Clinical Description
To date, approximately 80 individuals have been identified with biallelic pathogenic variants in SLC17A5 [Alajoki et al 2004, Zielonka et al 2019]. (~300 individuals with free sialic acid storage disorders (FSASDs) are reported in the literature, but many reports do not include molecular data.) The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Select Features of Free Sialic Acid Storage Disorders
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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% |
| Failure to thrive | 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% |
| Hypoplasia of the corpus callosum | 16% |
- 1.
Includes features reported in entire spectrum of phenotype (less-severe to severe FSASD)
- 2.
Coarse facies are more frequent in severe FSASD.
The FSASDs comprise a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. 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.
Less Severe FSASD (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].
Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. Growth hormone and gonadotropin deficiencies were observed in one individual [Grosso et al 2001].
Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed.
Severe FSASD (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 ). 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]. 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, 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].
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.
