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
OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. RESULTS: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. CONCLUSION: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.
Asunto(s)
Osteoporosis/diagnóstico , Osteoporosis/terapia , Guías de Práctica Clínica como Asunto , Síndrome de Rett/complicaciones , Absorciometría de Fotón , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Consenso , Difosfonatos/uso terapéutico , Manejo de la Enfermedad , Testimonio de Experto , Humanos , Osteoporosis/etiologíaRESUMEN
PURPOSE: To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil. METHODS: A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1-18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2-11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits. RESULTS: CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75-100% reduction, 25 (34%) reported 50-75% reduction, 9 (12%) reported 25-50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal. In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients. CONCLUSIONS: The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.