Sialic Acid Storage Diseases

Sialic Acid Storage Diseases Class: BIOL 10001 Instructor: Dr. Vivegananthan Submitted by: Lyndsay Grover Date Submitted: Thursday March 24 th, 2011

Introduction to Sialic Acid Storage Diseases Sialic Acid Storage Diseases is a rare autosomal inherited lysosomal storage disease that has three main forms: Infantile free sialic storage disease (ISSD), Salla, and intermediate severe Salla disease. Infantile free sialic storage disease is onset at birth and is regarded as the most severe form of Sialic acid storage diseases causing the children to only live into early childhood. Salla disease is less severe; allowing suffers to survive into adulthood, but has only been recorded to occur amongst the Finnish. Intermediate severe Salla disease has very few recorded cases and is just regarded as having symptoms varying between those of ISSD and Salla, no official medical information on the disease exists ("Sialic acid storage," 2008). Description of Symptoms Associated with Sialic Acid Storage Diseases Infantile free sialic acid storage disease (ISSD) is onset at birth and occurs in both sexes. Symptoms include: Failure to thrive: the inability for children to grow as well as obtain the essential nutrients to sustain themselves. Hypotonia: weakened muscle tone. Psychomotor delay: lack of development in their motor functions (Magalini, & Magalini, 1997). Children affected with ISSD may also have coarse facial features, show signs of hyperpigmentation: which displays itself in an extreme redness of the skin, suffer from seizures, bone malformations and may have conditions such as hepatosplenomegaly: enlargement of the liver and spleen, and cardiomegaly: an enlargement of the heart ("Sialic acid storage," 2008). Due to the varying conditions and the failure to thrive many children are unable to develop in any way and will often die in the first year of life. There are no recorded cases of children suffering from ISSD living past early childhood (Magalini, & Magalini, 1997).

Salla disease is onset at 12-18 months, occurs in both sexes and is ethnic specific to Finland and Sweden (Wynbrandt, & Ludman M.D., 2008). Symptoms include: Hypotonia: weakened muscle tone, ataxia: problems with movement and balance, spasticity: displayed by abnormal tensing of the muscles, athetosis: a slow, sinuous involuntary movement of the limbs ("Sialic acid storage," 2008). As well they suffer from seizures, developmental delay and mental retardation, showing signs of progressively worsening neurological disorders with age. Children that develop Salla in their early years are usually able to survive well into adulthood (Magalini, & Magalini, 1997). A) Infant suffering from ISSD displaying hepatosplenomegaly B) Infant suffering from ISSD displaying coarse facial features. Both infants display hyperpigmentation.

Occurrences of Sialic Acid Storage Disease Sialic acid storage disease is an extremely rare form of lysosomal storage diseases. The most severe form of sialic acid storage disease, infantile free sialic storage disease (ISSD), has only had a few dozen recorded cases of it in infants from all around the world. Salla disease has only had approximately150 reported cases of it and the majority of them are reported only in Finland. Intermediate severe Salla disease has only had a few reported cases ("Sialic acid storage," 2008). Cause of Genetic Defects Associate with Sialic Acid Storage Disease Sialic acid storage disease has a genetic defect basis for the cause of this disorder. The gene defect occurs in 6q14-15 or the SLC17A5 gene. This gene affects the enzyme Sialin which is a membrane protein which is found in the lysosome membrane (Krasnewich, LaMarca, Lang, Sidransky, & Staretz-Chacham, 2009). Sialin is crucial in the movement of free sialic acid in the cell and ensuring it binds to another molecule. The defect in the SLC17A5 gene cause the Sialin enzyme to be non-operational or to have its productivity severely reduced which leads to a buildup of free sialic acid in the cell ("Sialic acid storage," 2008). This build-up of free sialic acid results in an accumulation of it in tissues as well as excretion of it through the urine. This increased concentration of free sialic acid in the tissue and urine is what cause the symptoms present by ISSD and Salla disease (Wishart, 2010). Experimental Proof of Defects Associate with Sialic Acid Storage Disease Using DNA analysis scientists have been able to discover the cause for the enzyme Sialin being unable to function or be produced at all in some cases. Taking samples of genomic DNA from 12 patients suffering from ISSD and Salla disease and using PCR to amplify the quantity of

DNA. Using various DNA polymerases they were able to cut the DNA at various parts and identify the base pair sequences present in the DNA. When reviewing the DNA analysis they found 14 different sequence alterations. The majority of the alterations were varying degrees of deletions ending in stop codons, followed by 2 splice site mutation, 2 nonsense mutations and 2 missense mutations. The premature production of stop codon in the sequence prevented the proteins essential to create the Sialin enzyme to be produced (Bonnet, V, Bouvier, R, Cheillan, D, Froissart, R, & Tourret, S., 2005). In addition to understanding the defect in the Sialin enzyme, scientists have also been able to prove the inability for the sialic acid to be bound to the sialin enzyme and its increased amounts in the body. Using cultured fibroblasts of lysosomal membrane vesicles specific to sialic acid transport from patients with Salla disease they measured the transport activity of sialic acid and glucuronic acid (an acid found to pair with the Sialin enzyme as well as sialic acid) in various ph solutions to make the most optimal environment from the proton-dependent carriers in Sialin. Despite creating optimal environments for the transfer of both sialic acid and glucuronic acid their levels of transport recorded in the cell were extremely low. To prove that this is indeed the autosomal inheritance disorder Salla and not another occurrence they tested cultured fibroblast from the parents of the patients and found the exact same deficiency in transportation of sialic and glucuronic acids (Aula, Beerens, Mancini, & Verheijen, 1991).

Sialic acid (NeuAc) and glucuronic acid (GlcAc) uptake levels in Control vs. Patient suffering from Salla disease.

Transport levels of sialic acid (NeuAc) and glucuronic acid (GlcAc) in various test subjects. Other Information Regarding Sialic Acid Storage Disease Aside from the overall rarity of the disease, with accumulated worldwide reports of its various forms totalling to slightly fewer than 200, the origins of it are interesting. The form of sialic acid storage disease called Salla, also known as Finnish type sialuria, takes its name from the region of Finland where the disease is specific to. Almost all reported cases of Salla have been found in Salla, Finland (Wynbrandt, & Ludman M.D., 2008). What is also interesting is the very rare mentioning of the third form of sialic acid storage disease, intermediate severe salla disease, it has been referenced to in a handful of medical papers and journals but no official entries of it exist in any medical dictionary or encyclopaedia. This is most likely due to the fact that there have only been a few reported cases of it worldwide to date.

References Aula, P.P., Beerens, C.E.M.T., Mancini G.M.S., & Verheijen, F.W. (1991). Sialic acid storage diseases. Lysosomal Transport of Acidic Sugars in Sialic Acid Storage Diseases, 87. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/pmc295166/pdf/jcinvest00058-0203.pdf Bonnet, V, Bouvier, R, Cheillan, D, Froissart, R, & Tourret, S. (2005). Clinical, morphological, and molecular aspects of sialic acid storage disease manifesting in utero. Sialic Acid with In Utero Presetation, 42. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1735939/pdf/v042p00829.pdf?tool=pmcentrez doi: 10.1136/jmg.2004.029744 Krasnewich, D, LaMarca, M.E., Lang, T.C., Sidransky, E, & Staretz-Chacham, O. (2009). Lysosomal storage disorders in the newborn. Pediatrics, 123(4), 1191-1207. Magalini, S.C., & Magalini, S.I. (1997). ISSD. (1997). Dictionary of medical syndromes. Philadelphia, PA: Lippincott-Raven Publishers. Magalini, S.C., & Magalini, S.I. (1997). Salla. (1997). Dictionary of medical syndromes. Philadelphia, PA: Lippincott-Raven Publishers. Sialic acid storage disease. (2008, February). Retrieved from http://ghr.nlm.nih.gov/condition/sialic-acid-storage-disease Wishart, DS. (2010, January). Salla disease/infantile sialic acid storage disease. Retrieved from http://pathman.smpdb.ca/pathways/smp00240/pathway

Wynbrandt, J, & Ludman M.D., M.D. (2008). Salla Disease. (2008). The encyclopaedia of genetic disorders and birth defects. New York, NY: Facts on File Inc.