Prenatal diagnosis of free sialic acid storage disorders (SASD)

Abstract

Free sialic acid storage disorders, Salla disease (SD) and Infantile sialic acid storage disease (ISSD), are lysosomal storage diseases due to impaired function of a sialic acid transporter, sialin, at the lysosomal membrane. Several mutations of the sialin gene, SLC17A5, are known, leading either to the severe neonatal/infantile disease or to the milder, adult-type developmental disorder, Salla disease. Free sialic acid accumulation in lysosomes causes increased tissue concentration and consequently elevated urinary excretion. Prenatal diagnosis of SASD is possible either by determination of free sialic acid concentration or by mutation analysis of the SLC17A5 gene in fetal specimen, in chorionic villus biopsy particularly. Both techniques have been successfully applied in several cases, sialic acid assay more often in ISSD cases but mutation analysis preferentially in SD. Sialic acid assay of amniotic fluid supernatant or cultured amniotic fluid cells may give erroneous results and should not be used for prenatal diagnosis of these disorders. The present comments are mainly based on our experience of prenatal diagnosis of SD in Finnish families. A founder mutation in SLC17A5 gene, 115C-> T, represents 95% of the disease alleles in the Finnish SD patients, which provides a unique possibility to apply mutation analysis. Therefore, molecular studies have successfully been used in 17 families since the identification of the gene and the characterization of the SD mutations. Earlier, eight prenatal studies were performed by measuring the free sialic acid concentration in chorionic villus samples.

Prenatal screening of sialic acid storage disease and confirmation in cultured fibroblasts by LC‐MS/MS

“…FSA determination merely requires mixing of an AFS sample with a sialic acid stable isotope solution, immediately followed by LC-MS/MS. The whole procedure including sample preparation, analysis and calculation of results can be performed in 2–4 h. The reference values described here (0–6.3 μmol/L; 95 % confidence interval for gestational age 15–25 weeks) appear to be similar to previously published values determined by the thiobarbiturate assay (1.7-5.3 μmol/L; Aula and Aula 2006). FSA concentrations in AFS samples from five fetuses affected with ISSD (23.9 to 58.9 μmol/L) were 2- to 9-fold the upper limit of the corresponding reference values and demonstrate that this method is able to distinguish ISSD pregnancies from normal controls.…”

“…A number of other lysosomal storage disorders may also present as hydrops fetalis (Stone and Sidransky 1999) and diagnostic tests to investigate the cause of hydrops fetalis should include assays for these lysosomal disorders (Piraud et al 1996; Kooper et al 2006). To date HPLC has been the preferred method to measure FSA in AFS (Aula and Aula 2006). Other existing methods for determination of FSA in AFS such as the colorimetric Warren test or TLC have limited specificity or sensitivity or consist of elaborate procedures.…”

“…Our method may also be useful for prenatal diagnosis of ISSD in families with an ISSD index case with no additional molecular workup. Cases of Salla disease may only have mildly elevated FSA concentrations in AFS and in these instances the preferred method of prenatal diagnosis is mutation testing in a chorionic villus biopsy (Aula and Aula 2006). …”

“…Prenatal diagnosis of SASD in families with a known index case is preferentially performed by mutation analysis (Aula and Aula 2006). However, to investigate ISSD (along other possible causes) in prenatal studies of hydrops fetalis, measurement of FSA in amniotic fluid supernatant (AFS) is more appropriate as a first screening test.…”

A mass spectrometric strategy for profiling glycoproteinoses, Pompe disease, and sialic acid storage diseases

“…These diseases differ in the amount of sialic acid urinary excreted. The diagnosis of SASD is based on clinical presentations in combination with detection of free sialic acid urinary excreted in an important amount [13]. The quantification of free sialic acid in tissues and urine of patients can be classically performed using thiobarbituric acid (TBA)based assays [14,15].…”