RESUMO
OBJECTIVE: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents. METHODS: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents. RESULTS: We identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta. CONCLUSIONS: These results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.
Assuntos
Adenosina Trifosfatases/genética , Doença de Moyamoya/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idade de Início , Doenças da Aorta/genética , Doenças da Aorta/fisiopatologia , Arteriopatias Oclusivas/genética , Arteriopatias Oclusivas/fisiopatologia , Pré-Escolar , Feminino , Artéria Femoral , Humanos , Artéria Ilíaca , Masculino , Doença de Moyamoya/fisiopatologia , Mutação , Obstrução da Artéria Renal/genética , Obstrução da Artéria Renal/fisiopatologiaRESUMO
High-capacity mitochondrial calcium (Ca2+) uptake by the mitochondrial Ca2+ uniporter (MCU) is strategically positioned to support the survival and remyelination of axons in multiple sclerosis (MS) by undocking mitochondria, buffering Ca2+ and elevating adenosine triphosphate (ATP) synthesis at metabolically stressed sites. Respiratory chain deficits in MS are proposed to metabolically compromise axon survival and remyelination by suppressing MCU activity. In support of this hypothesis, clinical scores, mitochondrial dysfunction, myelin loss, axon damage and inflammation were elevated while remyelination was blocked in neuronal MCU deficient (Thy1-MCU Def) mice relative to Thy1 controls subjected to experimental autoimmune encephalomyelitis (EAE). At the first sign of walking deficits, mitochondria in EAE/Thy1 axons showed signs of activation. By contrast, cytoskeletal damage, fragmented mitochondria and large autophagosomes were seen in EAE/Thy1-MCU Def axons. As EAE severity increased, EAE/Thy1 axons were filled with massively swollen mitochondria with damaged cristae while EAE/Thy1-MCU Def axons were riddled with late autophagosomes. ATP concentrations and mitochondrial gene expression were suppressed while calpain activity, autophagy-related gene mRNA levels and autophagosome marker (LC3) co-localization in Thy1-expressing neurons were elevated in the spinal cords of EAE/Thy1-MCU Def compared to EAE/Thy1 mice. These findings suggest that MCU inhibition contributes to axonal damage that drives MS progression.
Assuntos
Canais de Cálcio/deficiência , Encefalomielite Autoimune Experimental/patologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/deficiência , Bainha de Mielina/patologia , Neurônios/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Autofagia/genética , Axônios/patologia , Canais de Cálcio/genética , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/patologia , Expressão Gênica/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Dilatação Mitocondrial , Fagossomos/patologia , Medula Espinal/patologiaRESUMO
Natalizumab is an efficacious disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS), often limited by risk of progressive multifocal leukoencephalopathy. We describe the clinical course of RRMS patients switched from natalizumab to another DMT. We identified all RRMS patients treated with natalizumab ≥3 months with JC virus antibody positivity who switched to another DMT. Overall, 84 individuals switched DMT with 57 (68%) beginning fingolimod. On fingolimod, survival without a relapse was 74% (55.8-85.6%) at 36 months and survival without disease progression was 78% (62.6-87.6%) at 36 months. In conclusion, fingolimod is an effective therapy post-natalizumab.
L'évolution clinique de patients atteints de la forme cyclique de la sclérose en plaques ayant opté pour un traitement autre que celui au natalizumab. Le natalizumab est un médicament modificateur de l'évolution de la sclérose en plaques (MMSP) efficace pour le traitement de la sclérose en plaques récurrente-rémittente (SEP-RR), souvent limité par le risque de la leucoencéphalopathie multifocale progressive. Nous décrivons l'évolution clinique des patients atteints de SEP-RR qui sont passés du natalizumab à un autre MMSP. Nous avons identifié tous les patients atteints de SEP-RR ayant été traités avec le natalizumab ≥3 mois avec la positivité des anticorps anti-virus JC et ayant opté pour un autre MMSP. Globalement, 84 personnes ont changé de MMSP avec 57 (68%) ayant changé au fingolimod. Parmi les patients sous le fingolimod, la survie sans rechute était de 74% (55,8 à 85,6%) à 36 mois et la survie sans progression était de 78% (62,6 à 87,6%) à 36 mois. En conclusion, le fingolimod est une thérapie post-natalizumab efficace.
