The KIF5A gene (OMIM 602821) encodes a neuron-specific kinesin heavy chain involved in intracellular transport of mitochondria and other cargoes. KIF5A protein comprises the N terminal motor domain, the stalk domain and the C-terminal cargo binding domain. The binding between KIF5A and its cargoes is mediated by kinesin adaptor proteins such as TRAK1 and TRAK2. Numerous missense KIF5A mutations in the motor and stalk domains cause spastic paraplegia type 10 (SPG10, OMIM 604187). Conversely, the role of loss-of-function mutations, especially those affecting the cargo binding domain, is unclear. We describe a novel de novo KIF5A p.Ser974fs/c.2921delC mutation found by whole exome sequencing in a patient with a congenital severe disease characterized by myoclonic seizures and progressive leukoencephalopathy. Since this phenotype differs considerably from the KIF5A/SPG10 disease spectrum we propose that the KIF5A p.Ser974fs and possibly other mutations which lead to truncation of the C-terminal tail of the protein cause a novel disorder. We speculate that the unique effect of the C-terminal truncating KIF5A mutations may result from the previously described complex role of this protein domain in binding of the TRAK2 and possibly other kinesin adaptor protein(s).
Background/Aims: The recent improvements of management of patients in pediatric intensive care units (PICU) are associated with improved outcome. However, this decrease in mortality is associated with an increased number of children with acute kidney injury (AKI), especially in patients with multiorgan failure. Methods: The report presents a retrospective analysis of 25 cases of AKI (assessed based on the pRIFLE criteria) in PICU within 7 years. Results: AKI was diagnosed in 1.24% of all hospitalized children. AKI percentage duration (as compared to the total hospitalization time) in the children who died vs. the survivors was 79.55% vs. 46.19%, respectively (p<0.05). The mortality rate of AKI patients was 40% which was 4.4-times higher as compared to the total mortality rate in PICU. The final cumulative survival ratio (FCSR) of patients meeting the oliguria criterion (which was met in 48% of AKI patients) was 37% vs. 49% in non-oliguric children. Averaged urine output values in the first week of hospitalization in the deceased vs. survivors were 1.49 vs. 2.57 ml/kg/h, respectively (p<0.05). Conclusions: Oliguria should not be considered as a sensitive parameter for AKI diagnosing in children below one year of age. A decreased mean urine output in the first week of PICU hospitalization (less than 1.4 ml/kg/h) should be considered as a poor prognostic factor. In many cases AKI was diagnosed too infrequently and too late.
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