ABSTRACT
Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.
Subject(s)
Cognition Disorders/genetics , Genes, Recessive/genetics , High-Throughput Nucleotide Sequencing , Intellectual Disability/genetics , Brain/metabolism , Brain/physiology , Cell Cycle , Consanguinity , DNA Mutational Analysis , Exons/genetics , Gene Regulatory Networks , Genes, Essential/genetics , Homozygote , Humans , Metabolic Networks and Pathways , Mutation/genetics , Organ Specificity , Synapses/metabolismABSTRACT
BACKGROUND: Aneurysmal subarachnoid haemorrhage (SAH) is a devastating disease with high mortality and disability. The data from large longitudinal studies on health-related quality of life (HRQoL) in patients with SAH are limited. The objective was to investigate HRQoL in patients after SAH and to identify predictors of HRQoL. METHODS: 113 patients with aneurysmal SAH were assigned to either neurosurgery (n = 57) or endovascular coiling (n = 56). Clinical assessments (Barthel Index, modified Rankin Scale) and evaluation of HRQoL [36-Item Short-Form Survey, EuroQol (EQ5D), EQ visual analogue scale (EQ VAS)] were performed at discharge, and at 6 and 12 months of follow-up. Independent predictors of HRQoL were determined using multiple regression analysis. RESULTS: HRQoL in SAH patients was considerably reduced compared to the normal population. At discharge, 92.2% of the patients had moderate or severe problems on the EQ5D. The EQ VAS score was 57.8 +/- 19.3. However, HRQoL still showed improvement from 3 months up to 1 year. At 12 months after SAH, the EQ VAS score was approximately 12-14% higher than at discharge. The independent predictors of decreased HRQoL included female gender, severe SAH, functional disability, depression, a lower level of education and the lack of a stable partnership. CONCLUSIONS: The long-term HRQoL outcome after SAH is unfavourable. HRQoL outcome measures should be included in future studies to provide better evidence of the long-term outcomes after SAH. In addition, the independent determinants of HRQoL identified in this study should be considered in the healthcare programmes aimed at increasing the HRQoL in SAH survivors.
