Clinical Description
Free sialic acid storage disorder (FSASD) comprises a spectrum of neurodegenerative phenotypes resulting from increased lysosomal storage of free sialic acid [Huizing et al 2021]. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term "Salla" has been used in the literature to refer to less severe FSASD in general. Less severe FSASD is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delay, spasticity, athetosis, and epileptic seizures. More severe FSASD, also known as ISSD, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood. To date, approximately 260 individuals have been reported worldwide with biallelic pathogenic variants in SLC17A5 [Aula et al 2000, Alajoki et al 2004, Zielonka et al 2019, Huizing et al 2021]; an additional 50 individuals with FSASD are reported in the literature without molecular data. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Free Sialic Acid Storage Disorder: Frequency of Select Features
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Feature 1 | % of Persons w/Feature |
---|
Developmental delay / cognitive impairment | 75% |
Facial dysmorphism / coarse facies 2 | 50%-68% 2 |
Hepatosplenomegaly | 54% |
Truncal hypotonia | 54% |
Skeletal abnormalities | 50% |
Spasticity | 48% |
Ataxia | 44% |
Poor weight gain | 42% |
Short stature | 27% |
Hydrops fetalis | 24% |
Epilepsy | 22% |
Neurodegenerative course | 20% |
Neonatal ascites | 19% |
Cardiomegaly | 19% |
Hernias | 19% |
Microcephaly | 18% |
Recurrent airway infections | 16% |
Nystagmus | 12% |
Nephropathy | 10% |
Optic atrophy | 7% |
Athetosis | 6% |
Ptosis | 3% |
Hoarse voice | 2% |
Corneal clouding | 1% |
Brain MRI findings | Brain atrophy | 23% |
Hypomyelination | 22% 3 |
Hypoplasia of the corpus callosum | 16% |
- 1.
Includes features reported in entire spectrum of phenotypes (less severe to severe FSASD)
- 2.
Coarse facies are more frequent in severe FSASD.
- 3.
This was likely underascertained in this cohort. Severe hypomyelination and delayed brain myelination is a consistent hallmark of FSASD [D Adams, M Huizing, & M Wasserstein, unpublished data]
Less Severe FSASD (including Salla disease)
Salla disease, which serves as a model for less severe FSASD, has the mildest phenotype [Varho et al 2002]. It is characterized by a normal appearance and normal neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delay [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. Expressive language development can be limited to single words, but receptive 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].
T2-weighted bright cerebral white matter changes on brain MRI are typical but variable. Abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings [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].
Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed.
Severe FSASD (including infantile free sialic acid storage disease [ISSD])
ISSD, the most severe phenotype, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly. Additional reported features include early truncal hypotonia with later spasticity and ataxia, skeletal abnormalities, and seizures (see Table 2). No single feature occurs in all individuals.
ISSD can present prenatally and in the neonatal period with nonimmune hydrops fetalis (24% of individuals) [Lemyre et al 1999, Stone & Sidransky 1999, Froissart et al 2005, Zielonka et al 2019, Huizing et al 2021]. Some affected infants are born prematurely. Other affected infants appear normal at birth but lose developmental milestones during infancy [Kleta et al 2003, Kleta et al 2004].
Skeletal abnormalities can include irregular metaphyses, diffuse hypomineralization, clubfeet, short femurs, enlarged metaphyses, fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges [Froissart et al 2005].
Dysmorphic facial features are nonspecific and generally fall into the spectrum of "coarsened" features (e.g., epicanthal folds, ptosis, anteverted nose, gum hypertrophy).
Reported ocular findings include nystagmus, exotropia, optic atrophy, and albinoid fundi. Corneal clouding has been rarely reported.
Additional reported features include nephropathy and/or nephrotic syndrome and hernias [Lemyre et al 1999, Ishiwari et al 2004].
Death usually occurs in early childhood, typically from recurrent respiratory infections.
Nomenclature
Reference to FSASD by historically defined terms such as Salla disease, intermediate severe Salla disease, and ISSD has resulted in confusion for clinicians, affected individuals, researchers, diagnostic laboratories, disease databases, and the pharmaceutical rare disease industry. The designation "free sialic acid storage disorder" (FSASD) was proposed as an encompassing term for the entire spectrum of disease severity in order to improve worldwide disease awareness and to facilitate diagnosis, estimation of disease prevalence, and therapeutic research [Huizing et al 2021].
Prevalence
The prevalence of FSASD was estimated to be 1-3 in 1,000,000 individuals worldwide using population databases of genetic variants [Huizing et al 2021]. Higher estimated prevalence rates of ~35 in 1,000,000 occur in Finland, due to the increased carrier frequency of the SLC17A5
p.Arg39Cys founder variant [Aula et al 2000, Huizing et al 2021].
To date, there are about 260 individuals reported worldwide with biallelic pathogenic variants in SLC17A5 [Aula et al 2000, Zielonka et al 2019, Huizing et al 2021], of which ~80% have the p.Arg39Cys variant in homozygous or heterozygous form [Huizing et al 2021]. Homozygosity for p.Arg39Cys was reported in the Old Order Mennonite population [Strauss et al 2005]. A variety of other SLC17A5 pathogenic variants are reported in more than 70 individuals worldwide, including Canadian Inuit (homozygous for c.526-2A>G) [Lines et al 2014], Israeli Bedouin (homozygous for p.Gly328Glu) [Landau et al 2004], Dominican, French, Italian, Japanese, Kurdish, Polish, and Saudi Arabian [Verheijen et al 1999, Ishiwari et al 2004, Biancheri et al 2005, Froissart et al 2005, Matsuura et al 2018, Mochel et al 2009, Tarailo-Graovac et al 2017, Zielonka et al 2019].