Last updated:
8/2/2023
Years published: 2010, 2013, 2016, 2019, 2023
NORD gratefully acknowledges Marjan Huizing, PhD, Marya Sabir, BS, Lynne Wolfe, MS, CRNP, BC, and David Adams, MD, PhD, Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Summary
Free sialic acid storage disorder (FSASD) is a rare neurodegenerative, multisystem disorder characterized by abnormal accumulation of free sialic acid (a sugar molecule) in various tissues and organs of the body. FSASD occurs because of changes (variants) in the SLC17A5 gene and is inherited in an autosomal recessive pattern meaning each parent passes down one variant to the affected child. FSASD comprises a spectrum of disease severity, historically divided into three subtypes, ranging from the most severe form (also called infantile free sialic acid storage disorder (ISSD)), often lethal in utero or in early childhood, to an intermediate severe form, to the mildest, slowly progressive form (also called Salla disease) with patients living into adulthood. The specific symptoms associated with these subtypes can vary greatly. All subtypes are associated with some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment.
Introduction
FSASD belongs to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks.
The protein SLC17A5, also called sialin, transports sialic acid out of lysosomes. Low levels or inactivity of SLC17A5 leads to abnormal accumulation (storage) of free sialic acid inside the lysosomes of tissues and organs of individuals affected with FSASD. Sialic acid is a charged sugar involved in various biological processes, including cellular recognition, cell-cell attachment and cell signaling. Abnormal sialic acid levels in tissues and organs likely contribute to the symptoms of individuals with FSASD. Like some other lysosomal storage diseases, the spectrum of FSASD disease severity correlates with the severity of the genetic variants (e.g., variants in the SLC17A5 gene in FSASD) and the amount of stored material (e.g., free sialic acid in FSASD) in lysosomes.
The symptoms and severity of FSASD are highly variable. Some individuals will develop severe, life-threatening complications; others will have milder findings. The more severely affected patients usually exhibit symptoms within six months of birth or even before birth; milder cases may become apparent later during infancy or childhood. Affected individuals may not have all the symptoms discussed below.
Severe FSASD
Symptoms of severe FSASD (also called infantile sialic acid storage disorder, ISSD) are usually apparent at birth or early in infancy; some infants may be born prematurely or die in the womb. Affected infants may have fluid accumulation in the abdominal cavity (ascites), abnormal enlargement of the liver and spleen (hepatosplenomegaly) and coarse facial features. Some infants have diminished muscle tone (hypotonia) and may be referred to as “floppy babies”.
Affected infants may also fail to gain weight and grow at the normal rate for age and sex (failure to thrive), may experience significant delays in attaining developmental milestones (developmental delays) or may lose milestones that have been previously acquired. Cognitive deficits and seizures may occur.
Skeletal abnormalities in infants with severe FSASD can include malformation (dysplasia) near the ends of the long bones (metaphyses), clubbed feet, abnormally short thigh bones (femurs), malformation (dysplasia) of the hip and underdevelopment of certain bones of the fingers and toes (phalanges).
Severe FSASD eventually progresses to cause life-threatening complications such as serious respiratory infections and abnormal enlargement of the heart (cardiomegaly). Some infants develop nephrotic syndrome, in which damage to the kidneys causes them to leak large quantities of protein into the urine. Nephrotic syndrome can cause swelling in the arms and legs, around the eyes or in other areas due to fluid accumulation (edema). Additional symptoms may include a swollen abdomen, unintended weight gain and high blood pressure. Most individuals with severe FSASD die in early childhood.
Mild FSASD
Mild FSASD (also called Salla disease) is the least severe form of the disorder. The specific symptoms and severity can vary from one individual to another. Although Salla disease can cause life-threatening complications, some individuals have lived into their 70s. Affected infants appear normal at birth but may develop symptoms during the first year of life. Such symptoms include diminished muscle tone (hypotonia), rapid, involuntary eye movements (nystagmus) and difficulty coordinating voluntary movements (ataxia). Affected infants often exhibit delays in reaching developmental milestones (developmental delays) such as sitting, walking or talking.
Approximately two-thirds of children with mild FSASD eventually learn to walk. Some degree of speech impairment is usually present. Affected infants may learn single words or small sentences, but this ability may be lost as they age. The ability to speak is affected more severely than the ability to understand speech. Affected children exhibit some degree of cognitive impairment as well.
Some individuals with mild FSASD may not develop symptoms until later in childhood when a variety of neurological findings become apparent. These include seizures, involuntary muscles spasms that result in slow, stiff movements of the legs (spasticity) and repetitive, involuntary, writhing movements of the arms and legs (athetosis). Some individuals who previously developed the ability to walk or talk may lose these skills (regression). Some individuals may experience a gradual coarsening of facial features.
Intermediate FSASD
The severity of intermediate FSASD can vary greatly from one individual to another. Only a handful of people with intermediate lysosomal free sialic acid storage disease have been reported in the medical literature. The symptoms are similar to those of the mild and severe forms of the disease, but less severe than severe FSASD and more severe than mild FSASD.
FSASD is caused by changes (variants) in the SLC17A5 gene. The SLC17A5 gene contains instructions for producing (encoding) a protein called sialin that is required to transport free sialic acid out of lysosomes and into the cytosol of cells. Sialic acid is a charged sugar produced when lysosomes break down certain sugar-containing proteins (glycoproteins), carbohydrates or fats (glycolipids). In sialic acid storage disorders, deficient levels of functioning sialin result in the accumulation (storage) of free sialic acid in lysosomes.
FSASD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a changed gene from each parent. If an individual receives one normal gene and one changed gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the changed gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
FSASD affect males and females in equal numbers. The worldwide prevalence of FSASD is estimated at less than 1 per 1,000,000 individuals. Higher estimated prevalence rates occur in the Salla region of Finland and in other Scandinavian countries.
Approximately 250 individuals with FSASD have been reported in the literature, of which the majority (> 160 cases) are of Finnish or Swedish ancestry. Individuals with FSASD may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disease in the general population.
A diagnosis of a FSASD may be suspected based upon identification of characteristic signs and symptoms and by performing a thorough clinical evaluation, a detailed patient history (including family history) and specialized tests that detect elevated levels of free sialic acid in certain cells and tissues or in urine.
A suspected diagnosis before birth (prenatally) is possible through chorionic villus sampling (CVS). During CVS, fetal tissue samples are removed, and tests (assays) are performed on cultured tissue cells and/or white blood cells (leukocytes) to detect elevated levels of free sialic acid.
The diagnosis of FSASD is ultimately confirmed by identifying disease-causing genetic variant(s) in the SLC17A5 gene by molecular genetic testing. This testing is available on a clinical basis.
Treatment
There is no disease-modifying treatment specific for FSASD. Treatment is directed toward the specific symptoms that are apparent in each individual. Seizures are treated by generally accepted standards including the use of anticonvulsants.
Early intervention is important in ensuring that children with FSASD reach their highest potential. Services that may be beneficial include special education, physical therapy to improve strength and coordination, speech therapy and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.
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JOURNAL ARTICLES
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;755:135896. DOI: 10.1016/j.neulet.2021.135896
Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M. A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease-an ultra-orphan multisystemic lysosomal storage disorder. Genet Med. 2019;21(2):347-352. DOI: 10.1038/s41436-018-0051-3
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;74:87-91.e2. DOI: 10.1016/j.pediatrneurol.2017.05.022
Paavola LE, Remes AM, Harila MJ, Varho TT, Korhonen TT, Majamaa K. A 13-year follow-up of Finnish patients with Salla disease. J Neurodev Disord. 2015;7(1):20. DOI: 10.1186/s11689-015-9116-7
Alajoki L, Varho T, Posti K, Aula P, Korhonen T. Neurocognitive profiles in Salla disease. Dev Med Child Neurol. 2004;46:832-837. DOI: 10.1017/s0012162204001458
Aula N, Aula P. Prenatal diagnosis of free sialic acid storage disorders (SASD). Prenat Diagn. 2006;26:655-658. DOI: 10.1002/pd.1431
Morse RP, Kleta R, Alroy J, Gahl WA. Novel form of intermediate salla disease: clinical and neuroimaging features. J Child Neurol. 2005;20:814-816. DOI: 10.1177/08830738050200100601
Wrenden CC, Wlizla M, Reimer RJ. Varied mechanisms underlie the free sialic acid storage disorders. J Biol Chem. 2005;280:1408-1416. DOI: 10.1074/jbc.M411295200
Kleta R, Aughton DJ, Rivkin MJ, et al. Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children. Am J Med Genet A. 2003;120A:28-33. DOI: 10.1002/ajmg.a.20024
Aula N, Salomaki P, Timonen R, et al. Sialin expression in free sialic acid-storage diseases indicates some genotype-phenotype correlation. Am J Hum Genet. 2000;67:832-840. DOI: 10.1086/303077
Verheijen FW, Verbeek E, Aula N, Beerens CEMT, Havelaar AC, Joosse M, Peltonen L, Aula P, Galjaard H, van der Spek PJ, Mancini GM. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet. 1999; 23:462. DOI: 10.1038/70585
INTERNET
Adams D, Wasserstein M. Free Sialic Acid Storage Disorders. 2003 Jun 13 [Updated 2020 Jan 23]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1470/ Accessed Aug 2, 2023.
Aula P, Gahl WA. Disorders of Free Sialic Acid Storage. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2019. Accessed November 30, 2022. https://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225891389 Accessed Aug 2, 2023.
Salla Disease. Online Mendelian Inheritance in Man (OMIM). Last Update 01/02/2014. Available at: https://omim.org/entry/604369 Accessed Aug 2, 2023.
Sabir MS. SciBites 2022. Free Sialic Acid Storage Disorder. https://www.youtube.com/watch?v=_KGLD_UK0og Accessed Aug 2, 2023.
Sabir MS. Three Minute Talks (TmT) NIH IRP 2022. Free Sialic Acid Storage Disorder. https://www.youtube.com/watch?v=PU_ektiuSQY Accessed Aug 2, 2023.
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