Free sialic acid storage disorder

Free sialic acid storage disorder (FSASD) is an inherited condition that primarily affects the brain and spinal cord (central nervous system). The signs and symptoms of FSASD can vary from person to person, and the condition is often divided into three forms based on the severity of these features. 

The severe form of FSASD is called infantile free sialic acid storage disease or ISSD. The signs and symptoms of this form typically appear in infancy. In some cases, a condition called hydrops fetalis, in which excess fluid accumulates in the body, occurs before or soon after birth. Babies with the severe form of FSASD typically have severe developmental delays, weak muscle tone (hypotonia), and an inability to gain weight and grow at the expected rate (failure to thrive). Additional signs and symptoms may include unusual facial features that are often described as "coarse," bone malformations, an enlarged liver and spleen (hepatosplenomegaly), an enlarged heart (cardiomegaly), and seizures. Respiratory infections are common and can be life-threatening; children with the severe form of FSASD typically only survive into early childhood.

Children with the least severe form of FSASD, also called Salla disease, may not have the signs and symptoms of the condition at birth. The age at which people develop the signs and symptoms of Salla disease can vary, but hypotonia usually appears during the first year of life. People with Salla disease typically have intellectual disabilities and developmental delays, which can make it difficult for them to learn to walk and talk. Additional signs and symptoms include problems with movement and balance (ataxia); abnormal tensing of the muscles (spasticity); and involuntary slow, writhing movements of the limbs (athetosis). Signs and symptoms typically worsen over time. Although life expectancy may be shortened, individuals with Salla disease often survive into adulthood.

People with the intermediate form of FSASD, also called intermediate severe Salla disease, have signs and symptoms that are typically more severe than the signs and symptoms seen in people with Salla disease and less severe than those seen in people with ISSD.

Fewer than 300 people with FSASD have been reported in the medical literature. Salla disease is more common among people of Finnish and Swedish descent and has been reported in approximately 150 people.

Variants (also called mutations) in the SLC17A5 gene cause all the forms of FSASD. This gene provides instructions for producing a protein called sialin. This protein is located on the membranes of lysosomes, which are compartments in the cell that digest and recycle different types of molecules.

Sialin moves (transports) a molecule called free sialic acid to other parts of the cell. Sialic acid is produced when fats and proteins are broken down, and it plays an important role in cell communication and in the attachment of cells to one another (adhesion). Sialic acid is "free" when it is not attached (bound) to other molecules. 

Some SLC17A5 gene variants cause cells to produce a sialin protein that does not function properly; others prevent sialin from being produced. In a few cases, sialin is produced but cannot travel to the lysosomal membrane where it is needed.

SLC17A5 gene variants that alter or eliminate sialin activity cause free sialic acid to build up in the lysosomes. It is not known exactly how this buildup causes the neurologic signs and symptoms of FSASD.

FSASD belongs to a large family of conditions called lysosomal storage disorders. Each of these disorders is caused by the deficiency of a specific lysosomal enzyme or protein. 

Genetic Testing Information

• Genetic Testing Registry: Salla disease
• Genetic Testing Registry: Sialic acid storage disease, severe infantile type

Genetic and Rare Diseases Information Center

• Free sialic acid storage disease

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• INFANTILE SIALIC ACID STORAGE DISEASE; ISSD
• SALLA DISEASE; SD

Scientific Articles on PubMed

• PubMed

• Adams D, Wasserstein M. Free Sialic Acid Storage Disorders. 2003 Jun 13 [updated 2020 Jan 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1470/ Citation on PubMed
• Aula N, Kopra O, Jalanko A, Peltonen L. Sialin expression in the CNS implicates extralysosomal function in neurons. Neurobiol Dis. 2004 Mar;15(2):251-61. doi: 10.1016/j.nbd.2003.11.017. Citation on PubMed
• Barmherzig R, Bullivant G, Cordeiro D, Sinasac DS, Blaser S, Mercimek-Mahmutoglu S. A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease. Pediatr Neurol. 2017 Sep;74:87-91.e2. doi: 10.1016/j.pediatrneurol.2017.05.022. Epub 2017 Jun 1. Citation on PubMed
• Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 2003 Mar;13(3):137-45. doi: 10.1016/s0962-8924(03)00005-9. Citation on PubMed
• Huizing M, Hackbarth ME, Adams DR, Wasserstein M, Patterson MC, Walkley SU, Gahl WA; FSASD Consortium. Free sialic acid storage disorder: Progress and promise. Neurosci Lett. 2021 Jun 11;755:135896. doi: 10.1016/j.neulet.2021.135896. Epub 2021 Apr 20. Citation on PubMed
• Lemyre E, Russo P, Melancon SB, Gagne R, Potier M, Lambert M. Clinical spectrum of infantile free sialic acid storage disease. Am J Med Genet. 1999 Feb 19;82(5):385-91. Citation on PubMed
• Mach L. Biosynthesis of lysosomal proteinases in health and disease. Biol Chem. 2002 May;383(5):751-6. doi: 10.1515/BC.2002.078. Citation on PubMed
• Morin P, Sagne C, Gasnier B. Functional characterization of wild-type and mutant human sialin. EMBO J. 2004 Nov 24;23(23):4560-70. doi: 10.1038/sj.emboj.7600464. Epub 2004 Oct 28. Citation on PubMed or Free article on PubMed Central
• Suwannarat P. Disorders of free sialic acid. Mol Genet Metab. 2005 Jun;85(2):85-7. doi: 10.1016/j.ymgme.2005.04.005. No abstract available. Citation on PubMed