Infantile Sialic Acid Storage Disease

In contrast to lysosomal hydrolytic enzymes, the lysosomal membrane remains poorly characterized. In particular, although the genetic study of cystinosis and sialic acid storage disorders led to the identification of two lysosomal transporters for cystine and sialic acids, respectively, ten years ago, most transporters responsible for exporting lysosomal hydrolysis products to the cytosol are still unknown at the molecular level. However, two lines of investigation recently started to fill this gap in the knowledge of lysosomal biology. First, novel proteomic approaches are now able to provide a reliable inventory of lysosomal membrane proteins. On the other hand, a novel functional approach based on intracellular trafficking mechanisms allows direct transport measurement in whole cells by redirecting recombinant lysosomal transporters to the cell surface. After surveying the current state of knowledge in this field, the review focuses on the sialic acid transporter sialin and shows how recent functional data using the above whole-cell approach shed new light on the pathogenesis of sialic acid storage disorders by revealing the existence of a residual transport activity associated with Salla disease.

Background Salla disease (SD) is a rare lysosomal storage disorder leading to severe intellectual disability. SD belongs to the Finnish disease heritage, and it is caused by mutations in the SLC17A5 gene. The aim of the study was to investigate the course of neurocognitive features of SD patients in a long-term follow-up. Methods Neuropsychological and neurological investigations were carried out on 24 SD patients, aged 16–65 years, 13 years after a similar examination. Results The survival analysis showed excess mortality among patients with SD after the age of 30 years. The course of the disease was progressive, but follow-up of SD patients revealed that motor skills improved till the age of 20 years, while mental abilities improved in most patients till 40 years of age. Verbal comprehension skills did not diminish during the follow-up, but productive speech deteriorated because of dyspraxia and dysarthria. Motor deficits were marked. Ataxia was prominent in childhood, but it was replaced by athetotic movements during the teens. Spasticity became more obvious with age especially in severely disabled SD patients. Conclusions Younger SD patients performed better in almost every task measuring mental abilities that then seem to remain fairly constant till early sixties. Thus, the results indicate better prognosis in cognitive skills than earlier assumed. There is an apparent decline in motor skills after the age of 20 years. The early neurocognitive development predicts the later course of motor and cognitive development.