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.

Beta-thalassemia intermedia due to a complex alpha-globin rearrangement and a heterozygous beta thalassemia mutation.

The alpha-thalassaemia alleles are very frequent in the world's population. The main molecular mechanism is a large deletion with the loss of one or two alpha genes. Another type of rarer abnormality exists: the gain of alpha genes. The consequence of a gain is an overproduction of alpha-globin chains, which aggravates a beta-thalassaemia trait into an intermedia phenotype (non-transfusion-dependent thalassaemia, NTDT). Here, we report the case of a young girl referred for a beta-NTDT with a combination never described in the literature: a heterozygous beta-thalassaemia mutation associated with a copy number gain of the alpha-globin locus and -alpha 3.7 deletion on the same allele.

[Pharmacogenetics of aminoglycoside ototoxicity: State of knowledge and practices - Recommendations of the Francophone Network of Pharmacogenetics (RNPGx)]. / Pharmacogénétique de l'ototoxicité des aminosides : état des connaissances et des pratiques ­ recommandations du Réseau francophone de pharmacogénétique (RNPGx).

The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment.

Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

SKAP2 Modular Organization Differently Recognizes SRC Kinases Depending on Their Activation Status and Localization.

Dimerization of SRC kinase adaptor phosphoprotein 2 (SKAP2) induces an increase of binding for most SRC kinases suggesting a fine-tuning with transphosphorylation for kinase activation. This work addresses the molecular basis of SKAP2-mediated SRC kinase regulation through the lens of their interaction capacities. By combining a luciferase complementation assay and extensive site-directed mutagenesis, we demonstrated that SKAP2 interacts with SRC kinases through a modular organization depending both on their phosphorylation-dependent activation and subcellular localization. SKAP2 contains three interacting modules consisting in the dimerization domain, the SRC homology 3 (SH3) domain, and the second interdomain located between the Pleckstrin homology and the SH3 domains. Functionally, the dimerization domain is necessary and sufficient to bind to most activated and myristyl SRC kinases. In contrast, the three modules are necessary to bind SRC kinases at their steady state. The Pleckstrin homology and SH3 domains of SKAP2 as well as tyrosines located in the interdomains modulate these interactions. Analysis of mutants of the SRC kinase family member hematopoietic cell kinase supports this model and shows the role of two residues, Y390 and K7, on its degradation following activation. In this article, we show that a modular architecture of SKAP2 drives its interaction with SRC kinases, with the binding capacity of each module depending on both their localization and phosphorylation state activation. This work opens new perspectives on the molecular mechanisms of SRC kinases activation, which could have significant therapeutic impact.

Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common genetic disorder associated with a high risk for premature atherosclerotic cardiovascular disease attributable to increased levels of LDL-cholesterol (LDL-C) from birth. FH is both underdiagnosed and undertreated. OBJECTIVE: We describe the clinical, biological, and genetic characteristics of 147 patients in France with clinical FH (including a group of 26 subjects aged < 20 years); we explore how best to detect patients with monogenic FH. METHODS: We retrospectively reviewed all available data on patients undergoing genetic tests for FH from 2009 to 2019. FH diagnoses were based on the Dutch Lipid Clinics Network (DLCN) scores of adults, and elevated LDL-C levels in subjects < 20 years of age. We evaluated LDLR, APOB, and PCSK9 status. RESULTS: The mutations of adults (in 25.6% of all adults) were associated with DLCN scores indicating "possible FH," "probable FH, and "definitive FH" at rates of 4%, 16%, and 53%, respectively. The areas under the ROC curves of the DLCN score and the maximum LDL-C level did not differ (p = 0.32). We found that the pediatric group evidenced more monogenic etiologies (77%, increasing to 91% when an elevated LDL-C level was combined with a family history of hypercholesterolemia and/or premature coronary artery disease). CONCLUSION: Diagnosis of monogenic FH may be optimized by screening children in terms of their LDL-C levels, associated with reverse-cascade screening of relatives when the children serve as index cases.

[New perspectives on the role of αIIbß3 integrin in defective megakaryopoiesis]. / L'intégrine αIIbß3 - Une actrice insoupçonnée dans la formation des plaquettes sanguines.

In recent years, the understanding of the molecular mechanisms involved in platelet production (megakaryopoiesis) has extremely increased, thanks to the study of genetic diseases causing inherited thrombocytopenia. Among the wide variety of transmembrane receptors covering the platelet membrane, αIIbß3 integrin is the major one, allowing platelets to aggregate upon the occurrence of vascular breach. Platelet counts are usually normal in patients with αIIbß3 deficiency, suggesting that its role for normal platelet production and morphology is very limited. However, recently, new clinical observations of genetic diseases provided evidence against this hypothesis, bringing new data on the role of αIIbß3 integrin in defective megakaryopoiesis.