Author: Beatrice Brusasco
Date: 03/07/2014



Salla disease (SD), or adult-type free sialic acid storage disease, is an autosomal recessive lysosomal storage disorder characterized by impaired transport of free sialic acid across the lysosomal membrane and severe psychomotor retardation.
The genetic locus for free sialic acid storage disease maps to the long arm of chromosome 6, jun,1994


This disorder is characterised by defective storage of free sialic acid and belongs to the Finnish disease heritage. However, sporadic cases of SD have been reported in many countries. The disease is caused by mutation of the SLC17A5 gene.
An Unusual Developmental Profile of Salla Disease in a Patient with the SallaFIN Mutation, 2012
This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes.
Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity, jun, 1982
Defects of the sialic acid transporter SLC17A5 cause a lysosomal storage disease characterized by systemic accumulation of free sialic acid in a wide range of tissues.
Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation, jul, 2013

The allelic disorder of free sialic acid metabolism cause:

  • Salla Disease (SD)
  • Intermediate severe Salla disease
  • Infantile free sialic acid storage disease (ISSD)

The mildest phenotype is Salla disease, which is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures.
The most severe phenotype is ISSD, characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Free Sialic Acid Storage Disorders. jun, 2013.

Similarities in biochemical findings have suggested that Salla disease (SD) and the infantile form of sialic acid storage disease (ISSD) could represent allelic disorders, despite their drastically different clinical phenotypes. SD and ISSD are both characterized by lysosomal storage of free N-acetyl neuraminic acid.
All forms of the disease show linkage to the same locus on 6q14-q15.
Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15. oct,1995.
The classical form of SD, enriched in the Finnish population, is related to the p.R39C designed Salla(FIN) founder mutation. A more severe phenotype is due both to compound heterozygosity for the p.R39C mutation and to different mutations.
Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla disease. set, 2005.


Salla disease is the mildest phenotype characterized by a normal appearance and normal neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor retardation. Muscular hypotonia is often first recognized at approximately age six months. One third of affected children learn to walk. Speech can be limited to single words but understanding of speech is good. Slow developmental progress often continues until the third decade, after which regression can occur.
Some individuals with Salla disease present later in life with spasticity, athetosis, and epileptic seizures, becoming nonambulatory and nonverbal. Affected individuals are characterized as good-humored and sociable.
Abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings. MRI reveals these predominant white matter changes. Cerebellar white matter changes are also present and can explain the ataxia.

In addition to the central dysmyelination, a peripheral dysmyelination with the clinical picture of a polyneuropathy occurs with variable neurologic presentations.
Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. In a single individual, growth hormone and gonadotropin deficiencies were observed.
Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed.
Free Sialic Acid Storage Disorders. jun, 2013.

Neurocognitive profile

The characteristic cognitive profile consisted of a lower non-verbal performance (mean developmental age 13mo) compared with linguistic skills (mean developmental age 17mo). In particular, spatial and visual-constructive impairments were typical of these patients. Tactile and visual discrimination of forms was poor. Tasks demanding hand–eye coordination, maintenance of visual attention, and those requiring short-term visual memory and executive skills were performed better. Receptive language skills were notably better compared with expressive speech. The patients’interactive and non-verbal communication skills were quite strong.
Neurocognitive profiles in Salla disease. dec, 2004


The diagnosis of Salla disease is suspected in individuals who manifest truncal ataxia and hypotonia at age approximately one year, developmental delays and growth retardation in early childhood, and severe cognitive and motor impairment or intellectual disability in adulthood. The association of intellectual disability,_spasticity_, ataxia, myelination defects, and facial coarsening in adulthood is suggestive of Salla disease.
The diagnosis of infantile free sialic acid storage disease (ISSD) is suspected in individuals with early multisystemic involvement including: hydrops fetalis, hepatosplenomegaly, failure to thrive, increasingly coarse facial features, neurologic deterioration typical of a lysosomal storage disease, dysostosis, and early death
Free Sialic Acid Storage Disorders. jun, 2013.
Salla disease must be suspected in patients with unexplained psychomotor retardation associated with ataxia and/or pyramidal symptoms, and MRI findings consistent with cerebral hypomyelination, irrespective of the patient's ethnic origin. A mutation screening based on R39C change does not exclude Salla disease outside Finland.
An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease. jun, 2002.


  • Free sialic acid. Sialic acids are a family of negatively charged sugars, one of which, N-acetylneuraminic acid, is elevated in lysosomes in free sialic acid storage disorders:
  • Urinary excretion of free sialic acid, measured by the fluorimetric thiobarbituric acid assay, thin-layer chromatography or mass spectrometry, is elevated about tenfold in individuals with Salla disease and about 100-fold in individuals with ISSD. HPLC/tandem mass spectrometry is also able to detect free sialic acid in urine
  • Cultured fibroblasts from individuals with Salla disease and individuals with ISSD show increased concentration of free sialic acid
  • Lysosomal localization of free sialic acid, suspected by electron microscopy of biopsy material (e.g., skin or liver), confirms the diagnosis of a free sialic acid storage disorder. Subcellular fractionation studies can demonstrate the lysosomal localization of the elevated free sialic acid.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD):

  • Testing of at-risk pregnancies using SLC17A5 sequence analysis requires prior identification of the disease-causing mutations in the family.
  • For suspected ISSD, cultured amniocytes or tissue obtained by CVS can be used for measurement of tissue free sialic acid levels.
  • For suspected Salla disease, cultured amniocytes may have sialic acid levels that are inadequately elevated to reliably differentiate them from the sialic acid levels seen in normals/carriers. Therefore, uncultured tissue derived from CVS is the preferred specimen for free sialic acid measurement.
    Free Sialic Acid Storage Disorders. jun, 2013.


Screening is performed by determination of free sialic acid (FSA) in urine or amniotic fluid supernatant (AFS). Subsequent diagnosis of SASD is performed by quantification of FSA in cultured fibroblasts and by mutation analysis of the sialin gene, SLC17A5. The whole procedure can be performed in 2-4 h. Reference values in AFS were 0-8.2 μmol/L for 15-25 weeks of gestation and 3.2-12.0 μmol/L for 26-38 weeks of gestation. In AFS samples from five fetuses affected with ISSD FSA was 23.9-58.9 μmol/L demonstrating that this method is able to discriminate ISSD pregnancies from normal ones.
FSA in SASD fibroblasts was clearly elevated compared to normal controls 0.3-2.2 nmol/mg.
Prenatal screening of sialic acid storage disease and confirmation in cultured fibroblasts by LC-MS/MS. oct, 2011


Mutations in SLC17A5 lead to defective sialin and elevated intralysosomal free sialic acid. How elevated intralysosomal free sialic acid causes pathology is not understood. Expression of sialin in the brain may explain part of the neurologic sequelae of Salla disease/ISSD

Gene structure. SLC17A5 consists of 11 exons, all of which are coding exons. Northern blot analysis shows major transcripts of 3.5 kb and 4.5 kb.

Benign allelic variants. One known benign variant in the coding region is p.Ala43Thr.

Pathogenic allelic variants. Different missense, nonsense, and splice site mutations, insertions, and deletions have been recognized as causing lysosomal free sialic acid storage disorders. The p.Arg39Cys mutation is highly prevalent among affected individuals of Finnish heritage.

Normal gene product. The gene product of SLC17A5, sialin, is a 495-amino acid lysosomal membrane transport protein. Sialin has 42% sequence identity with transport proteins found in rat and mouse. Sialin is an integral lysosomal membrane transporter that exports free sialic acid from lysosomes. Deficient or defective sialin results in excessive lysosomal storage of the free sialic acid produced by lysosomal degradation of glycoproteins and glycolipids.

Abnormal gene product. It is presumed that most SLC17A5 mutations result in defective or absent sialin. However, for two known mutations in SLC17A5, sialin is misrouted and fails to incorporate into the lysosomal membrane, which may be thought of as the functional equivalent of absent sialin.
Free Sialic Acid Storage Disorders. jun, 2013.


The medical and psychosocial management of individuals with free sialic acid storage disorders is symptomatic and supportive.
Management focuses on rehabilitation to optimize mobility and communication.
Programs to foster normal development and assure adequate nutrition should be implemented.
Treatment of seizures follows standard management principles.
Free Sialic Acid Storage Disorders. jun, 2013.

2014-07-05T21:57:54 - Beatrice Brusasco
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