Clinical and Genetic Characteristics of Free Sialic Acid Storage Disorder

Free sialic acid storage disorder (FSASD) is a lysosomal storage disorder that results from biallelic pathogenic variants in the SLC17A5 gene. This gene codes for sialin, a 12‐transmembrane domain protein that exports the charged sugar N‐acetylneuraminic acid (Neu5Ac; sialic acid) out of the lysosome. Dysfunctional sialin causes accumulation of free sialic acid within lysosomes and a range of clinical manifestations, such as intellectual disability, facial dysmorphisms, and increased urinary excretion of free sialic acid. These findings, along with characteristic brain abnormalities on MRI, make the diagnosis of FSASD. Despite recognition of the clinical and imaging phenotype, the natural history of FSASD has not been extensively elucidated. Therefore, we prospectively characterized the clinical, molecular, laboratory, and imaging findings of eight children with FSASD in order to pursue biomarker discovery with collaborators in a consortium of FSASD investigators. Our cohort displayed a high prevalence of ophthalmologic and auditory abnormalities, including myopia, exotropia, and abnormal ABR. Prominent features include impaired CNS myelination, a very thin corpus callosum, documentation of varying levels of intellectual disability, elevated urine, plasma, and CSF free sialic acid levels, and essentially normal endocrine, hematologic, and immunologic parameters. The consistent finding of delayed but progressive myelination suggests that quantitative assessment of myelination by MRI and 1 H MRS should be added to the list of potential clinical outcome measures for future clinical trials.