Salla Disease

A number sign (#) is used with this entry because of evidence that Salla disease (SD) is caused by homozygous or compound heterozygous mutation in the SLC17A5 gene (604322) on chromosome 6q13.

Infantile sialic storage disease (ISSD; 269920) is an allelic disorder.

Description

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).

Clinical Features

Salla disease is an adult form of sialuria, also called sialic acid storage disease, that has been found particularly in residents of an area of Finland. In a northeastern part of Finland, Aula et al. (1979) observed Salla disease in 4 adults in 2 sibships related as second cousins. In addition, 27 possible cases in 10 sibships were known. Features are mental retardation, clumsiness, onset at 12 to 18 months of age with deterioration in the second decade, 4 to 15% vacuolated lymphocytes, enlarged storage lysosomes, and increased sialic acid in the urine. The disease was named for the geographic area where the kindred lived. Urinary excretion of mucopolysaccharides, amino acids, glycoasparagines, and oligosaccharides was normal. Three brothers were affected in 1 sibship, as well as a female third cousin of theirs. The disorder was first detected during a survey for aspartylglucosaminuria, in a search for cytoplasmic vacuoles.

Using both clinical and laboratory methods in an examination of mentally retarded patients mainly in northern Finland, Renlund et al. (1983) identified 34 patients who satisfied the following criteria for Salla disease: progressive psychomotor retardation of early onset, lysosomal storage, and increased urinary excretion of free sialic acid (N-acetylneuraminic acid; NeuAc). The patients showed ataxia, athetosis, rigidity, spasticity, and impaired speech. Growth retardation, thick calvaria, and exotropia were present in about half the patients. Progressive diminution in the amplitude of the EEG was noted. Life span appeared to be normal; patients ranged from 3 to 63 years in age.

No precisely similar patients with urinary excretion of free sialic acid had, it seemed, been reported outside Finland. However, 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 Salla patients.

Wolburg-Buchholz et al. (1985) reported 3 affected sibs in a sibship of 8. One affected girl died at 8 years and another at age 17. A 9-year-old boy was alive with severe psychomotor retardation with spastic tetraparesis and convulsions. Microscopic studies including ultrastructural examinations showed lysosomal vacuolization in mesenchymal and parenchymal cells. Increased amounts of free sialic acid in the urine and sialic acid storage in cultured fibroblasts were consistent with Salla disease. The family had no known Finnish ancestry. Echenne et al. (1986) described the case of a 5-year-old boy from southern France.

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 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.

Haataja et al. (1994) described 4 patients with an unusually severe form of Salla disease, more severe than those of 86 other Finnish patients. Hypotonia and developmental delay were first noted between 2 and 4 months of age. The patients were living, with ages ranging from 11 to 24, but were severely mentally retarded, either not responsive to the environment or responding only with facial gestures. All of them suffered from generalized tonic-clonic seizures, unlike the typical absence-like epilepsy in usual Salla disease. Magnetic resonance imaging (MRI) of the severely affected individuals demonstrated abnormally high signal intensity of subcortical white matter with sparing of the U fibers. There was no abnormality of basal ganglia. In these 4 severe cases and more typical cases, there were similar white matter changes in the thin string-like corpus callosum. Cerebellar atrophy was noted in the severely affected individuals but was not apparent on the scans of patients with typical Salla disease. In all these patients the MRI resembled the myelination pattern of a several-month-old infant. Linkage and haplotype analysis did not distinguish these 4 patients with the unusually severe course from the other Finnish patients with typical Salla disease. The authors raised the possibility of homoallelic heterogeneity.

Diagnosis

Prenatal Diagnosis

Renlund and Aula (1987) reported successful prenatal identification of Salla disease on the basis of free sialic acid and free/total sialic acid ratio in amniocytes.

Mapping

In a study of 27 Finnish families, Haataja et al. (1994) localized the Salla disease locus to chromosome 6q. The highest lod score, 8.95, was obtained with a microsatellite marker at locus D6S286 at theta = 0.00. Evidence for linkage disequilibrium was observed between the SD locus and the alleles of 3 closely linked markers, suggesting that the length of the critical region is of the order of 190 kb.

Similarities in biochemical findings suggested to Schleutker et al. (1995) that Salla disease and the infantile form of sialic acid storage disease 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 either with the Finnish type of Salla disease, the 'intermediate' form of the disease, or the infantile form of sialic acid storage disease (ISSD). 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 that 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.

Leppanen et al. (1996) carried out extensive haplotype analysis to monitor ancient recombination events in Finnish families with Salla disease to refine the critical map interval for the SD gene. This haplotype analysis placed the SD locus proximal to the marker D6S1622. Genetic mapping positioned SD in a 1-cM region between D6S280 and D6S1622. Leppanen et al. (1996) then screened P1 and PAC libraries to isolate clones mapping in the critical region. Fiber-FISH (fluorescence in situ hybridization on extended DNA fibers) was used to order clones and revealed that the critical map region was covered with 3 PAC clones. Within the critical DNA region 2 potential CpG islands were identified. Based on fiber-FISH and pulsed field gel analysis Leppanen et al. (1996) concluded that the critical region for the SD locus is 200 kb in size and is flanked by the D6S1622 and D6S280 markers.

Exclusion Studies

Using DNA polymorphisms (RFLPs) of 2 genes encoding lysosomal membrane proteins, LAMP-A (153330) and LAMP-B (309060), Schleutker et al. (1991) could demonstrate no linkage with the Salla disease phenotype, thus excluding these as candidate genes.

By exclusion mapping, Haataja et al. (1992) excluded at least 55% of the genome as the locus for the Salla disease gene, while some chromosome areas, particularly the long arm of chromosome 2, were highlighted as possible sites.

Molecular Genetics

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.

Pathogenesis

Renlund et al. (1986) described experiments that led them to conclude that the basic defect in Salla disease was deficient transport of free sialic acid at the lysosomal membrane. Bound sialic acid gets into the lysosome but has difficulty in egress. Fibroblast endogenous synthesis of sialic acid and lysosomal cleavage of exogenous glycoconjugates are normal but transport of free sialic acid through the lysosomal membrane is defective. Neutral monosaccharides and amino acids are thought to cross the lysosomal membrane by passive diffusion. Lysosomal transport of the basic amino acid cystine is carrier-mediated and is defective in cystinosis (219800). Sialic acid, a negatively charged compound (pK 2.6), may also require a specific transport mechanism.

Thomas (1989) postulated that the infantile form of sialuria was likely to be allelic to Salla disease; the disorder showed lysosomal storage of free sialic acid and probably represents, as did Salla disease, a defect in lysosomal transmembrane transport.

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.

Miyaji et al. (2008) presented evidence that the SLC17A5 gene also acts as a vesicular glutamic acid/aspartate transporter in the brain. The mouse sialin mutant R39C (604322.0001), which is found in patients with Salla disease (604369), was completely inactive in the energy-dependent uptake of aspartate and glutamic acid, but retained 34% of wildtype sialic acid/H+ cotransport activity. In contrast, mouse sialin mutant H183R (604322.0004), which is found in the severe infantile form of the human disorder ISSD (269920), showed active energy-dependent transport, but inactive H+/sialic acid cotransport. Miyaji et al. (2008) suggested that impaired aspartergic and glutamatergic neurotransmission could explain the severe CNS manifestations in patients with Salla disease who survive to adulthood.