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1.
Brain ; 146(6): 2285-2297, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36477332

RESUMEN

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.


Asunto(s)
Microcefalia , Animales , Humanos , Microcefalia/genética , Claudina-5/genética , Claudina-5/metabolismo , Pez Cebra/metabolismo , Barrera Hematoencefálica/metabolismo , Convulsiones/genética , Síndrome
2.
J Cell Biochem ; 119(12): 10021-10032, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30129250

RESUMEN

The deficiency of the enzyme glutaryl-CoA dehydrogenase, known as glutaric acidemia type I (GA-I), leads to the accumulation of glutaric acid (GA) and glutarilcarnitine (C5DC) in the tissues and body fluids, unleashing important neurotoxic effects. l-carnitine (l-car) is recommended for the treatment of GA-I, aiming to induce the excretion of toxic metabolites. l-car has also demonstrated an important role as antioxidant and anti-inflammatory in some neurometabolic diseases. This study evaluated GA-I patients at diagnosis moment and treated the oxidative damage to lipids, proteins, and the inflammatory profile, as well as in vivo and in vitro DNA damage, reactive nitrogen species (RNS), and antioxidant capacity, verifying if the actual treatment with l-car (100 mg kg-1 day-1 ) is able to protect the organism against these processes. Significant increases of GA and C5DC were observed in GA-I patients. A deficiency of carnitine in patients before the supplementation was found. GA-I patients presented significantly increased levels of isoprostanes, di-tyrosine, urinary oxidized guanine species, and the RNS, as well as a reduced antioxidant capacity. The l-car supplementation induced beneficial effects reducing these biomarkers levels and increasing the antioxidant capacity. GA, in three different concentrations, significantly induced DNA damage in vitro, and the l-car was able to prevent this damage. Significant increases of pro-inflammatory cytokines IL-6, IL-8, GM-CSF, and TNF-α were shown in patients. Thus, the beneficial effects of l-car presented in the treatment of GA-I are due not only by increasing the excretion of accumulated toxic metabolites, but also by preventing oxidative damage.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Encefalopatías Metabólicas/metabolismo , Carnitina/farmacología , Daño del ADN , Glutaril-CoA Deshidrogenasa/deficiencia , Estrés Oxidativo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Carnitina/uso terapéutico , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/efectos de los fármacos , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lactante , Masculino , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Especies de Nitrógeno Reactivo
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