Psychiatric symptoms in Salla disease.

Salla disease (SD) is a rare lysosomal storage disorder characterised by intellectual disability ataxia, athetosis, nystagmus, and central nervous system demyelination. Although the neurological spectrum of SD's clinical phenotype is well defined, psychotic symptoms in SD remain unreported. We reviewed the presence of psychiatric symptoms in patients diagnosed with SD. Medical records of all SD patients at Oulu University Hospital during the years 1982-2015 were systematically reviewed to evaluate the presence of psychiatric symptoms. Psychiatric symptoms were frequently associated with SD (10/24, 42%), and two patients were described as developing psychosis as adolescents. We reported their clinical characteristics in detail and assessed the prevalence of psychiatric symptoms in a cohort of 24 patients. Other psychiatric factors associated with SD were sleeping disorders (8/24, 32%), aggressive behaviour disorders or restlessness (6/24, 25%), and off-label antipsychotic medication (4/24, 17%). This report expands the knowledge of the phenotypic spectrum of SD and demonstrates the importance of recognising the possibility of psychiatric symptoms, including psychosis, in persons with SD.

Allele-specific silencing of the dominant disease allele in sialuria by RNA interference.

Dominant disease alleles are attractive therapeutic targets for allele-specific gene silencing by small interfering RNA (siRNA). Sialuria is a dominant disorder caused by missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid biosynthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase. The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessive production of free sialic acid. For this study we employed synthetic siRNAs specifically targeting the dominant GNE mutation c.797G>A (p.R266Q) in sialuria fibroblasts. We demonstrated successful siRNA-mediated down-regulation of the mutant allele by allele-specific real-time PCR. Importantly, mutant allele-specific silencing resulted in a significant decrease of free sialic acid, to within the normal range. Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered after silencing demonstrating specificity of this effect. These findings indicate that allele-specific silencing of a mutated allele is a viable therapeutic strategy for autosomal dominant diseases, including sialuria.