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. 

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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.

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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.

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Salla disease is the mildest phenotype, characterized by a normal appearance and normal neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to- moderate psychomotor retardation. 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. Abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings. MRI reveals these predominant white matter changes. Cerebellar white matter changes are also present and can explain the ataxia. In addition to the central dysmyelination, a peripheral dysmyelination with the clinical picture of a polyneuropathy occurs with variable neurologic presentations. Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. In a single individual, growth hormone and gonadotropin deficiencies were observed. Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed. 

 

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.

 

Salla disease is believed to have been reported in approximately 150 individuals, mainly from Finland and Sweden. Individuals with molecularly proven Salla disease have been identified outside of Finland and Sweden.

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From "Free Sialic Acid Storage Disorders" (2013) by David Adams, MD, PhD and William A Gahl, MD, PhD