Autosomal Recessive Spastic Paraparesis Research Articles

Novel mutations in ATP13A2 associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay

BackgroundKufor-Rakeb Syndrome (KRS) is an autosomal recessive disease characterized by Parkinsonism, pyramidal signs, dementia, and supranuclear gaze palsy. KRS is caused by mutations in ATP13A2producing a transmembrane protein responsible for the regulation of intracellular inorganic cations. ObjectiveTwo siblings born to a Turkish family of consanguineous marriage had mixed neurological presentations with the presence of hypointense images on T2-weighted MRI and were pre-diagnosed as having autosomal recessive spastic paraparesis or ataxia.We aimed to identify the disease-causing mutation by whole-exome sequencing and elucidate the underlying molecular mechanism of the causative mutation. MethodsPrussian blue staining was conducted for the detection of cellular iron accumulation. Disease-causing mutation inATP13A2was detected by whole-exome sequencing. Expression levels of ATP13A2 mRNA and protein were assessed by qRT-PCR and Western Blot. ResultsIron deposits in the patients’ fibroblasts were detected by Prussian blue staining. Novel homozygous mutation c.1422_1423del:p.P474fs was detected intheATP13A2. As this mutation caused a premature termination codon (PTC), the expression of mutant ATP13A2 mRNA through qRT-PCR analysis was found to be degraded by nonsense-mediated decay and this prevented the expression of ATP13A2 protein in the patients’ fibroblasts. ConclusionsNovel frameshift mutation causing a PTC in ATP13A2 lead to degradation of ATP13A2 mRNA by NMD. Iron accumulation due to the absence of ATP13A2 protein in the patient’s fibroblasts and hypointense areas on T2-weighted images may expand the spectrum of KRS to consider it as neurodegeneration with brain iron accumulation disorders.

Mutations of the SPG11 gene in patients with autosomal recessive spastic paraparesis and thin corpus callosum

Hereditary spastic paraparesis (HSP) with thin corpus callosum (TCC) is a rare autosomal recessive form of complicated HSP (ARHSP-TCC). The clinical phenotype is characterised by slowly progressive spastic paraparesis and...