JIMD Rep

Primary carnitine deficiency (PCD) is an inherited disease of fatty acid beta-oxidation with autosomal recessive inheritance. The disease manifests as metabolic decompensation with hypoketotic hypoglycaemia associated with cardiomyopathy, hepatomegaly, rhabdomyolysis, and seizures. Various outcomes are described from asymptomatic adults to dramatic sudden infant death syndrome cases. We present a severe case of PCD decompensation in an 18-week-old female. She presented with hypotonia, moaning, diarrhea, and vomiting at the pediatric emergency. Initially suspected as intracranial hypertension, the clinical condition evolved rapidly and caused a reversible cardiac arrest with profound hypoglycemia. Despite carnitine supplementation, she succumbed from cardiac arrhythmia and multivisceral failure 4 days after admission. The genetic analyses showed a PCD with biallelic pathogenic variants of gene. The case report is notable for the severity of the cardiac damage possibly favored by maternal carnitine deficiency during pregnancy. The analysis of previously published PCD cases highlights (i) the importance of having large access to emergency biochemical tests for early therapeutic care although the disease has unpredictable severity and (ii) the fact that the clinical outcome remains unpredictable if carnitine treatment is initiated late

Rôle du Lipolysis Stimulated Receptor (LSR) (expression chez la souris adulte et au cours de l'embryogénèse)

Le Lipolysis Stimulated Receptor (LSR) fixe les lipoprotéines contenant l'apolipoprotéine (apo) B et l'apoE en présence des acides gras, et son affinité est optimale pour les fractions lipoprotéiniques les plus riches en triglycérides. Dans notre étude, nous avons utilisé les techniques du Northern blot, de la PCR quantitative en temps réel et de l'immunofluorescence pour examiner l'expression du LSR chez la souris adulte et au cours du développement embryonnaire. Chez l'adulte l'ARNm LSR est retrouvé dans tous les tissus étudiés sauf dans le muscle et le coeur. Les ARNm sont abondants dans le foie, le poumon, l'intestin, le rein et dans certains tissus stéroidogéniques (ovaires et testicules). Ils sont également présents à tous les stades embryonnaires étudiés. Les résultats de l'expression protéique sont corrélés à ceux de l'expression transcriptionnelle. Ainsi, le "patron" d'expression du LSR chez la souris adulte apporte des arguments supplémentaires sur son rôle possible de ce récepteur dans le transport lipidique au niveau de ces organes. Afin d'étudier le rôle physiologique du LSR in vivo, nous avons tenté d'obtenir des souris LSR-/- par recombinaison homologue. Sur un total de 379 souris génotypées, trois homozygotes seulement ont été identifiées. Cette répartition montre une grande létalité des homozygotes. Celle-ci se produit entre 12,5 et 15,5 jours de gestation. Les embryons LSR-/- se distinguent par un foie de taille réduite. Ces résultats indiquent que le LSR est indispensable pour le développement embryonnaire. Par ailleurs, étant donné que les souris hétérozygotes ne présentent aucun phénotype particulier, nous avons voulu analyser l'impact de l'invalidation de l'un des deux allèles du LSR chez des souris totalement déficientes en un autre récepteur de lipoprotéines à apoB/E, le LDLR. Comparés aux souris LDL-/-, les doubles mutants [LSR+/- ; LDR-/-] appelés LDLSR ont des taux plasmatiques de cholestérol total significativement plus faibles par diminution du cholestérol contenu dans les lipoprotéines non LDL et HDL. Ce résultat pourrait être expliqué par l'intervention de mécanismes compensateurs comme l'augmentation de l'activité d'autres récepteurs de lipoprotéines. Grâce au modèle LDLSR, nous avons pu mettre en évidence pour la première fois un rôle in vivo du LSR dans la régulation du métabolisme du cholestérol et des lipoprotéines.The lipolysis stimulated receptor (LSR) recognizes apolipoprotein B/E-containing lipoproteins in the presence of free fatty acids, and is thought to be involved in the clearance of triglyceride-rich lipoproteins (TRL). The distribution of LSR in mice was studied by Northern blots, quantitative PCR and immunofluorescence. In the adult, LSR mRNA was detectable in all tissues except muscle and heart, and was abundant in liver, lung, intestine, kidney, ovaries and testes. During embryogenesis, LSR mRNA was detectable at 7.5 days post-coitum (E7) and increased up to E17 in parallel to prothrombin, a liver marker. In adult liver, immunofluorescence experiments showed a staining at the periphery of hepatocytes as well as in fetal liver at E12 and E15. These results are in agreement with the assumption that LSR is a plasma membrane receptor involved in the clearance of lipoproteins by liver, and suggest a possible role in steroidogenic organs, lung, intestine and kidney. To explore the role of LSR in vivo, the LSR gene was inactivated in 129/Ola ES cells by removing a gene segment containing exons 2-5, and 129/Ola-C57BL/6 mice bearing the deletion were produced. Although heterozygotes appeared normal, LSR homozygotes were not viable, with the exception of three males, while the total progeny of genotyped wild-type and heterozygote pups was 376. Mortzality of the homozygote embryos was observed between days 12.5 and 15.5 of gestation, a time at which their liver was much smaller than that of their littermates, indicating that the expression of LSR is critical for liver and embryonic devellopment. To evaluate the effect of inactivation of one allele LSR in LDL receptor-deficient mice, we produce double knockout animals [LSR+/-] called LDLSR Total plasma cholesterol concentration were approximately 40 % less as compared with LDLR-/- mice These finding supported the hypothesis of upregulation of other receptors in LDLSR mice.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Rôle du Lipolysis Stimulated Receptor (LSR) (expression chez la souris adulte et au cours de l'embryogénèse)

Le Lipolysis Stimulated Receptor (LSR) fixe les lipoprotéines contenant l'apolipoprotéine (apo) B et l'apoE en présence des acides gras, et son affinité est optimale pour les fractions lipoprotéiniques les plus riches en triglycérides. Dans notre étude, nous avons utilisé les techniques du Northern blot, de la PCR quantitative en temps réel et de l'immunofluorescence pour examiner l'expression du LSR chez la souris adulte et au cours du développement embryonnaire. Chez l'adulte l'ARNm LSR est retrouvé dans tous les tissus étudiés sauf dans le muscle et le coeur. Les ARNm sont abondants dans le foie, le poumon, l'intestin, le rein et dans certains tissus stéroidogéniques (ovaires et testicules). Ils sont également présents à tous les stades embryonnaires étudiés. Les résultats de l'expression protéique sont corrélés à ceux de l'expression transcriptionnelle. Ainsi, le "patron" d'expression du LSR chez la souris adulte apporte des arguments supplémentaires sur son rôle possible de ce récepteur dans le transport lipidique au niveau de ces organes. Afin d'étudier le rôle physiologique du LSR in vivo, nous avons tenté d'obtenir des souris LSR-/- par recombinaison homologue. Sur un total de 379 souris génotypées, trois homozygotes seulement ont été identifiées. Cette répartition montre une grande létalité des homozygotes. Celle-ci se produit entre 12,5 et 15,5 jours de gestation. Les embryons LSR-/- se distinguent par un foie de taille réduite. Ces résultats indiquent que le LSR est indispensable pour le développement embryonnaire. Par ailleurs, étant donné que les souris hétérozygotes ne présentent aucun phénotype particulier, nous avons voulu analyser l'impact de l'invalidation de l'un des deux allèles du LSR chez des souris totalement déficientes en un autre récepteur de lipoprotéines à apoB/E, le LDLR. Comparés aux souris LDL-/-, les doubles mutants [LSR+/- ; LDR-/-] appelés LDLSR ont des taux plasmatiques de cholestérol total significativement plus faibles par diminution du cholestérol contenu dans les lipoprotéines non LDL et HDL. Ce résultat pourrait être expliqué par l'intervention de mécanismes compensateurs comme l'augmentation de l'activité d'autres récepteurs de lipoprotéines. Grâce au modèle LDLSR, nous avons pu mettre en évidence pour la première fois un rôle in vivo du LSR dans la régulation du métabolisme du cholestérol et des lipoprotéines.The lipolysis stimulated receptor (LSR) recognizes apolipoprotein B/E-containing lipoproteins in the presence of free fatty acids, and is thought to be involved in the clearance of triglyceride-rich lipoproteins (TRL). The distribution of LSR in mice was studied by Northern blots, quantitative PCR and immunofluorescence. In the adult, LSR mRNA was detectable in all tissues except muscle and heart, and was abundant in liver, lung, intestine, kidney, ovaries and testes. During embryogenesis, LSR mRNA was detectable at 7.5 days post-coitum (E7) and increased up to E17 in parallel to prothrombin, a liver marker. In adult liver, immunofluorescence experiments showed a staining at the periphery of hepatocytes as well as in fetal liver at E12 and E15. These results are in agreement with the assumption that LSR is a plasma membrane receptor involved in the clearance of lipoproteins by liver, and suggest a possible role in steroidogenic organs, lung, intestine and kidney. To explore the role of LSR in vivo, the LSR gene was inactivated in 129/Ola ES cells by removing a gene segment containing exons 2-5, and 129/Ola-C57BL/6 mice bearing the deletion were produced. Although heterozygotes appeared normal, LSR homozygotes were not viable, with the exception of three males, while the total progeny of genotyped wild-type and heterozygote pups was 376. Mortzality of the homozygote embryos was observed between days 12.5 and 15.5 of gestation, a time at which their liver was much smaller than that of their littermates, indicating that the expression of LSR is critical for liver and embryonic devellopment. To evaluate the effect of inactivation of one allele LSR in LDL receptor-deficient mice, we produce double knockout animals [LSR+/-] called LDLSR Total plasma cholesterol concentration were approximately 40 % less as compared with LDLR-/- mice These finding supported the hypothesis of upregulation of other receptors in LDLSR mice.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

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

Massive lead poisoning from a gunshot with high soft lead charge.

International audienceObjective:To report a case of unusually rapid onset of lead poisoning after a special ammunition gunshot.Case report:A 38-year-old man with no history of lead poisoning was shot. The bullet blew through a door before reachingthe victim, fragmented, and resulted in a riddling of 60 secondaryprojectiles in the victim. Initial lesions mainly concerned the left chest, left shoulder, and left brachial plexus. The first blood lead level (BLL) was collected on day 7 after the wound and analysed by graphite furnace atomic absorption spectrometry. BLL was1048 μg/L (French reference value in exposed adult men < 200 μg/L), with a peak to 1566 μg/L on day 11. Symptomatology was a sensation of extreme fatigue, constipation, and peripheral neurologic involvement of the left ulnar. Other markers on day 11 were slight anemia (hemoglobin 11.6 g/dL), erythrocyte protoporphyrin level (1.911 μmol/L) and urine delta-aminolevulinic acid (13 μmol/mmol of creatinine). Two subcutaneous metallic residues and a hair sample were sent for analysis by inductively coupled plasma mass spectrometry to confirm the presence oflead; they confirmed that lead was present in the residues (817 and 841 mg per gram), there was a recent incorporation of lead in hair (63 ng/mg in the end and 119 ng/mg in the basis), and the lead in the hair was from the same origin as the bullet (isotopic ratios were the same Pb 206/Pb 207 ¼1.17, Pb 208/Pb 207 ¼ 2.44, Pb 208/Pb 206 ¼ 2.08). Several chelation treatments with succimer and sodium calcium edetate together with surgicalextraction of lead fragments did not prevent clinical and biological signs of chronic lead poisoning.Conclusion:This special ammunition contained 30 g inert soft lead not protected with a metallic envelope. It is not intended to be used directly on living argets. Such a rapid, high, and massive contamination is linked to a pure and important lead charge of the cartridge not protected by a metallic envelope, the presence of “soft lead, which is more prone to fragmentation than hard lead ”, and the location of the lead fragments in the body, especially in the pleura and near the shoulder joint. The presence of a substantial lead store in the body is now responsible for chronic lead poisoning, probably for the rest of the patient ’s life

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 β-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

Adult-Onset Diagnosis Of Urea Cycle Disorders: Results Of A French Cohort Of 71 Patients

BACKGROUND: Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. AIMS: Description of a cohort of patients with adult onset of UCDs. METHODS: Multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). RESULTS: Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (i) a metabolic decompensation (42%), (ii) family history (55%), or (iii) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16-86). Eighty-nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD - 6 decompensations and 1 epilepsy secondary to inaugural decompensation. CONCLUSION: This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life-threatening condition. Physicians working in adult care must be aware of late-onset presentations given the implications for patients and their families. This article is protected by copyright. All rights reserved

Novel risk factors for premature peripheral arterial occlusive disease in non-diabetic patients: a case-control study.

BACKGROUND: This study aimed to determine the prevalence of genetic and environmental vascular risk factors in non diabetic patients with premature peripheral arterial disease, either peripheral arterial occlusive disease or thromboangiitis obliterans, the two main entities of peripheral arterial disease, and to established whether some of them are specifically associated with one or another of the premature peripheral arterial disease subgroups. METHODS AND RESULTS: This study included 113 non diabetic patients with premature peripheral arterial disease (diagnosis <45-year old) presenting either a peripheral arterial occlusive disease (N = 64) or a thromboangiitis obliterans (N = 49), and 241 controls matched for age and gender. Both patient groups demonstrated common traits including cigarette smoking, low physical activity, decreased levels of HDL-cholesterol, apolipoprotein A-I, pyridoxal 5'-phosphate (active form of B6 vitamin) and zinc. Premature peripheral arterial occlusive disease was characterized by the presence of a family history of peripheral arterial and carotid artery diseases (OR 2.3 and 5.8 respectively, 95% CI), high lipoprotein (a) levels above 300 mg/L (OR 2.3, 95% CI), the presence of the factor V Leiden (OR 5.1, 95% CI) and the glycoprotein Ia(807T,837T,873A) allele (OR 2.3, 95% CI). In thromboangiitis obliterans group, more patients were regular consumers of cannabis (OR 3.5, 95% CI) and higher levels in plasma copper has been shown (OR 6.5, 95% CI). CONCLUSIONS: According to our results from a non exhaustive list of study parameters, we might hypothesize for 1) a genetic basis for premature peripheral arterial occlusive disease development and 2) the prevalence of environmental factors in the development of thromboangiitis obliterans (tobacco and cannabis). Moreover, for the first time, we demonstrated that the 807T/837T/873A allele of platelet glycoprotein Ia may confer an additional risk for development of peripheral atherosclerosis in premature peripheral arterial occlusive disease