Case report: Two siblings with very late onset of holocarboxylase synthase deficiency and a mini-review

Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. This report describes two siblings in a family with late-onset forms of HCS deficiency. The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration. The results of the organic urine profile confirmed multiple carboxylase deficiency, and genetic testing revealed a novel pathogenic variant in the HLCS gene (NM_000411.8) in the homozygous state: c.995A>G; p. (Gln332Arg). No further decompensation was observed for her during the 3-year follow-up period. His older brother was diagnosed at the age of 23 years-old through biochemical tests, without any history of acidotic decompensation. A mini-review of HCS deficiency with late onset (>1 year) or early onset (<1 month) revealed that splice variants are associated with late onset, while both variants p. (Leu216Arg) and p. (Leu237Pro) are associated with early onset. However, the majority of genotypes do not show a clear correlation with the timing of HCS deficiency onset. The most significant point here is the description of extremely late-onset cases of HCS deficiency. This can prompt metabolic investigations and raise suspicion of this rare disease in cases of unexplained metabolic acidosis, even beyond early childhood

Case report: Unveiling genetic and phenotypic variability in Nonketotic hyperglycinemia: an atypical early onset case associated with a novel GLRX5 variant

Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive metabolic disorder usually associated with mutations in genes AMT, GLDC or GCSH involved in the glycine cleavage complex. Other genes have been linked with less severe NKH, associated with deficiency of lipoate cofactor such as GLRX5, LIAS, BOLA3. We identified a new case of GLRX5-mediated NKH who presented at 2-month with severe developmental delay and seizures. The initial suspicion was raised by the MRI and then confirmed by glycine measurements in cerebrospinal fluid and blood. Genetic analysis revealed a previously undescribed homozygous variant in the GLRX5 gene [NM_016417.3:c.367G>C; p. (Asp123His)]. Despite medication and supportive care, he died at the age of 4 months after a sudden neurological deterioration. It was decided to limit therapeutic interventions due to the severity of the prognosis. The case was more severe than the previous GLRX5-mediated NKH described, regarding the early age at onset and the severity. Moreover, the genetic variant was located at a potentially crucial site for glutathione binding in the GLRX5 protein. This report, thereby, expands our understanding of NKH’s genetic underpinnings and phenotypic variability, highlighting the crucial role of GLRX5 and other related genes in variant NKH

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia

The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.This work was supported by funds from the followinginstitutions: Agencia Estatal de Investigacion/Euro-pean Regional Development Fund, European Union(PGC2018-096244-B-I00, SAF2016-75442-R), Ministryof Science, Innovation and Universities of Spain,Spanish National Research Council—CSIC, InstitutNational de la Sante et de la Recherche Medicale—INSERM, Ligue Contre le Cancer—Gironde, Univer-site de Bordeaux, Fondation pour la Recherche Medi-cale, the Conseil Regional d’Aquitaine, SIRIC-BRIO,Fondation ARC and Institut Europeen de Chimie etBiologie. MJN was supported by a bourse d’excellencede la Federation Wallonie-Bruxelles (WBI) and a post-doctoral fellowship from Fondation ARC. We thankVincent Pitard (Flow Cytometry Platform, Universitede Bordeaux, France) for technical assistance in flowcytometry experiments. We thank Diana Cabrera(Metabolomics Platform, CIC bioGUNE, Spain) fortechnical assistance in metabolomics analysi

Postauthorization safety study of betaine anhydrous

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013–2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0–9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia

International audienc

Significance of two point mutations present in each HEXB allele of patients with adult GM2 gangliosidosis (Sandhoff disease) Homozygosity for the Ile207 → Val substitution is not associated with a clinical or biochemical phenotype

AbstractThe molecular defects in the HEXB gene encoding the common β-subunit of lysosomal β-hexosaminidase A (β-Hex A, αβ) and β-Hex B (ββ) were investigated in a Portuguese family affected with late onset Sandhoff disease (GM2-gangliosidosis variant 0). This family comprised two unaffected daughters and three affected sibs who developed at about age 17 cerebellar ataxia and mental deficiency. Their parents were consanguineous and clinically asymptomatic. There was no detectable β-Hex B activity and a profound reduction in the activity of β-Hex A in the leukocytes and transformed lymphoid cell lines from the affected sibs. The expected intermediate values were observed in the parents as well as in one daughter and her children. Western analysis revealed the presence of reduced, but detectable amounts of mature β-chain protein in cell lysates from the probands and intermediate levels in the parents. Nucleotide sequencing of amplified, reverse-transcribed β-chain mRNA demonstrated the presence of two single point mutations: an A619 to G transition in exon 5 (Ile207 → Val), and a G1514 to A transition in exon 13 (Arg505 → Gln). Both of these two mutations have been previously linked to the adult form of Sandhoff disease in compound heterozygote patients. All three affected sibs were found to be homoallelic for both mutations. Interestingly, while the mother was heterozygous for each mutation, the father was homozygote for the A619 → G substitution and heterozygote for the G1514 → A transition. Since the father is homozygote for the A619 → G mutation but expresses a biochemical phenotype consistent with a carrier of Sandhoff disease and is clinically asymptomatic, this substitution is likely a neutral mutation. We confirmed this hypothesis by finding this transition present in 4 of 30 alleles from normal individuals. We conclude that homozygosity for the G1514 → A mutation is exclusively responsible for the adult form of Sandhoff disease in this family, and that the A619 → G substitution is not a deleterious mutation but rather a common HEXB polymorphism

Detection of an Intragenic Deletion Expands the Spectrum of CTSC Mutations in Papillon–Lefèvre Syndrome

The Papillon–Lefèvre syndrome (PLS) is an autosomal recessive disorder. The gene responsible for the disease, cathepsin C (CTSC), is localized in 11q14.1–q14.21. We performed mutational and functional analyses of CTSC in two patients affected by this condition. Three previously unreported CTSC mutations were identified. The first patient had a compound heterozygous status with a p.G386R missense mutation and an intragenic deletion spanning exons 3–7. Second patient carried a homozygous splice site mutation, p.A253SfsX30. CTSC activity was undetectable in both patients, thus demonstrating the pathological effect of these mutations. We describe early evidence of an original intragenic deletion reported in PLS. Since this mutational mechanism could not be detected by direct sequencing, intragenic deletion has to be specifically investigated using gene dosage analysis techniques such as quantitative multiplex fluorescent polymerase chain reaction. We consider that this technique should be performed in patients with apparently homozygous CTSC mutations when one parent does not carry the expected mutation or is not available for analysis

Ann Biol Clin (Paris)

La dénutrition comme la malnutrition induisent des déficits en micronutriments, éléments-trace et vitamines nécessaires aux fonctions physiologiques et au fonctionnement du système immunitaire. Ces carences et les maladies infectieuses coexistent souvent en complexes interactions. Une évaluation de l’état nutritionnel en micronutriments des patients Covid-19 n’a pas été au centre des priorités face à l’urgence médicale et à l’absence de preuves directes et rapides des effets de supplémentation. Peu de recommandations ont émané des sociétés savantes par manque de preuves significatives des effets de supplémentations, avec une nécessité d’études robustes. S’il est reconnu que les oligo-éléments essentiels et les vitamines sont nécessaires à la différenciation, l’activation et l’exécution de fonctions des cellules immunitaires, leur rôle spécifique reste encore à définir. Cette synthèse aborde dans la Covid-19 l’importance des micronutriments (sélénium, cuivre, zinc, vitamines C, D, A et groupe B) chez l’hôte pour tendre vers une optimisation de la réponse immunitaire aux infections. En prévention primaire, en population générale, un équilibre nutritionnel reste central pour atteindre l’homéostasie des micronutriments, pour diminuer le risque des situations de déséquilibre et de fragilisation face à des situations sanitaires d’ampleur.Nutritional status is an important protection factor against viral infections. Both undernutrition and malnutrition cause deficits in micronutrients, trace elements and vitamins necessary for various physiological functions and the appropriate functioning of the immune system. These deficiencies and infectious diseases often coexist, with complex interactions. An assessment of the micro-nutrient nutritional status of Covid-19 patients has not been at the center of priorities and recommendations, due to both the medical emergency and the absence of direct evidence and rapid effects of supplementation. Few recommendations have come from learned societies due to the lack of significant evidence of the effects of supplementation in positive patients and a need for robust studies. Essential trace elements and vitamins are necessary for the differentiation, activation and execution of many functions of immune cells, but their specific role has yet to be defined. This review article discusses in the context of Covid-19 the importance of micronutrients (selenium, copper, zinc, vitamins C, D, A and those of group B) in the host to tend towards an optimization of the immune response to infections. A nutritional balance remains the key word for achieving micronutrient homeostasis. Attention had to be paid to micronutrients in primary prevention, in the general population, in order to reduce the risk of impaired nutritional status in case of major health situations