Sialic Acid Storage Disorder (Salla Disease) via the SLC17A5 Gene

Sialic acid storage disorder is an early onset neurodegenerative disease resulting from accumulation of free sialic acid within the lysosomes of most tissues, particularly in the brain. The spectrum of clinical phenotypes includes Salla disease and Infantile free sialic acid storage disease (Verheijen et al. 1999), as well as an intermediate form.

Salla disease is the mild form of sialic acid storage disorder, characterized by normal appearance at birth. Cerebellar ataxia and hypotonia occur during infancy, followed by progressive developmental delay in childhood, and psychomotor impairment, spasticity, ataxia, epileptic seizures, or intellectual disability in adulthood (Aula et al. 2000; Mochel et al. 2010).

Infantile free sialic acid storage disease (ISSD) or Salic acid storage disease, severe infantile type is the severe form of sialic acid storage disorder. Onset can occur in the embryo stage as hydrops fetalis, or at birth. The symptoms of ISSD include severe psychomotor retardation, dysostosis multiplex, and typical manifestations of lysosomal diseases such as severe developmental delay, coarse face, hepatosplenomegaly and cardiomegaly. Seizures are common. Patients have a shortened life span, and usually die before reaching 2 years (Verheijen et al. 1999; Froissart et al. 2005).

Sialic acid storage disorder is inherited in an autosomal recessive manner and caused by pathogenic variants in the SLC17A5 gene (solute carrier family 17, member 5) encoding the protein sialin. Sialin is a lysosomal membrane transport protein which transports free sialic acid out of lysosomes, or acts as a vesicular glutamic acid/aspartate transporter or maintains functional myelination in the brain (Miyaji et al. 2008; Wreden et al 2005; Morin et al. 2004; Sreedharan et al. 2010; Prolo et al. 2009). SLC17A5 is the only gene known to be responsible for Salla disease and Infantile free sialic acid storage disease.

Pathogenic variants in SLC17A5 gene include missense, nonsense, small deletions and insertions, and splice mutations, as well as large deletions and duplications. Most of SLC17A5 pathogenic variants cause defective or absent sialin. Of note, a single homozygous Finnish founder pathogenic variant (c.115C>T, p.Arg39Cys) presented in 91% of positive findings in Finnish patients. Variable expression has been noted in a family (Aula et al. 2000; Froissart et al. 2005; Paavola et al. 2015).

SLC17A5 is the only gene known to be involved with Salla disease and Infantile free sialic acid storage disease. A founder pathogenic variant (c.115C>T, p.Arg39Cys) is found in over 91% of Finnish patients (Aula et al. 2000). To date, there are about 30 other rare pathogenic SLC17A5 alleles that have been characterized at the molecular level (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SLC17A5 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.