Clinical Description
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.
Salla Disease
Salla disease is the mildest phenotype [Varho et al 2002], characterized by a normal appearance and normal neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor retardation [Renlund et al 1983, Alajoki et al 2004]. 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 [Varho et al 2002].
Abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings. MRI reveals these predominant white matter changes [Sonninen et al 1999]. Cerebellar white matter changes are also present and can explain the ataxia [Linnankivi et al 2003, Biancheri et al 2004].
In addition to the central dysmyelination, a peripheral dysmyelination with the clinical picture of a polyneuropathy occurs with variable neurologic presentations [Varho et al 2000, Varho et al 2002].
Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. In a single individual, growth hormone and gonadotropin deficiencies were observed [Grosso et al 2001].
Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed.
Intermediate severe Salla disease. Since the advent of molecular studies, phenotypes with a severity between those of Salla disease and ISSD [Aula & Gahl 2001] have been attributed to compound heterozygosity for the Salla disease-causing common pathogenic variant and another SLC17A5 pathogenic variant [Kleta et al 2003]. Thus the term "intermediate severe Salla disease" was proposed [Aula et al 2000].
Infantile Free Sialic Acid Storage Disease (ISSD)
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.
Genotype-Phenotype Correlations
Correlations between the type of SLC17A5 pathogenic variant 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 pathogenic
missense variant , a single Finnish
founder variant, leads to Salla disease, with its slow clinical course of neurologic deterioration.
Compound heterozygosity for the p.Arg39Cys
pathogenic variant and another
SLC17A5 pathogenic variant leads to intermediate severe Salla disease, as does homozygosity for the pathogenic variant [
Biancheri et al 2005].
Compound heterozygosity for pathogenic variants 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. However, Mochel et al [2009] reported a case of two individuals with homozygous pathogenic variants, no detectable urinary sialic acid abnormality, and elevated CSF free sialic acid suggesting that penetrance based on urinary studies alone may be incomplete.
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 firm molecular proof, and show variable clinical expression in affected individuals.
