BackgroundHuman 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.MethodsClinical 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.ResultsWe 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.ConclusionOur 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.
Certain alleles, genotypes, and haplotypes in TGFB genes were over represented in patients with FS, which possibly could predispose individuals to this disease.
Epilepsy might have adverse effect on bone density due to underlying disease, drugs, vitamin D deficiency, immobilization and malnutrition. We investigated the bone mineral density in ambulatory vitamin-D supplemented children with epilepsy. This case-control study was conducted on 90 epileptic children aged 11.4 ± 3.3 years, and age and gender matched controls in pediatric neurology clinics of Shiraz, in Southern Iran, 2016. Anthropometric measurements, puberty, sun exposure, physical activity and biochemical variables were assessed. Bone mineral density was evaluated by dual-energy X-ray absorptiometry method. Data were analyzed by SPSS.v21. Prevalence of low bone mass in femur was more in patients (27%) than the controls (9%) (P value = 0.002). Age, weight Z score and height Z score were the most significant associated factors on lumbar BMD, BMAD, and femur BMD. Seizure duration and how it responded to anticonvulsants were the most associated factors with both lumbar and femur bone density. Sodium valproate and carbomazepin usage had negative association with lumbar Z score (beta = - 0.216, P = 0.017 and beta = - 0.336, P = 0.027, respectively). We hypothesized that epilepsy per se could affect bone density by an unknown pathophysiology, which was independent from vitamin D deficiency, effects of anticonvulsant and physical activity.
BackgroundMitochondrial DNA depletion syndromes (MDS) are clinically and phenotypically heterogeneous disorders resulting from nuclear gene mutations. The affected individuals represent a notable reduction in mitochondrial DNA (mtDNA) content, which leads to malfunction of the components of the respiratory chain. MDS is classified according to the type of affected tissue; the most common type is hepatocerebral form, which is attributed to mutations in nuclear genes such as DGUOK and MPV17. These two genes encode mitochondrial proteins and play major roles in mtDNA synthesis.Case presentationIn this investigation patients in three families affected by hepatocerebral form of MDS who were initially diagnosed with tyrosinemia underwent full clinical evaluation. Furthermore, the causative mutations were identified using next generation sequencing and were subsequently validated using sanger sequencing. The effect of the mutations on the gene expression was also studied using real-time PCR. A pathogenic heterozygous frameshift deletion mutation in DGUOK gene was identified in parents of two affected patients (c.706–707 + 2 del: p.k236 fs) presenting with jaundice, impaired fetal growth, low-birth weight, and failure to thrive who died at the age of 3 and 6 months in family I. Moreover, a novel splice site mutation in MPV17 gene (c.461 + 1G > C) was identified in a patient with jaundice, muscle weakness, and failure to thrive who died due to hepatic failure at the age of 4 months. A 5-month-old infant presenting with jaundice, dark urine, poor sucking, and feeding problems was also identified to have another novel mutation in MPV17 gene leading to stop gain mutation (c.277C > T: p.(Gln93*)).ConclusionsThese patients had overlapping clinical features with tyrosinemia. MDS should be considered a differential diagnosis in patients presenting with signs and symptoms of tyrosinemia.
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