Clinical Diagnosis

The diagnosis of Salla disease is suspected in individuals who manifest truncal ataxia and hypotonia at approximately age 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].

Testing

For laboratories offering biochemical testing, see .

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 spectrophotometric or fluorimetric thiobarbituric acid assay or by thin-layer chromatography, 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. (3) High-performance liquid chromatography and proton nuclear magnetic resonance spectroscopy for free sialic acid are performed on a research basis only.

• 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 known to be associated with Salla disease and ISSD.

Clinical testing

• Targeted mutation analysis. Testing for the common SLC17A5 p.Arg39Cys mutation causing Salla disease is available on a clinical basis.

• Sequence analysis. Sequence analysis of SLC17A5 is available on a limited clinical basis. The mutation detection frequency in individuals with a biochemically confirmed free sialic acid storage disorder other than Salla disease is not known.

Table 1. Summary of Molecular Genetic Testing Used in Free Sialic Acid Storage Disorders

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SLC17A5	Targeted mutation analysis	p.Arg39Cys	Homozygous p.Arg39Cys: 91% 2	Clinical
	Sequence analysis	Sequence variants 3	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Finnish individuals with Salla disease [Aula et al 2000]

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• Consistent clinical findings in the presence of an elevated urinary free sialic acid level suggest the diagnosis of Salla disease/ISSD.

• Targeted mutation analysis for SLC17A5 can confirm the presence of Salla disease/ISSD.

• On a research basis, subcellular fractionation studies can prove the predominance of free sialic acid within the lysosomal compartment, confirming Salla disease/ISSD and differentiating the disease from sialuria.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

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

Prenatal diagnosis may be performed using molecular or biochemical studies:

• Testing of at-risk pregnancies using SLC17A5 DNA sequencing 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 [Salomaki et al 2001, Aula & Aula 2006, Gopaul & Crook 2006].

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Salla disease, ISSD, and intermediate severe Salla disease are the only phenotypes known to be associated with mutations in SLC17A5.

Natural History

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.

Genotype-Phenotype Correlations

Correlations between the type of SLC17A5 mutation 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 missense mutation p.Arg39Cys, a single Finnish founder mutation, leads to Salla disease, with its slow clinical course of neurologic deterioration.

• Compound heterozygosity for the p.Arg39Cys mutation and another SLC17A5 mutation leads to intermediate severe Salla disease, as does homozygosity for the p.Lys136Glu mutation [Biancheri et al 2005].

• Compound heterozygosity for mutations 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].

Penetrance

Free sialic acid storage disorders seem to be fully penetrant.

Nomenclature

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 having firm molecular proof and show variable clinical expression in affected individuals.

Prevalence

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 mutation 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 mutation. The prevalence of other SLC17A5 mutations 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, Sonderby Christensen et al 2003, Kleta et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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.

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.

Surveillance

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 ClinicalTrials.gov 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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

Myelin Disorders Bioregistry Project
Phone: 202-476-6230
Fax: 202-476-2864
Email: myelin@cnmc.org
Web: www.myelindisorders.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 mutant 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 Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

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) [Salomaki et al 2001]. Such biochemical prenatal testing is clinically available in only a few centers.

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. If the disease-causing mutations in the family are known, prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

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 [Aula et al 2004].

Normal allelic variants. 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]. One known normal allelic variant in the coding region is p.Ala43Thr.

Pathologic allelic variants. At least 19 different missense, nonsense, and splice site mutations, 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].

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 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 [Aula et al 2002, Wreden et al 2005].

Literature Cited

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Suggested Reading

1. Aula P, Gahl WA. Disorders of free sialic acid storage. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 200. Available at www.ommbid.com. Accessed 2-29-12.

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

• 3 July 2008 (me) Comprehensive update posted live

• 4 October 2005 (me) Comprehensive update posted to live Web site

• 13 June 2003 (ca) Review posted to live Web site

• 28 February 2003 (wg) Original submission