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Free Sialic Acid Storage Disorders

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: June 6, 2013.

Estimated reading time: 16 minutes


Clinical characteristics.

The allelic disorders of free sialic acid metabolism – Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) ‒ are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. 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 result from defective free sialic acid transport out of lysosomes caused by pathogenic variants in SLC17A5, encoding the lysosomal transport protein sialin. The diagnosis of a free sialic acid storage disorder is suggested by significantly elevated free (i.e., unconjugated) sialic acid (referred to as N-acetylneuraminic acid, a negatively charged sugar) in urine and/or cerebrospinal fluid using the fluorimetric thiobarbituric acid assay, thin-layer chromatography, or mass spectrometry. The diagnosis is established either by demonstrating lysosomal (rather than cytoplasmic) localization of elevated free sialic acid or by identifying pathogenic variants in SLC17A5.


Treatment of manifestations: Management is symptomatic and supportive: rehabilitation to optimize mobility and communication; provision of adequate nutrition; standard treatment of seizures.

Surveillance: Regular evaluation by a rehabilitation specialist to identify potentially helpful interventions.

Genetic counseling.

The free sialic acid storage disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing for pregnancies at increased risk is possible by measuring free sialic acid either in chorionic villus biopsy specimens (obtained by chorionic villus sampling at ~10-12 weeks' gestation) or in amniocytes (obtained by amniocentesis usually performed at ~15-18 weeks' gestation). Carrier testing for relatives at increased risk and prenatal testing for pregnancies at increased risk is an option if both causing pathogenic variants have been identified in a family.

GeneReview Scope

Free Sialic Acid Storage Disorders: Included Phenotypes 1
  • Salla disease
  • Infantile free sialic acid storage disease

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Clinical Diagnosis

There are no consensus clinical diagnostic criteria for Salla disease. 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 [Helip-Wooley et al 2007].


Affected individuals

  • 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 [Valianpour et al 2004].
      Note: (1) In the thiobarbituric acid assay, interfering substances may lower the measurement and chromophores may contribute to absorbance, creating a false measurement. (2) In thin-layer chromatography, an elevation of free sialic acid may be overlooked.
  • Cultured fibroblasts from individuals with Salla disease and individuals with ISSD show increased concentration of free sialic acid [Renlund et al 1986].
  • 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.

Carriers. Biochemically based carrier testing is not feasible.

Molecular Genetic Testing

Gene. SLC17A5 is the only gene in which pathogenic variants are known to cause Salla disease and ISSD.

Table 1.

Molecular Genetic Testing Used in Free Sialic Acid Storage Disorders

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
SLC17A5Sequence analysisSequence variants 4Unknown
Targeted analysis / scanning of select exons for pathogenic variants 5p.Arg39Cys 6Homozygous p.Arg39Cys in individuals of Finnish origin (91%) 7
Deletion/duplication analysis 8Exon or whole-gene deletions 8Unknown

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Scanning of exon 2 for pathogenic variants may be used to detect the p.Arg39Cys variant.


The prevalence of p.Arg39Cys is high in the founder region of northeastern Finland (see Prevalence).


Finnish individuals with Salla disease [Aula et al 2000]


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband. Strong evidence for a sialic acid storage disorder (in order of the frequency of use in a clinical setting):

  • Urinary excretion of sialic acid on the order of 100-fold normal
  • Sequence analysis of SLC17A5 that reveals biallelic, well-described pathogenic variants
  • Elevated fibroblast concentration of free sialic acid
  • Cell biologic studies showing localization of sialic acid to lysosomes

Supportive evidence for a sialic acid storage disorder:

  • Characteristic physical findings
  • Hypomelination evident on brain MRI
  • Urinary excretion of sialic acid on the order of tenfold normal
  • Elevated CSF sialic acid with or without elevated urinary excretion of sialic acid
  • Pathogenic-appearing but novel biallelic SLC17A5 pathogenic variants detected by sequence analysis

Carrier testing of at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies may be performed using molecular or biochemical studies:

  • Testing of at-risk pregnancies using SLC17A5 sequence analysis requires prior identification of the pathogenic variants 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 [Salomäki et al 2001, Aula & Aula 2006, Gopaul & Crook 2006].

Clinical Characteristics

Clinical Description

The phenotypes of the allelic disorders of free sialic acid metabolism ‒ Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) ‒ range from mild to severe. All are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid [Aula & Gahl 2001]. Onset varies from apparently unaffected in the newborn period to severely affected prenatally.

Salla Disease

Salla disease is the mildest phenotype [Varho et al 2002], characterized by a normal appearance and normal neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor retardation [Renlund et al 1983, Alajoki et al 2004]. 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 [Varho et al 2002].

Abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings. MRI reveals these predominant white matter changes [Sonninen et al 1999]. Cerebellar white matter changes are also present and can explain the ataxia [Linnankivi et al 2003, Biancheri et al 2004].

In addition to the central dysmyelination, a peripheral dysmyelination with the clinical picture of a polyneuropathy occurs with variable neurologic presentations [Varho et al 2000, Varho et al 2002].

Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. In a single individual, growth hormone and gonadotropin deficiencies were observed [Grosso et al 2001].

Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed.

Intermediate severe Salla disease. Since the advent of molecular studies, phenotypes with a severity between those of Salla disease and ISSD [Aula & Gahl 2001] have been attributed to compound heterozygosity for the Salla disease-causing common pathogenic variant p.Arg39Cys and another SLC17A5 pathogenic variant [Kleta et al 2003]. Thus the term "intermediate severe Salla disease" was proposed [Aula et al 2000].

Infantile Free Sialic Acid Storage Disease (ISSD)

ISSD, the most severe phenotype, is characterized by severe developmental delays, coarse facial features, hepatosplenomegaly, and cardiomegaly. ISSD can present prenatally and in the neonatal period with nonimmune hydrops fetalis [Lemyre et al 1999, Stone & Sidransky 1999, Froissart et al 2005]. Some affected infants are born prematurely. Other affected infants appear normal at birth but deteriorate and lose milestones during infancy [Kleta et al 2003, Kleta et al 2004]. Seizures are common.

Some infants with ISSD develop proteinuria and nephrotic syndrome [Lemyre et al 1999, Ishiwari et al 2004].

Skeletal changes may include irregular metaphyses, diffuse hypomineralization, club feet, short femurs, enlarged metaphyses, fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges [Froissart et al 2005].

Death usually occurs in early childhood, typically from respiratory infections.

Genotype-Phenotype Correlations

Correlations between the type of SLC17A5 pathogenic variant and the severity of the lysosomal free sialic acid storage disease have been identified [Aula et al 2000, Varho et al 2000, Kleta et al 2003]:

  • Homozygosity for the pathogenic missense variant p.Arg39Cys, a single Finnish founder variant, leads to Salla disease, with its slow clinical course of neurologic deterioration.
  • Compound heterozygosity for the p.Arg39Cys pathogenic variant and another SLC17A5 pathogenic variant leads to intermediate severe Salla disease, as does homozygosity for the p.Lys136Glu pathogenic variant [Biancheri et al 2005].
  • Compound heterozygosity for pathogenic variants other than p.Arg39Cys leads to the severe phenotype of ISSD, with early onset and multisystemic involvement.

Variable expression has been observed among affected family members [Landau et al 2004].


Free sialic acid storage disorders seem to be fully penetrant. However, Mochel et al [2009] reported a case of two individuals with homozygous p.Lys136Glu pathogenic variants, no detectable urinary sialic acid abnormality, and elevated CSF free sialic acid suggesting that penetrance based on urinary studies alone may be incomplete.


Free sialic acid storage disorders have been and continue to be labeled with different terms, mainly because of the different names used to denote N-acetylneuraminic acid. Although no consensus exists, the terms Salla disease, intermediate severe Salla disease, and ISSD are the most widely accepted; NANA disease is falling into disuse. Further confusion results from the fact that ISSD and Salla disease are often diagnosed without firm molecular proof, and show variable clinical expression in affected individuals.


Salla disease has been reported in approximately 150 individuals, mainly from Finland and Sweden [Aula et al 2000, Erikson et al 2002]. Individuals with molecularly proven Salla disease have been identified outside of Finland and Sweden [Martin et al 2003]. The prevalence of the SLC17A5 pathogenic variant p.Arg39Cys is high in the founder region of northeastern Finland, where the carrier frequency is in the range of 1:100 [Aula et al 2000]. Ninety-five percent of individuals of Finnish heritage with Salla disease have the p.Arg39Cys pathogenic variant. The prevalence of other SLC17A5 pathogenic variants appears to be independent of the geographic origin or ethnicity of affected individuals; their presence has been documented in more than 30 individuals from several countries throughout the world [Lemyre et al 1999, Aula et al 2000, Kleta et al 2003, Martin et al 2003, Sønderby Christensen et al 2003, Kleta et al 2004].

Differential Diagnosis

Increased Urinary and Cellular Free Sialic Acid

Sialuria (OMIM 269921). The clinical course of sialuria involves developmental delay and hepatomegaly but does not include severe neurologic involvement or early death [Seppala et al 1999, Enns et al 2001, Leroy et al 2001]. In sialuria, elevation of free sialic acid occurs in the cytoplasm rather than in the lysosome. The only disorders in which significantly elevated urinary and cellular free sialic acid are known to occur are sialuria and the free sialic acid storage disorders (Salla disease and ISSD).

Based on clinical suspicion and the finding of elevated free sialic acid in the urine, one of two steps is taken to distinguish these conditions:

  • The cellular (cytoplasmic versus lysosomal) localization of free sialic acid can be documented; a predominantly lysosomal localization indicates Salla disease or ISSD.
  • Molecular studies of SLC17A5 (for Salla disease and ISSD) or GNE (for sialuria) can be performed. Of interest, all of the published sialuria-causing pathogenic variants in GNE have been localized to a small region of the gene (p.Arg263 – p.Arg266) thought to be important for allosteric feedback regulation [Ferreira et al 1999].

Other causes of mild elevation in urinary free sialic acid may exist.

Sialidosis and galactosialidosis. If sialic acid bound to glycoproteins or glycolipids is stored, disorders such as sialidosis caused by sialidase (neuraminidase) deficiency and galactosialidosis caused by combined sialidase and galactosidase deficiency should be considered. These enzyme deficiencies involve lysosomal storage of sialic acid-containing glycoconjugates [Gahl et al 1996]. Both of these disorders have features typical of lysosomal storage diseases but vary widely in their manifestations.

Clinical Findings

Several lysosomal storage disorders display the clinical manifestation of coarse facial features and developmental delays. Other causes of nonimmune hydrops fetalis include: alpha-iduronidase deficiency (MPS1), glycosylceramidase deficiency (Gaucher disease), beta-glucuronidase deficiency, I-cell disease, beta-glucosidase deficiency, acid sphingomyelinase deficiency, acid lipase deficiency, galactosylcerabrosidase deficiency (Krabbe disease), sialidase deficiency, and galactosialidosis.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a free sialic acid storage disorder, the following evaluations are recommended:

  • Neurologic and developmental evaluations to establish a baseline for educational and rehabilitation interventions
  • MRI
    Note: MRI may reveal classic brain findings, but correlations between such findings and disease severity have not been established.
  • Biochemical genetics or neurogenetics consultation

Treatment of Manifestations

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.


Regular evaluation by a rehabilitation specialist may identify potentially helpful interventions.

Evaluation of Relatives at Risk

No routine testing is recommended because adult presentations are unusual and no early interventions are available.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The free sialic acid storage disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and thus carry one mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. Because of the severity of the disease, affected individuals are unlikely to reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Biochemical genetic testing. Prenatal testing for pregnancies at increased risk is possible by measuring free sialic acid either in chorionic villus biopsy specimens (obtained by chorionic villus sampling at ~10-12 weeks' gestation) or in amniocytes (obtained by amniocentesis usually performed at ~15-18 weeks' gestation) [Salomäki et al 2001].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular genetic testing. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
  • National Tay-Sachs and Allied Diseases Association, Inc. (NTSAD)
    2001 Beacon Street
    Suite 204
    Boston MA 02135
    Phone: 800-906-8723 (toll-free)
    Fax: 617-277-0134
  • Myelin Disorders Bioregistry Project

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Free Sialic Acid Storage Disorders: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Free Sialic Acid Storage Disorders (View All in OMIM)


Molecular Pathogenesis

Pathogenic variants 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 [Aula et al 2004].

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 [Verheijen et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene.

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

Pathogenic variants. Different missense, nonsense, and splice site variants, insertions, and deletions have been recognized as causing lysosomal free sialic acid storage disorders [Verheijen et al 1999, Aula et al 2000, Varho et al 2002, Kleta et al 2003, Martin et al 2003]. The p.Arg39Cys pathogenic variant is highly prevalent among affected individuals of Finnish heritage (see Prevalence).

Table 2.

SLC17A5 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

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 [Renlund et al 1986, Mancini et al 1991]. 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 pathogenic variants result in defective or absent sialin. However, for two known pathogenic variants 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 [Aula et al 2002, Wreden et al 2005].


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Chapter Notes

Author Notes

David Adams, MD, PhD is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases at the National Institutes of Health.

William A Gahl, MD, PhD is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases at the National Institutes of Health.

Revision History

  • 6 June 2013 (me) Comprehensive update posted live
  • 3 July 2008 (me) Comprehensive update posted live
  • 4 October 2005 (me) Comprehensive update posted live
  • 13 June 2003 (ca) Review posted live
  • 28 February 2003 (wg) Original submission

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