi-centered rWGS network in Belgium.

BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening.

There are few causes of treatable neurodevelopmental diseases described to date. Branched-chain ketoacid dehydrogenase kinase (BCKDK) deficiency causes branched-chain amino acid (BCAA) depletion and is linked to a neurodevelopmental disorder characterized by autism, intellectual disability and microcephaly. We report the largest cohort of patients studied, broadening the phenotypic and genotypic spectrum. Moreover, this is the first study to present newborn screening findings and mid-term clinical outcome. In this cross-sectional study, patients with a diagnosis of BCKDK deficiency were recruited via investigators' practices through a MetabERN initiative. Clinical, biochemical and genetic data were collected. Dried blood spot (DBS) newborn screening (NBS) amino acid profiles were retrieved from collaborating centres and compared to a healthy newborn reference population. Twenty-one patients with BCKDK mutations were included from 13 families. Patients were diagnosed between 8 months and 16 years (mean: 5.8 years, 43% female). At diagnosis, BCAA levels (leucine, valine and isoleucine) were below reference values in plasma and in CSF. All patients had global neurodevelopmental delay; 18/21 had gross motor function (GMF) impairment with GMF III or worse in 5/18, 16/16 intellectual disability, 17/17 language impairment, 12/17 autism spectrum disorder, 9/21 epilepsy, 12/15 clumsiness, 3/21 had sensorineural hearing loss and 4/20 feeding difficulties. No microcephaly was observed at birth, but 17/20 developed microcephaly during follow-up. Regression was reported in six patients. Movement disorder was observed in 3/21 patients: hyperkinetic movements (1), truncal ataxia (1) and dystonia (2). After treatment with a high-protein diet (≥ 2 g/kg/day) and BCAA supplementation (100-250 mg/kg/day), plasma BCAA increased significantly (P < 0.001), motor functions and head circumference stabilized/improved in 13/13 and in 11/15 patients, respectively. Among cases with follow-up data, none of the three patients starting treatment before 2 years of age developed autism at follow-up. The patient with the earliest age of treatment initiation (8 months) showed normal development at 3 years of age. NBS in DBS identified BCAA levels significantly lower than those of the normal population. This work highlights the potential benefits of dietetic treatment, in particular early introduction of BCAA. Therefore, it is of utmost importance to increase awareness about this treatable disease and consider it as a candidate for early detection by NBS programmes.

Financial cost and quality of life of patients with spinal muscular atrophy identified by symptoms or newborn screening.

AIM: To compare the societal financial costs and quality of life (QoL) of untreated patients with spinal muscular atrophy (SMA) and treated patients identified because they presented symptoms or were identified by early testing (sibling or newborn screening). METHOD: Data from two different sources were used: data collected prospectively in untreated patients from 2016 to 2018 and data collected during a prospective follow-up study from 2018 to 2021. Patients or their caregiver completed a questionnaire that included questions on direct medical and non-medical costs, indirect non-medical costs, and health-related QoL. RESULTS: Data (median; range) were available for 149 patients (93 untreated - 10 years; 2 years-59 years), 42 patients (6 years 3 months; 9 months-58 years) treated after presenting with symptoms, and 14 patients (1 year 7 months; 5 months-2 years) treated after early diagnosis. Total costs were lower in untreated patients due to the high cost of drugs used in treated patients. Costs were lower for treated patients who were identified by early testing than for treated patients identified because they presented with symptoms. In all groups, patients with two SMN2 copies had higher costs than those with more copies. INTERPRETATION: Early patient identification and treatment offer the opportunity to reduce the total societal costs of SMA where treatments are available for presymptomatic and postsymptomatic patients. WHAT THIS PAPER ADDS: Untreated patients with spinal muscular atrophy had lower total financial costs than treated patients. Total financial costs were lower for treated patients identified by early screening than for treated patients identified after symptom onset. Direct financial costs excluding treatment were much lower in treated patients identified by early screening. Hospitalization costs were much lower in patients identified by early screening.

COSTO ECONÓMICO Y CALIDAD DE VIDA DE PACIENTES CON ATROFIA MUSCULAR ESPINAL IDENTIFICADOS POR SÍNTOMAS O CRIBADO NEONATAL: OBJETIVO: Comparar los costos financieros sociales y la calidad de vida (QoL) de pacientes no tratados con atrofia muscular espinal (AME) y pacientes tratados, identificados porque presentaron síntomas o fueron identificados mediante pruebas tempranas (cribado de hermanos o recién nacidos). MÉTODO: Se utilizaron datos de dos fuentes diferentes: datos recopilados prospectivamente en pacientes no tratados de 2016 a 2018 y datos recopilados durante un estudio de seguimiento prospectivo de 2018 a 2021. Los pacientes o sus cuidadores completaron un cuestionario que incluía preguntas sobre cuestiones médicas y no médicas directas. -costos médicos, costos indirectos no médicos y calidad de vida relacionada con la salud. RESULTADOS: Los datos (mediana; rango) estaban disponibles para 149 pacientes (93 sin tratamiento - 10 años; 2 años - 59 años), 42 pacientes (6 años 3 meses; 9 meses - 58 años) tratados después de presentar síntomas y 14 pacientes (1 año 7 meses; 5 meses-2 años) tratados tras un diagnóstico precoz. Los costos totales fueron menores en los pacientes no tratados debido al alto costo de los medicamentos utilizados en los pacientes tratados. Los costos fueron más bajos para los pacientes tratados que fueron identificados mediante pruebas tempranas que para los pacientes tratados identificados porque presentaban síntomas. En todos los grupos, los pacientes con dos copias de SMN2 tuvieron costos más altos que aquellos con más copias. INTERPRETACIÓN: La identificación y el tratamiento tempranos de los pacientes ofrecen la oportunidad de reducir los costos sociales totales de la AME, en lugares donde los tratamientos están disponibles para pacientes presintomáticos y postsintomáticos.

Pairing parents and offspring's HemoTypeSC Test to validate results and confirm sickle cell pedigree: a case study in Kisangani, the Democratic Republic of the Congo.

OBJECTIVES: HemoTypeSCTM is one of the immunoassay methods currently used for the early diagnosis of Sickle Cell Disease (SCD) in newborns. Earlier diagnosis remains the key strategy for early preventive care needs and parents' education about the child's future well-being throughout his life. Before considering these children as sick and aligning them for regular medical monitoring, it may be valuable to confirm the HemoTypeSC result with a secondary laboratory testing method. In resource-limited settings, where confirmatory methods are not always available, we propose testing the parents to validate the HemoTypeSC result. METHODS: This study explored this approach in the city of Kisangani. It was a prospective diagnostic accuracy study using genotype biological parents to evaluate HemoTypeSC's performance in the newborn. RESULTS: Fifty-eight children born to 46 known mothers, and 37 known fathers, have been tested. The phenotyping showed that 41 (70.7%) children were SS, whose 37 were born to a couple AS/AS and 4 to a couple AS/xx. Of the 41 SS children, 8 (19.5%) were newborns and 33 (80.4%) were children; 12 (20.6%) children were AS, one of whom was born to a couple SS/AA and 11 to a couple AA/SS; 5 (8.6%) children were AA. In this population, the probability of offspring born to AS/AS parents being SS rather than AS is high (odds, 1.25). No statistical difference was observed between girls and boys. The pedigree of all 58 children has been confirmed. CONCLUSION: We demonstrated that testing biological parents with HemoTypeSC is a reliable confirmatory method for newborn screening but it presents some limitations discussed in the present article.

Acer pseudoplatanus: A Potential Risk of Poisoning for Several Herbivore Species.

Acer pseudoplatanus is a worldwide-distributed tree which contains toxins, among them hypoglycin A (HGA). This toxin is known to be responsible for poisoning in various species, including humans, equids, Père David's deer and two-humped camels. We hypothesized that any herbivore pasturing with A. pseudoplatanus in their vicinity may be at risk for HGA poisoning. To test this hypothesis, we surveyed the HGA exposure from A. pseudoplatanus in species not yet described as being at risk. Animals in zoological parks were the major focus, as they are at high probability to be exposed to A. pseudoplatanus in enclosures. We also searched for a toxic metabolite of HGA (i.e., methylenecyclopropylacetyl-carnitine; MCPA-carnitine) in blood and an alteration of the acylcarnitines profile in HGA-positive animals to document the potential risk of declaring clinical signs. We describe for the first instance cases of HGA poisoning in Bovidae. Two gnus (Connochaetes taurinus taurinus) exposed to A. pseudoplatanus in their enclosure presented severe clinical signs, serum HGA and MCPA-carnitine and a marked modification of the acylcarnitines profile. In this study, even though all herbivores were exposed to A. pseudoplatanus, proximal fermenters species seemed less susceptible to HGA poisoning. Therefore, a ruminal transformation of HGA is hypothesized. Additionally, we suggest a gradual alteration of the fatty acid metabolism in case of HGA poisoning and thus the existence of subclinical cases.

Altered Serum Acylcarnitines Profile after a Prolonged Stay in Intensive Care.

A stay in intensive care unit (ICU) exposes patients to a risk of carnitine deficiency. Moreover, acylated derivates of carnitine (acylcarnitines, AC) are biomarkers for metabolic mitochondrial dysfunction that have been linked to post-ICU disorders. This study aimed to describe the AC profile of survivors of a prolonged ICU stay (≥7 days). Survivors enrolled in our post-ICU clinic between September 2020 and July 2021 were included. Blood analysis was routinely performed during the days after ICU discharge, focusing on metabolic markers and including AC profile. Serum AC concentrations were determined by LC-MS/MS and were compared to the reference ranges (RR) established from serum samples of 50 non-hospitalized Belgian adults aged from 18 to 81 years. A total 162 patients (65.4% males, age 67 (58.7−73) years) survived an ICU stay of 9.7 (7.1−19.3) days and were evaluated 5 (3−8) days after discharge. Their AC profile was significantly different compared to RR, mostly in terms of short chain AC: the sum of C3, C4 and C5 derivates reached 1.36 (0.98−1.99) and 0.86 (0.66−0.99) µmol/L respectively (p < 0.001). Free carnitine (C0) concentration of survivors (46.06 (35.04−56.35) µmol/L) was similar to RR (43.64 (36.43−52.96) µmol/L) (p = 0.55). C0 below percentile 2.5 of RR was observed in 6/162 (3.7%) survivors. Their total AC/C0 ratio was 0.33 (0.22−0.42). A ratio above 0.4 was observed in 45/162 (27.8%) patients. In ICU survivors, carnitine deficiency was rare, but AC profile was altered and AC/C0 ratio was abnormal in more than 25%. The value of AC profile as a marker of post-ICU dysmetabolism needs further investigations.

Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy.

Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999_1001delCAC; p.Thr334del) of BCKDK. Plasma and cerebrospinal fluid concentrations of BCAA were markedly reduced. Hyperactivity of BCKDH and over-consumption of BCAA were demonstrated by functional tests in cells transfected with the mutant BCKDK. Treatment with pharmacological doses of BCAA allowed the restoring of BCAA concentrations and greatly improved seizure control. Behavioral and developmental skills of the patients improved to a lesser extent. Importantly, a retrospective review of the newborn screening results allowed the identification of a strong decrease in BCAA concentrations on dried blood spots, suggesting that BCKDK is a new treatable metabolic disorder probably amenable to newborn screening programs.

Overview of current progress and challenges in diagnosis, and management of pediatric sickle cell disease in Democratic Republic of the Congo.

OBJECTIVES: Sickle cell disease (SCD) encompasses health complications, primarily affecting the hematologic system and leading to high death rates in childhood. As a rule, the World Health Organisation (WHO) stepwise gold-standard about the strategies for prevention, diagnosis, and treatment of SCD must be multidimensional. This overview aimed to highlight current advances and challenges linked to strategic issues, diagnosis, the prevalence, and treatment of pediatric cases in Sub-Saharan Africa, particularly the Democratic Republic of the Congo. METHODS: We searched data on Google Scholar, Medline, PubMed, Science Direct, Scopus, and ResearchGate. RESULTS: The laboratory diagnosis of SCD has progressed from conventional electrophoresis to rapid point-of-care tests that allows early neonate screening. HemoTypeSCTM is an affordable test for neonatal screening in DRC. The pediatric SCD prevalence in Sub-Saharan Africa lay within 1-7.7% of homozygous(SS) and 15-40% of the heterozygous(AS) forms of SCD, depending on the method used and the ethnic population tested. Various supportive management protocols for comorbidities and complications exist, but they are not standardized in the Region. CONCLUSION: Notwithstanding some progress accomplished, the disease is still challenging in Sub-Saharan Africa due to limited early diagnostic testing and a lack of specific medications. There is a need for harmonizing therapeutic protocols and conducting controlled valid clinical trials.

Newborn screening of neuromuscular diseases.

Neuromuscular diseases represent an heterogenous group of more than 400 diseases, with a very broad phenotypic spectrum. Given their rarity and complexity, neuromuscular diseases are often diagnosed with a very significant delay after which irreversible muscle damage may limit the efficacy of treatments when available. In this context, neonatal screening could constitute a solution for early detection and treatment. A systematic review of the literature in PubMed up to May 1, 2021, was conducted according to PRISMA guidelines, including classical neuromuscular diseases and diseases with a clear peripheral nervous system involvement (including central nervous system disease with severe neuropathy). We found seven diseases for which newborn screening data were reported: spinal muscular atrophy (9), Duchenne muscular dystrophy (9), Pompe disease (8), X-linked adrenoleukodystrophy (5), Krabbe disease (4), myotonic dystrophy type 1 (1), metachromatic leukodystrophy (1). The future of newborn screening for neuromuscular disorders pass through a global technological switch, from a biochemical to a genetic-based approach. The rapid development of therapy also requires the possibility to quickly adapt the list of treated conditions, to allow innovative therapies to achieve their best efficacy.

Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.