NORD gratefully acknowledges William A. Gahl, MD, PhD, Senior Investigator, National Human Genome Research Institute; Head, Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Free sialic acid storage disorders are a group of related disorders characterized by the abnormal accumulation of sialic acid in various cells and tissues of the body. Although these disorders comprise a spectrum of disease severity, they have historically been divided into three subtypes: infantile free sialic acid storage disease (ISSD), the most severe form; Salla disease, the mildest form; and intermediate lysosomal free sialic acid storage disease which is less severe than ISSD, but more serious than Salla disease. The specific symptoms associated with these disorders can vary greatly. All the disorders are characterized by some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment. Free sialic acid storage disorders occur because of changes (mutations) of the SLC17A5 gene and are inherited in an autosomal recessive pattern.
Free sialic acid storage disorders belong 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. Low levels or inactivity of a transport protein known as sialin leads to the abnormal accumulation (storage) of free sialic acid in the tissues of affected individuals. The function of sialin is to transport sialic acid out of lysosomes.
The symptoms and severity of free sialic acid storage disorders 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 of the symptoms discussed below.
INFANTILE FREE SIALIC ACID STORAGE DISEASE (ISSD)
Symptoms of ISSD are usually apparent at birth or early in infancy; some infants may be born prematurely. 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 ISSD 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).
ISSD 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.
Salla disease is the mildest form of the free sialic acid storage disorders. The specific symptoms and severity of the disorder 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 Salla disease 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 produce speech is affected more severely than the ability to understand speech. Affected children exhibit some degree of cognitive impairment as well.
Some individuals with Salla disease 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 SALLA DISEASE
The severity of intermediate lysosomal free sialic acid storage disease 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 ISSD and Salla disease, but less severe than ISSD and more severe than Salla disease.
Free sialic acid storage disorders are caused by mutations of the SLC17A5 gene. The SLC17A5 gene contains instructions for producing (encoding) a protein called sialin that is required to transport free sialic acid from inside lysosomes. Sialic acid is a sugar produced when lysosomes break down certain sugar-containing proteins (glycoproteins) or fats (glycolipids). In sialic acid storage disorders, deficient levels of functioning sialin result in the accumulation (storage) of free sialic acid in lysosomes.
These conditions are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Free sialic acid storage disorders affect males and females in equal numbers. The exact frequency of these disorders in the general population is unknown. Salla disease has been reported in more than 150 individuals, most from Finland and Sweden. Free sialic acid storage diseases may go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
AA diagnosis of a free sialic acid storage disorder may be suspected based upon identification of characteristic signs and symptoms. A diagnosis may be confirmed by 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.
Molecular genetic testing (which can identify mutations in the SLC17A5 gene) is available on a clinical basis to confirm the diagnosis.
Diagnosis before birth (prenatally) is possible through chorionic villus sampling (CVS). During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes) to detect elevated levels of free sialic acid.
There is no specific treatment for any of the free sialic acid storage disorders. Treatment is directed toward the specific symptoms that are apparent in each individual. Seizures are treated by generally accepted standards such as the use of anticonvulsants.
Early intervention is important in ensuring that children with free sialic acid storage disorders 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:2695-2697.
Aula P, Gahl WA. Disorders of Free Sialic Acid Storage. In: Scriver CR, Beaudet AL, Sly WS, et al. eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill Companies, 2001;5109-5120.
Lyon G, Adams RD, Kolodny EH. Eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. McGraw-Hill Companies. New York, NY; 1996:62-64.
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. Epub 2015 Jul 13. PMID: 26171070
Aula N, Aula P. Prenatal diagnosis of free sialic acid storage disorders (SASD). Prenat Diagn. 2006;26:655-658.
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.
Wrenden CC, Wlizla M, Reimer RJ. Varied mechanisms underlie the free sialic acid storage disorders. J Biol Chem. 2005;280:1408-1416.
Alajoki L, Varho T, Posti K, Aula P, Korhonen T. Neurocognitive profiles in Salla disease. Dev Med Child Neurol. 2004;46:832-837.
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.
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.
Adams D, Gahl WA. Free Sialic Acid Storage Disorders. 2003 Jun 13 [Updated 2013 Jun 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1470/ Accessed July 18, 2019.
Aula P, Aula N, Gahl WA. Recent Developments in Disorders of Free Sialic Acid Storage. In The Metabolic and Molecular Bases of Inherited Disease. Published online at: http://ommbid.mhmedical.com/content.aspx?sectionid=62655871&bookid=971&jumpsectionID=62655913&Resultclick=2 Accessed July 18, 2019.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:604369; Last Update 01/02/2014. Available at: http://omim.org/entry/604369 Accessed July 18, 2019.
Nelson SL. Lysosomal Storage Disease.Medscape. Updated: Apr 03, 2019. Available at: http://www.emedicine.com/neuro/topic668.htm Accessed July 18, 2019.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100