Multiomic analysis in fibroblasts of patients with inborn errors of cobalamin metabolism reveals concordance with clinical and metabolic variability.

BACKGROUND: The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways. METHODS: We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts. FINDINGS: CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated. INTERPRETATION: The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations. FUNDING: French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm.

Coma With Hyperammonemia in a Patient With Kwashiorkor.

We describe a case of coma-related hyperammonemia in a woman presenting with severe edematous malnutrition (Kwashiorkor-like), without underlying hepatic disease. Our main hypothesis is that the patient developed a functional urea cycle disorder, due to the inability to synthesize N-acetylglutamate which is the activator of the first enzymes (carbamoyl phosphate synthetase) of urea cycle, in a context of severe deficiency of essential amino acids and of acetyl-CoA. Severe hyperammonemia is a medical emergency exposing to the risk of cerebral edema. Urgent treatment should interrupt protein intake, stimulate protein anabolism, and remove ammonia from the blood using renal replacement therapy and ammonia scavengers. Hyperammonemia should be searched in case of unexplained coma, even among patients without hepatic disorder, in particular among young patients. Hyperammonemia should also be searched among patients with severe protein-calorie malnutrition.

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.

OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.

Blood phenylalanine fluctuation in phenylketonuric children treated by BH4 or low-phenylalanine diet from birth.

The prognosis of phenylketonuria (PKU) is related to the quality of metabolic control all life-long. PKU treatment is based on a low-Phe diet, 6R-tetrahydrobiopterin (BH4) treatment for the BH4-responsive PKU patients or enzyme replacement therapy. Fluctuations in blood phenylalanine (Phe) concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). The aim of this work is to study the fluctuation of Blood Phe in patients treated by BH4 from birth in comparison with patients treated by low-Phe diet. We conducted a retrospective study in a national reference center for PKU management. We compared mean phenylalanine blood concentration and its fluctuation in 10 BH4-responder patients (BH4R) and in 10 BH4 non-responder patients (BH4NR) treated from birth. The mean blood Phe concentration is similar between the two groups before 10 years of age (290 ± 135 (BH4R) vs. 329 ± 187 µmol/L, p = 0.066 (BH4NR)) while it is lower in the BH4R group after 10 years of age. (209 ± 69 vs. 579 ± 136 µmol/L, p = 0.0008). Blood Phe fluctuation is significantly lower in the BH4R group compared to the BH4NR group (70.2 ± 75.6 vs. 104.4 ± 111.6 µmol/L, p < 0.01) before 6 years of age. There are no significant differences observed on nutritional status, growth, and neuropsychological tests between the two groups. BH4 introduced in the neonatal period is associated with less blood Phe fluctuation before 6 years. Additional time and patients are required to determine if the decrease in Phe fluctuation would positively impact the long-term outcome of PKU patients.

Procalcitonin is associated with sudden unexpected death in infancy due to infection.

Infection is an important cause of death during infancy worldwide and is a frequent etiology of sudden unexpected death in infancy (SUDI). Procalcitonin (PCT) is a useful marker to diagnose infection in patients, and several studies report the stability of PCT after death. The added value of a biological marker, such as the PCT level in the blood, remains controversial in investigating SUDI. The aim of this study was to determine if PCT can help clinicians determine whether infection caused SUDI. We conducted a retrospective, multicenter study with the French SUDI registry (Observatoire National des Morts Inattendues du Nourrisson; OMIN). We collected data from this registry on children who died between May 2015 and June 2021. The levels of PCT in the blood of 540 SUDI patients were measured. We compared PCT and other biological tests performed in terms of infection status, autopsy results, and cause of death using clinical and biological data compiled by pediatricians at the SUDI referral center. PCT levels were significantly higher in the children who died from infection than in those who did not (0.12 µg/L vs. 0.08 µg/L, p < 0.001). A PCT blood level exceeding 0.2 µg/L was more frequently observed when infection was present than in the absence of infection (44.3% vs. 15.4%, p < 0.001). The same data were obtained with a 0.5 µg/L cut-off (36.1% with infection vs. 9.2% without, p < 0.001).  Conclusions: PCT is a sensitive biomarker for detecting infections postmortem; thus, additional samples may be necessary during autopsy. What is known: • PCT is a stable marker postmortem and increases earlier than CRP, i.e., 2-4 h after the beginning of an infection vs. 6 h. • PCT can be measured up to 140 h after death. What is new: • PCT is a sensitive marker for detecting infection in SUDI patients postmortem. • This test can reveal an infection from non-standardized samples obtained during autopsy if such an infection was not determined before death.

Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B12 metabolism: A meta-analysis.

Inherited disorders of B12 metabolism produce a broad spectrum of manifestations, with limited knowledge of the influence of age and the function of related genes. We report a meta-analysis on 824 patients with a genetically proven diagnosis of an inherited disorder of vitamin B12 metabolism. Gene clusters and age categories are associated with patients' manifestations. The "cytoplasmic transport" cluster is associated with neurological and ophthalmological manifestations, the "mitochondrion" cluster with hypotonia, acute metabolic decompensation, and death, and the "B12 availability" and "remethylation" clusters with anemia and cytopenia. Hypotonia, EEG abnormalities, nystagmus, and strabismus are predominant in the younger patients, while neurological manifestations, such as walking difficulties, peripheral neuropathy, pyramidal syndrome, cerebral atrophy, psychiatric disorders, and thromboembolic manifestations, are predominant in the older patients. These results should prompt systematic checking of markers of vitamin B12 status, including homocysteine and methylmalonic acid, when usual causes of these manifestations are discarded in adult patients.

Menstrual Toxic Shock Syndrome: A French Nationwide Multicenter Retrospective Study.

BACKGROUND: Studies describing the clinical features and short-term prognosis of patients admitted to the intensive care unit (ICU) for menstrual toxic shock syndrome (m-TSS) are lacking. METHODS: This was a multicenter retrospective cohort study of patients with a clinical diagnosis of m-TSS admitted between 1 January 2005 and 31 December 2020 in 43 French pediatric (n = 7) or adult (n = 36) ICUs. The aim of the study was to describe the clinical features and short-term prognosis, as well as to assess the 2011 Centers for Disease and Control (CDC) diagnostic criteria, in critically ill patients with m-TSS. RESULTS: In total, 102 patients with m-TSS (median age, 18 years; interquartile range, 16-24 years) were admitted to 1 of the participating ICUs. All blood cultures (n = 102) were sterile. Methicillin-sensitive Staphylococcus aureus grew from 92 of 96 vaginal samples. Screening for superantigenic toxin gene sequences was performed for 76 of the 92 vaginal samples positive for S. aureus (83%), and toxic shock syndrome toxin 1 was isolated from 66 strains (87%). At ICU admission, no patient met the 2011 CDC criteria for confirmed m-TSS, and only 53 (52%) fulfilled the criteria for probable m-TSS. Eighty-one patients (79%) were treated with antitoxin antibiotic therapy, and 8 (8%) received intravenous immunoglobulins. Eighty-six (84%) patients required vasopressors, and 21 (21%) tracheal intubation. No patient required limb amputation or died in the ICU. CONCLUSIONS: In this large multicenter series of patients included in ICUs for m-TSS, none died or required limb amputation. The CDC criteria should not be used for the clinical diagnosis of m-TSS at ICU admission.

Diagnostic yield of clinical exome sequencing as a first-tier genetic test for the diagnosis of genetic disorders in pediatric patients: results from a referral center study.

The emergence of next-generation sequencing enabled a cost-effective and straightforward diagnostic approach to genetic disorders using clinical exome sequencing (CES) panels. We performed a retrospective observational study to assess the diagnostic yield of CES as a first-tier genetic test in 128 consecutive pediatric patients addressed to a referral center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. CES was performed using the TruSight One (4811 genes) or the TruSight One expanded (6699 genes) panel on an Illumina sequencing platform. The median age was 6.5 years (IQR 2.0-12.0) with 43% of males (55/128), and the median disease duration was 7 months (IQR 1-47). In the whole analysis, the CES diagnostic yield was 55% (70/128). The median test-to-report time was 5 months (IQR 4-7). According to CES indications, the CES diagnostic yields were 81% (21/26) for hyperlipidemia, 75% (6/8) for osteogenesis imperfecta, 64% (25/39) for metabolic disorders, 39% (10/26) for neurological disorders, and 28% (8/29) for the subgroup of patients with miscellaneous conditions. Our results demonstrate the usefulness of a CES-based diagnosis as a first-tier genetic test to establish a molecular diagnosis in pediatric patients with a suspected genetic disorder with a median test-to-report time of 5 months. It highlights the importance of a close interaction between the pediatrician with expertise in genetic disorders and the molecular medicine physician to optimize both CES indication and interpretation. Diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020. The CES diagnostic yields are reported in the whole population and patients' subgroups (hyperlipidemia, osteogenesis imperfecta, metabolic diseases, neurological disorders, miscellaneous conditions) (Icons made by Flaticon, flaticon.com; CC-BY-3.0).

Educational Setting and SARS-CoV-2 Transmission Among Children With Multisystem Inflammatory Syndrome: A French National Surveillance System.

Background: Multisystem inflammatory syndrome in children (MIS-C) is the most severe form associated with SARS-CoV-2 infection in children. To reduce the spread of SARS-CoV-2 at the population level, educational setting closure have been implemented in many countries. However, the direct benefit of school closure on the MIS-C burden remains to be explored. We aimed to assess the role of educational settings in SARS-CoV-2 transmission among children with MIS-C. Methods: We conducted a French national prospective surveillance of MIS-C, coordinated by Public Health France, from April 2020 to March 2021. During this period, we included all children with MIS-C fulfilling the WHO definition who were reported to Public Health France. For each child, we traced the source of SARS-CoV-2 transmission. The main outcome was the proportion of children with MIS-C, with educational setting-related SARS-CoV-2 infection, during the period of school opening. Results: We included 142 children fulfilling WHO criteria for MIS-C: 104 (70%) cases occurred during school opening periods. In total, 62/104 children (60%, 95%CI [50; 69]) had been contaminated by a household contact and 5/104 in educational settings (5%, 95%CI [2; 11]). Among children with MIS-C occurring during school closure periods, the proportion of household transmission remained similar (66%, 25/38). Conclusion: Children with MIS-C were mainly infected by SARS-CoV-2 within their family environment, and the educational setting played a marginal role in this transmission. This suggests that mitigating school attendance may not reduce substantially the burden of MIS-C.

A bi-allelic loss-of-function SARS1 variant in children with neurodevelopmental delay, deafness, cardiomyopathy, and decompensation during fever.

Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.

Treatment of ARS deficiencies with specific amino acids.

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.

[Newborn screening of phenylketonuria in France]. / Le dépistage de la phénylcétonurie en France.

Phenylketonuria is the most common inborn error of metabolism and causes irreversible mental retardation if left untreated. Its newborn screening was made possible by the technique of blood collection on filter paper developed by Robert Guthrie. Neonatal PKU screening began in France in the early 1970s. It was initially carried out by a bacteriological method, then by fluorometry, and finally, since 2020, by tandem mass spectrometry. More than 35 million newborns have been screened to date. This resulted in the diagnosis of more than 3,500 children with PKU or mild hyperphenylalaninemia. The management of these children has improved over time, in particular thanks to the techniques of biochemistry and molecular genetics which lead to an accurate diagnosis and the arrival of drug treatment by sapropterin. Thanks to this screening, which allows for early management, the prognosis of PKU has been transformed and, although neurological or behavioral problems may arise, these patients are living normally today.

TITLE: Le dépistage de la phénylcétonurie en France. ABSTRACT: La phénylcétonurie (PCU) est la plus fréquente des erreurs innées du métabolisme et entraîne un retard mental irréversible en l'absence de traitement. Son dépistage néonatal a été rendu possible grâce à la technique de recueil de sang sur papier buvard mise au point par Robert Guthrie. Le dépistage néonatal de la PCU a débuté en France au début des années 1970. Il a été initialement réalisé par une technique bactériologique, puis fluorimétrique et, enfin, depuis 2020 par spectrométrie de masse en tandem. Plus de 35 millions de nouveau-nés ont été dépistés à ce jour, ce qui a permis de diagnostiquer plus de 3 500 enfants porteurs de PCU ou hyperphénylalaninémie modérée. La prise en charge de ces enfants a évolué avec le temps, en particulier grâce aux techniques de biochimie et de génétique moléculaire qui permettent un diagnostic précis et grâce à l'arrivée d'un traitement médicamenteux par saproptérine. Grâce à ce dépistage, qui permet une prise en charge précoce, le pronostic de la PCU a été transformé et, même s'il peut survenir des problèmes neurologiques ou comportementaux, ces patients ont une vie normale aujourd'hui.

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Factors Associated With Severe SARS-CoV-2 Infection.

BACKGROUND: Initial reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children suggested that very young age and comorbidities may increase risk of severe evolution, but these findings remained to be confirmed. We aimed to analyze the clinical spectrum of hospitalized pediatric SARS-CoV-2 infection and predictors of severe disease evolution. METHODS: We conducted a French national prospective surveillance of children hospitalized with SARS-CoV-2 infection. We included all children with confirmed SARS-CoV-2 infection in 60 hospitals during February 15 to June 1, 2020. The main outcome was the proportion of children with severe disease, defined by hemodynamic or ventilatory (invasive or not) support requirement. RESULTS: We included 397 hospitalized children with SARS-CoV-2 infection. We identified several clinical patterns, ranging from paucisymptomatic children, admitted for surveillance, to lower respiratory tract infection or multisystem inflammatory syndrome in children. Children <90 days old accounted for 37% of cases (145 of 397), but only 4 (3%) had severe disease. Excluding children with multisystem inflammatory syndrome in children (n = 29) and hospitalized for a diagnosis not related to SARS-CoV-2 (n = 62), 23 of 306 (11%) children had severe disease, including 6 deaths. Factors independently associated with severity were age ≥10 years (odds ratio [OR] = 3.4, 95% confidence interval: 1.1-10.3), hypoxemia (OR = 8.9 [2.6-29.7]), C-reactive protein level ≥80 mg/L (OR = 6.6 [1.4-27.5]). CONCLUSIONS: In contrast with preliminary reports, young age was not an independent factor associated with severe SARS-CoV-2 infection, and children <90 days old were at the lowest risk of severe disease evolution. This may help physicians to better identify risk of severe disease progression in children.

Expanding the phenotype of X-linked SSR4-CDG: Connective tissue implications.

Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.

Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect.

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.

[Phenylketonuria, from diet to gene therapy]. / La phénylcétonurie - De la diététique à la thérapie génique.

The prognosis for phenylketonuria (PKU) has been improved by neonatal screening and dietary management via a low-phenylalanine diet. This treatment must be followed throughout life, which induces severe compliance problems. Drug treatment with sapropterin (or BH4) has come to help a reduced percentage of patients who respond to this drug. A subcutaneous enzyme therapy is available in the USA and has obtained European marketing authorization, but generates significant side effects, which limits its effectiveness. New therapeutic options for PKU are currently being developed, in particular gene therapy. The purpose of this article is to take stock of the pathophysiology and the various new therapeutic modalities currently in development.

Title: La phénylcétonurie - De la diététique à la thérapie génique. Abstract: Le pronostic de la phénylcétonurie (PCU) a été transformé par le dépistage néonatal et la prise en charge diététique via un apport contrôlé en phénylalanine. Ce traitement doit être suivi toute la vie durant, ce qui pose des problèmes de compliances importants. Un traitement médicamenteux par saproptérine (ou BH4) est venu apporter une aide à un pourcentage réduit de patients qui répondent à ce médicament. Une enzymothérapie par voie sous-cutanée est disponible aux États-Unis et a obtenue une AMM européenne, mais génère des effets secondaires importants, ce qui en limite l'efficacité. De nouvelles options thérapeutiques de la PCU sont actuellement en développement, en particulier par thérapie génique. Le but de cet article est de faire le point sur la physiopathologie et sur les différentes nouvelles modalités thérapeutiques actuellement en développement.

Pubertal outcomes of children transplanted with allogeneic stem cells after myeloablative total body irradiation or busulfan: Influence of age and sex is confirmed, while a role of chronic graft-versus-host disease in delayed puberty onset is revealed.

INTRODUCTION: Myeloablative conditioning before allogeneic HSCT during childhood exposes to serious long-term complications, especially gonadal dysfunction. Pubertal issues are less described than other post-HSCT sequelae in childhood. METHODS: Pubertal development and biological gonadal parameters were assessed in a retrospective monocentric cohort of prepubertal patients who underwent HSCT after myeloablative conditioning with TBI or busulfan between 1981 and 2017. RESULTS: Seventy-four patients (28 girls and 46 boys) were included. No spontaneous pubertal development was found in 50% of girls and 10% of boys (P < .001), and delayed puberty or no spontaneous pubertal development was found in 57% of girls and 24% of boys (P = .009). HRT was used in 82% of girls and 24% of boys (P < .001). In univariate analysis, TBI conditioning (P = .05), female sex (P < .001), acute GVHD (P = .05), extensive chronic GVHD (P = .021), steroid treatment >6 months (P = .016), and malignant diseases (P = .016) were associated with no spontaneous pubertal development, whereas TBI conditioning (P = .003) and extensive chronic GVHD (P = .005) were associated with delayed puberty. In multivariate analysis, factors independently associated with no spontaneous puberty onset were female sex (P = .001) and age >10 years (P = .033). Factors independently associated with delayed puberty were extensive chronic GVHD (P = .041) and age >10 years (P = .031). CONCLUSION: This study highlighted the toxicity of MAC in prepubescent children: TBI did worse, but this was especially true for the most susceptible patients (girls, leukemic patients, and patients older than 10 years). It suggests a possible role of GVHD in delayed puberty.

Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1).

Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D3. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH)2 vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.