Alternative titles; symbols
SNOMEDCT: 34566007; ORPHA: 309324, 834;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q13 | Sialic acid storage disorder, infantile | 269920 | Autosomal recessive | 3 | SLC17A5 | 604322 |
A number sign (#) is used with this entry because of evidence that infantile sialic acid storage disease (ISSD) is caused by homozygous or compound heterozygous mutation in the SLC17A5 gene (604322) on chromosome 6q13.
Salla disease (604369) is an allelic disorder.
Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or as a slowly progressive adult form that is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia, and mental retardation; visceromegaly and coarse features are also present in the infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by MRI. Enlarged lysosomes are seen on electron microscopic studies, and patients excrete large amounts of free sialic acid in the urine (Verheijen et al., 1999).
Infantile sialic storage disease was described by Tondeur et al. (1982) and studied by Thomas et al. (1983). The infant son and daughter of unrelated Yugoslav parents reported by Tondeur et al. (1982) had a much more severe clinical course than that in Salla disease (604369). The sibs showed coarse facies, hepatosplenomegaly, prominent psychomotor retardation, and unexpectedly fair complexion. Electron microscopy showed generalized lysosomal storage of a polysaccharide-like material. Biochemical analyses of urine and cultured fibroblasts showed increased levels of unbound (free) sialic acid. Although both sibs were alive at the time of report, the eldest was said to be in a terminal stage at age 4.5 years. Aneurysmal dilatation of capillaries in the bulbar conjunctiva had appeared at age 3. He had been normal at birth except for an inguinal hernia which was repaired at age 1 week; developmental abnormality was first noted at age 5 months and was progressive thereafter. Thomas et al. (1983) found that unstained and unfixed, cultured fibroblasts showed, by phase microscopy, many vacuolated structures resembling a honeycomb. Electron microscopy, following fixation, showed that the honeycombing resulted from numerous, closely packed, cytoplasmic membrane-bound vacuoles. Biochemical studies of crude sonicate showed the presence at levels 4 to 7 times normal of an acid-soluble substance with the characteristics of sialic acid. Quantitative studies showed 39.8 nmoles of free sialic acid per mg protein as compared with the normal of 1 to 2 nmoles per mg. Bound sialic acid levels were at the upper limit of normal. After incubation of the fibroblasts with tritiated N-acetyl-mannosamine there was a 7-fold increase (over the normal) in radioactivity of free sialic acid with no increase in labeled, bound sialic acid.
Stevenson et al. (1982) reported a case of sialuria with infantile onset and severe manifestations. Free sialic acid was elevated in urine, serum and cellular cytosol.
Hancock et al. (1982) reported a patient with extensive accumulation of free NeuAc in tissues and abnormal storage lysosomes who pursued a fulminant clinical course ending in death at 5 months. The amount of free sialic acid in the urine was about 20 times higher than the 15- to 30-fold increase in patients with Salla disease.
Baumkotter et al. (1985) reported a patient with early-onset sialic acid storage disease whose early clinical course was similar to that of Salla disease but who had clinical and skeletal abnormalities not mentioned in that disorder.
In 3 patients with different forms of N-acetylneuraminic acid (NANA) storage disease, accumulation of free NANA in the lysosomes was found in cultured fibroblasts, suggesting a transport defect (Mancini et al., 1986). One of the samples came from a patient with Salla disease, a second came from an infant with the severe form of NSD, and the third came from a child with a milder infantile form.
Thomas et al. (1989) demonstrated striking cellular differences between the original French patient with sialuria (269921) and patients such as those reported by Hancock et al. (1983), Stevenson et al. (1983), and Tondeur et al. (1982) with infantile sialic acid storage disease. Whereas phase microscopy and immunochemical studies showed abnormal storage within intracellular inclusions in ISSD cells, Thomas et al. (1989) found no morphologic evidence of storage within any subcellular organelle in the French sialuria cells. Moreover, comparative subcellular fractionation studies on gradients of colloidal silica showed the excess sialic acid in ISSD cells to be located within the light (buoyant) lysosomal fraction, whereas the excessive, free sialic acid in the sialuria cells was found in the cytoplasmic fraction with no increased storage within the lysosomal fractions. Salla disease, which occurs predominantly in the Finnish population, is also a form of sialuria. Thomas (1989) suggested that Salla disease and ISSD may both be caused by a defect in transmembrane transport in the lysosome, leading to lysosomal storage of free sialic acid. Unlike Salla disease, ISSD has no particular ethnic prevalence; it presents with severe visceral involvement, dysostosis multiplex, psychomotor retardation, and early death.
Mancini et al. (1991) demonstrated a proton-driven carrier for sialic acid in human lysosomal membranes. This transporter had similar properties to those previously identified in rat liver. By measuring the uptake kinetics of labeled glucuronic acid, they excluded the existence of more than 1 acidic monosaccharide carrier. Uptake studies with labeled sialic acid and glucuronic acid in lysosomal membrane vesicles from cultured fibroblasts from patients with different clinical forms of sialic acid storage disease showed defective carrier-mediated transport for both sugars. Further evidence that the defective transport of acidic sugars represents the primary genetic defect in sialic acid storage diseases was provided by the observation of reduced, half-normal transport rates in lymphoblast-derived lysosomal membrane vesicles from 5 unrelated obligate heterozygotes. This was the first observation of a human lysosomal transport defect for multiple physiologic compounds. Blom et al. (1990) also demonstrated a defect in the egress of glucuronic acid and other acidic monosaccharides from lysosomes in these disorders.
Mancini et al. (1992) described a 10-year-old boy with free sialic acid storage disease. An unusual feature was slight corneal clouding. They noted that the patient's polymorphonuclear leukocytes showed a 10- to 30-fold increase in sialic acid content and that the values were slightly increased in the parents; they suggested that this was a means of identifying heterozygotes.
Studies of tissues from a 3-month-old baby who died with the diagnosis of ISSD permitted Berra et al. (1995) to confirm the lysosomal nature of the disease by electron microscopy. They showed that the amount of free and total sialic acid was markedly increased and confirmed that only acid monosaccharide transport from the lysosome compartment is involved in the pathogenesis of ISSD.
Lemyre et al. (1999) reported 3 new cases of ISSD and reviewed the literature regarding 24 additional cases. Each of the 3 new cases presented differently: the first with nephrotic syndrome, the second with fetal and neonatal ascites, and the third with fetal ascites and esophageal atresia type III. Coarse facies, fair complexion, hepatosplenomegaly, and severe psychomotor retardation were constant findings. Nephrotic syndrome occurred in 4 of 7 cases in which renal studies were performed. Fetal/neonatal ascites was the mode of presentation in 13 of 21 (60%) cases; Lemyre et al. (1999) suggested that ISSD should enter the differential diagnosis of hydrops fetalis with storage disease phenotype. Cardiomegaly was seen in 9 of 12 cases. Corneas were always clear, and 5 of 7 cases had albinoid fundi. Dysostosis multiplex was not prominent. Bone marrow aspiration was negative in 3 of 9 cases. Death usually occurred in infancy (range 1 month to 3.3 years, n = 20, mean 13.1 months); all reported deaths were caused by respiratory infection.
Prenatal Diagnosis
In a twin pregnancy of a mother who had had a previous child who died at the age of 17 months of infantile sialic acid storage disease, Lake et al. (1989) found by microscopic and biochemical analysis of chorionic villus sampling from both twins that 1 was affected. Selective feticide was performed. The unaffected twin completed the pregnancy uneventfully.
Recurrent nonimmune hydrops fetalis as a presentation of sialic acid storage disease was documented by Lefebvre et al. (1999). Hydrops fetalis was diagnosed in 2 fetuses on second-trimester ultrasonography. The diagnosis of sialic acid storage disorder was based on high levels of free sialic acid in amniotic fluid and fetal cell cultures and by specific histologic features on fetopathologic examination. Sections through placental villi showing numerous empty vacuoles in the cytoplasm of both trophoblastic and Hofbauer cells were illustrated, as well as liver sections showing cytoplasmic vacuoles in the hepatocytes, and sections showing changes in the cytoplasm of the podocytes of the renal glomeruli.
Haataja et al. (1994) localized the Salla disease locus to chromosome 6q. Similarities in biochemical findings suggested to Schleutker et al. (1995) that Salla disease and ISSD represent allelic disorders despite their drastically different clinical phenotypes. Schleutker et al. (1995) reported linkage studies to support this suggestion in 50 Finnish Salla disease families and 26 non-Finnish families with no genealogic connections to Finns affected with the Finnish type of Salla disease, the 'intermediate' form of the disease, or the infantile form of sialic acid storage disease. Linkage to the same locus on 6q14-q15 was found. The highest lod score of 17.30 was obtained with a microsatellite marker of locus D6S280. When linkage disequilibrium was adopted in the linkage analyses, they could further assign the locus to the immediate vicinity of marker locus D6S406. Linkage disequilibrium facilitated restriction of a critical chromosomal region to approximately 80 kb, well within limits of positional cloning techniques. Haplotype analysis of Finnish Salla disease chromosomes revealed 1 common haplotype which was also seen in most of the non-Finnish patients with the Finnish type of Salla disease. This ancestral haplotype differed from those observed in ISSD patients, who had a different common haplotype. The intermediate cases presumably represent compound heterozygotes. They lack the fetal and neonatal manifestations typical of ISSD but are more severely affected than the patients with Salla disease. Schleutker et al. (1995) studied 3 such families, each of which carried the Finnish Salla disease haplotype on 1 chromosome.
The transmission pattern of ISSD in the families reported by Verheijen et al. (1999) was consistent with autosomal recessive inheritance.
Verheijen et al. (1999) used a positional candidate gene approach to identify a gene, SLC17A5, encoding a protein, sialin, with a predicted transport function that belongs to a family of anion/cation symporters (ACS). They found a homozygous SLC17A5 mutation (R39C; 604322.0001) in 5 Finnish patients with Salla disease and 6 different SLC17A5 mutations in 6 ISSD patients of different non-Finnish ethnic origins.
Using DNA polymorphisms (RFLPs) of 2 genes encoding lysosomal membrane proteins, LAMPA (153330) and LAMPB (309060), Schleutker et al. (1991) could demonstrate no linkage with the Salla disease phenotype, thus excluding these as candidate genes.
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Verheijen, F. W., Verbeek, E., Aula, N., Beerens, C. E. M. T., Havelaar, A. C., Joosse, M., Peltonen, L., Aula, P., Galjaard, H., van der Spek, P. J., Mancini, G. M. S. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nature Genet. 23: 462-465, 1999. [PubMed: 10581036] [Full Text: https://doi.org/10.1038/70585]