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1.
Genet Med ; 25(6): 100314, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36305855

RESUMEN

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.


Asunto(s)
Fallo Hepático Agudo , Fallo Hepático , Adolescente , Niño , Preescolar , Humanos , Lactante , Adulto Joven , Acetilcisteína/uso terapéutico , Fallo Hepático/tratamiento farmacológico , Fallo Hepático/genética , Fallo Hepático Agudo/tratamiento farmacológico , Fallo Hepático Agudo/genética , Proteínas Mitocondriales/genética , Mutación , Estudios Retrospectivos , ARNt Metiltransferasas/genética
2.
J Med Genet ; 59(9): 878-887, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34656997

RESUMEN

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.


Asunto(s)
Proteínas Mitocondriales , Ubiquinona , Línea Celular , Niño , Humanos , Recién Nacido , Proteínas Mitocondriales/genética , Neuroimagen , Fenotipo , Ubiquinona/genética , Ubiquinona/metabolismo
3.
Mol Genet Metab ; 123(3): 289-291, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29246431

RESUMEN

Primary disorders of the human coenzyme Q10 (CoQ10) biosynthesis pathway are a known cause of severe pediatric diseases. So far, oral administration of CoQ10 is the only treatment strategy for affected individuals. However, the real benefit of CoQ10 supplementation remains questionable and clinical studies regarding efficiency are lacking. Here we provide an outlook on novel treatment approaches using CoQ precursor compounds. These metabolic bypass strategies might be a promising alternative for oral CoQ10 supplementation regimens.


Asunto(s)
Ataxia/tratamiento farmacológico , Hidroxibenzoatos/uso terapéutico , Enfermedades Mitocondriales/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Animales , Apoptosis/efectos de los fármacos , Ataxia/genética , Ataxia/patología , Vías Biosintéticas/efectos de los fármacos , Vías Biosintéticas/genética , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Modelos Animales de Enfermedad , Humanos , Hidroxibenzoatos/farmacología , Ratones , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Debilidad Muscular/genética , Debilidad Muscular/patología , Pirimidinas/metabolismo , Solubilidad , Resultado del Tratamiento , Ubiquinona/biosíntesis , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/uso terapéutico , Vitaminas/uso terapéutico
4.
Mol Genet Metab ; 121(3): 216-223, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28552678

RESUMEN

Coenzyme Q10 (CoQ10) is an essential cofactor of the mitochondrial oxidative phosphorylation (OXPHOS) system and its deficiency has important implications for several inherited metabolic disorders of childhood. The biosynthesis of CoQ10 is a complicated process, which involves at least 12 different enzymes. One of the metabolic intermediates that are formed during CoQ10 biosynthesis is the molecule 6-demethoxyubiquinone (6-DMQ). This CoQ precursor is processed at the level of COQ7 and COQ9. We selected this metabolite as a marker substance for metabolic analysis of cell lines with inherited genetic defects (COQ2, COQ4, COQ7 and COQ9) or siRNA knockdown in CoQ biosynthesis enzymes using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). In COQ4, COQ7 and COQ9 deficient cell lines, we detected significantly elevated levels of 6-DMQ. This suggests a functional interplay of these proteins. However, additional siRNA studies demonstrated that elevated 6-DMQ levels are not an exclusive marker of the COQ7/COQ9 enzymatic step of CoQ10 biosynthesis but constitute a more general phenomenon that occurs in disorders impairing the function or stability of the CoQ-synthome. To further investigate the interdependence of CoQ10 biosynthesis enzyme expression, we performed immunoblotting in various cell lines with CoQ10 deficiency, indicating that COQ4, COQ7 and COQ9 protein expression levels are highly regulated depending on the underlying defect. Supplementation of cell lines with synthetic CoQ precursor compounds demonstrated beneficial effects of 2,4-dihydroxybenzoic acid in COQ7 and COQ9 deficiency. Moreover, vanillic acid selectively stimulated CoQ10 biosynthesis and improved cell viability in COQ9 deficiency. However, compounds tested in this study failed to rescue COQ4 deficiency.


Asunto(s)
Ataxia/metabolismo , Enfermedades Mitocondriales/metabolismo , Debilidad Muscular/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiencia , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Humanos , Hidroxibenzoatos/farmacología , Mitocondrias/metabolismo , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Fosforilación Oxidativa , Espectrometría de Masas en Tándem , Ubiquinona/biosíntesis , Ubiquinona/metabolismo , Ácido Vanílico/farmacología
5.
Am J Hum Genet ; 99(4): 894-902, 2016 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-27616477

RESUMEN

To safeguard the cell from the accumulation of potentially harmful metabolic intermediates, specific repair mechanisms have evolved. APOA1BP, now renamed NAXE, encodes an epimerase essential in the cellular metabolite repair for NADHX and NADPHX. The enzyme catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. The clinical importance of the NAD(P)HX repair system has been unknown. Exome sequencing revealed pathogenic biallelic mutations in NAXE in children from four families with (sub-) acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate was elevated in cerebrospinal fluid of all affected individuals. Disease onset was during the second year of life and clinical signs as well as episodes of deterioration were triggered by febrile infections. Disease course was rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels were undetectable in fibroblasts from affected individuals of two families. In these fibroblasts we measured highly elevated concentrations of the toxic metabolite cyclic-NADHX, confirming a deficiency of the mitochondrial NAD(P)HX repair system. Finally, NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder.


Asunto(s)
Proteínas Portadoras/genética , Enfermedades Metabólicas/genética , Mutación , NAD/análogos & derivados , Enfermedades del Sistema Nervioso/genética , Racemasas y Epimerasas/genética , Proteínas Portadoras/metabolismo , Línea Celular , Preescolar , Resultado Fatal , Femenino , Fibroblastos , Humanos , Lactante , Masculino , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/patología , NAD/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , Neuroimagen , Anomalías Cutáneas/genética , Anomalías Cutáneas/patología
6.
Eur J Hum Genet ; 24(3): 450-4, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26081641

RESUMEN

Coenzyme Q10 (CoQ10) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone10. At the same time, the total amount of CoQ10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ10 levels and respiratory chain complex activities by CoQ10 supplementation points to the importance of an early diagnosis and immediate treatment.


Asunto(s)
Acidosis Láctica/complicaciones , Acidosis Láctica/genética , Encefalopatías/complicaciones , Encefalopatías/genética , Proteínas Mitocondriales/genética , Mutación/genética , Ubiquinona/genética , Encéfalo/patología , Encefalopatías/diagnóstico por imagen , Proteínas del Complejo de Cadena de Transporte de Electrón/genética , Resultado Fatal , Homocigoto , Humanos , Recién Nacido , Masculino , Ultrasonografía
7.
Hum Mutat ; 36(1): 34-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25339201

RESUMEN

COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits. Although monomeric complex IV is decreased in patient fibroblasts, the CI/CIII2 /CIVn -supercomplexes remain unaffected. Copper supplementation shows a partial rescue of complex IV deficiency in patient fibroblasts. We conclude that COA6 is required for complex IV subunit stability. Furthermore, the proposed role in the copper delivery pathway to complex IV subunits is substantiated and a therapeutic lead for COA6-deficient patients is provided.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Deficiencia de Citocromo-c Oxidasa/genética , Complejo IV de Transporte de Electrones/genética , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/patología , Cobre/administración & dosificación , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Células HEK293 , Humanos , Recién Nacido , Mitocondrias/metabolismo
8.
J Neurooncol ; 79(2): 197-201, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16598421

RESUMEN

The association of weight loss and pediatric brain tumors that affect the diencephalon or brain stem with weight loss is a recognized, but not fully understood phenomenon. Tumors located in the hypothalamic region may induce the diencephalic syndrome (DS), which is characterized by profound emaciation with almost complete loss of subcutaneous fatty tissue. Tumors that compress or infiltrate the brain stem rarely cause both psychological disturbance and emaciation. The clinical presentation may be different, depending on the location of the lesion and age of the patient. In this report we present an unusual case of severe emaciation in a 4(9)/(12)-year-old girl with a juvenile pilocytic astrocytoma of the hypothalamic region and brain stem with neuroaxis dissemination. This case illustrates the importance of considering intracranial mass-lesions in the differential diagnosis of weight loss, psychological disturbance and atypical eating disorder. We discuss the importance of tumor multifocality and the role of patient age in the clinical presentation with reference to the literature.


Asunto(s)
Astrocitoma/patología , Neoplasias Encefálicas/patología , Emaciación/etiología , Trastornos de Alimentación y de la Ingestión de Alimentos/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/complicaciones , Astrocitoma/tratamiento farmacológico , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/tratamiento farmacológico , Tronco Encefálico/patología , Preescolar , Diagnóstico Diferencial , Emaciación/patología , Emaciación/cirugía , Trastornos de Alimentación y de la Ingestión de Alimentos/patología , Trastornos de Alimentación y de la Ingestión de Alimentos/cirugía , Trastornos de Ingestión y Alimentación en la Niñez/diagnóstico , Femenino , Humanos , Hipotálamo/patología , Neoplasias de la Médula Espinal/complicaciones , Neoplasias de la Médula Espinal/secundario , Resultado del Tratamiento
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