RESUMEN
Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability. Whole-exome and subsequent whole-genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ10 supplementation.
Asunto(s)
Vías Biosintéticas/genética , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Metiltransferasas/deficiencia , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/deficiencia , Ubiquinona/análogos & derivados , Biopsia , Ataxia Cerebelosa/dietoterapia , Ataxia Cerebelosa/metabolismo , Variaciones en el Número de Copia de ADN , Suplementos Dietéticos , Transporte de Electrón , Femenino , Fibroblastos/metabolismo , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucocitos/metabolismo , Metiltransferasas/genética , Encefalomiopatías Mitocondriales/dietoterapia , Encefalomiopatías Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Músculos/patología , Consumo de Oxígeno , Linaje , Polimorfismo de Nucleótido Simple , Hermanos , Ubiquinona/biosíntesisRESUMEN
Pathological glomerular hyposialylation has been implicated in certain unexplained glomerulopathies, including minimal change nephrosis, membranous glomerulonephritis, and IgA nephropathy. We studied our previously established mouse model carrying a homozygous mutation in the key enzyme of sialic acid biosynthesis, N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Mutant mice died before postnatal day 3 (P3) from severe glomerulopathy with podocyte effacement and segmental glomerular basement membrane splitting due to hyposialylation. Administration of the sialic acid precursor N-acetylmannosamine (ManNAc) led to improved sialylation and survival of mutant pups beyond P3. We determined the onset of the glomerulopathy in the embryonic stage. A lectin panel, distinguishing normally sialylated from hyposialylated glycans, used WGA, SNA, PNA, Jacalin, HPA, and VVA, indicating glomerular hyposialylation of predominantly O-linked glycoproteins in mutant mice. The glomerular glycoproteins nephrin and podocalyxin were hyposialylated in this unique murine model. ManNAc treatment appeared to ameliorate the hyposialylation status of mutant mice, indicated by a lectin histochemistry pattern similar to that of wild-type mice, with improved sialylation of both nephrin and podocalyxin, as well as reduced albuminuria compared with untreated mutant mice. These findings suggest application of our lectin panel for categorizing human kidney specimens based on glomerular sialylation status. Moreover, the partial restoration of glomerular architecture in ManNAc-treated mice highlights ManNAc as a potential treatment for humans affected with disorders of glomerular hyposialylation.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedades Renales/genética , Animales , Biomarcadores/metabolismo , Carbohidrato Epimerasas/genética , Proteínas Portadoras/genética , Suplementos Dietéticos , Evaluación Preclínica de Medicamentos/métodos , Hexosaminas/uso terapéutico , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Glomérulos Renales/embriología , Glomérulos Renales/metabolismo , Glomérulos Renales/ultraestructura , Proteínas de la Membrana/metabolismo , Ratones , Ratones Mutantes , Microscopía Electrónica , Mutación , Ácido N-Acetilneuramínico/fisiología , Podocitos/metabolismo , Podocitos/ultraestructura , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Sialoglicoproteínas/metabolismoRESUMEN
Rift Valley fever (RVF) virus is a mosquito-borne phlebovirus of the Bunyaviridae family that causes frequent outbreaks of severe animal and human disease in sub-Saharan Africa, Egypt and the Arabian Peninsula. Based on its many known competent vectors, its potential for transmission via aerosolization, and its progressive spread from East Africa to neighbouring regions, RVF is considered a high-priority, emerging health threat for humans, livestock and wildlife in all parts of the world. Introduction of West Nile virus to North America has shown the potential for "exotic" viral pathogens to become embedded in local ecological systems. While RVF is known to infect and amplify within domestic livestock, such as taurine cattle, sheep and goats, if RVF virus is accidentally or intentionally introduced into North America, an important unknown factor will be the role of local wildlife in the maintenance or propagation of virus transmission. We examined the potential impact of RVF transmission via white-tailed deer (Odocoileus virginianus) in a typical north-eastern United States urban-suburban landscape, where livestock are rare but where these potentially susceptible, ungulate wildlife are highly abundant. Model results, based on overlap of mosquito, human and projected deer densities, indicate that a significant proportion (497/1186 km(2), i.e. 42%) of the urban and peri-urban landscape could be affected by RVF transmission during the late summer months. Deer population losses, either by intervention for herd reduction or by RVF-related mortality, would substantially reduce these likely transmission zones to 53.1 km(2), i.e. by 89%.
Asunto(s)
Culicidae , Ciervos/parasitología , Sistemas de Información Geográfica/instrumentación , Insectos Vectores/parasitología , Fiebre del Valle del Rift/transmisión , Zoonosis/transmisión , Aerosoles , Animales , Bioterrorismo , Brotes de Enfermedades/estadística & datos numéricos , Reservorios de Enfermedades , Métodos Epidemiológicos , Humanos , New England/epidemiología , Fiebre del Valle del Rift/epidemiología , Medición de Riesgo/métodos , Zoonosis/epidemiologíaRESUMEN
A 25-year-old Caucasian man had difficulty swallowing and shortness of breath during an episode of infectious mononucleosis. His tonsils were "kissing" and erythematous but no superimposed infection with a streptococcal organism was identified. His symptoms improved rapidly upon administration of intravenous steroids. This case demonstrates a rare and short-term complication that is well described in young adults with infectious mononucleosis. Physicians should routinely counsel their patients with infectious mononucleosis to be aware of potentially life-threatening airway obstruction in addition to splenic rupture and meningitis.