Free sialic acid storage disease (ORPHA:834)
A rare lysosomal storage disease characterized by a spectrum of clinical manifestations including neurological and developmental disorders with a severity ranging from the milder form, also called Salla disease (SD), to the most severe phenotype, also called infantile free sialic acid storage disease (ISSD).
Epidemiology
The worldwide prevalence is approximately 1/1,000,000. In the Salla region of Finland, where the carrier frequency of the p.Arg39Cys variant of SLC17A5 is 1/100, the prevalence is estimated to be around 1-9/1,000,000. There have been ~250 patients with bi-allelic mutations in SLC17A5 reported in the literature, reflective of the suspected underdiagnosis of free sialic acid storage disorder (FSASD).
Clinical description
Patients with FSASD suffer from progressive neurologic deterioration with psychomotor delay and childhood onset of hypotonia, spasticity and ataxia. Other clinical signs include coarse facial features, organomegaly, bones anomalies, failure to thrive, short stature, neonatal ascites, microcephaly, seizures and cardiac anomalies. Patients with the intermediate form have earlier onset and more severe symptoms. Patients with the infantile form present with very severe symptoms and suffer from early death prenatally or in infancy.
Etiology
The disease is caused by biallelic mutations to the SLC17A5 gene which encodes the sialin protein responsible for the efflux of free sialic acid from lysosomes and the transport of certain neurotransmitters into synaptic vesicles. Loss of function of this transporter causes the symptoms associated with FSASD. There have been approximatey 50 mutations reported to be linked to this disease to date.
Diagnostic methods
Diagnosis is established by measurement of free (unbound) sialic acid accumulation in fibroblast lysosomes, urine or cerebrospinal fluid, and confirmed by genetic testing confirming bi-allelic mutations in the SLC17A5 gene. Quantification of free sialic acid in fibroblasts lysosomes and cytoplasm provides discrimination between sialuria and FSASD. Predominant lysosomal sialic acid overload is suggestive of FSASD, whereas increased concentrations of this metabolite in the cytoplasm are suggestive of sialuria. Normal concentrations of sialic acid in the urine may correlate with milder forms of FSASD. FSASD patients often experience diagnostic delays due to the rarity of the disorder, non-specific clinical symptoms, and absence of routine urine sialic acid testing.
Differential diagnosis
Differential diagnosis includes sialuria (urinary and cellular free sialic acid elevation) and galactosialidosis (sialic acid bound to glycoproteins or glycolipids). FSASD is in the differential diagnosis for severe hypomyelinating leukodystrophies.
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of free sialic acid concentration in chorionic villi or amniotic fluid cells and by genetic analysis of the SLC17A5 gene. Fetal ultrasound may reveal ascites, hydrops fetalis (NIHF), organomegaly, dysostosis, facial dysmorphia and in utero growth delay which can be indicative of lysosome overload.
Genetic counseling
Transmission of FSASD is autosomal recessive. Genetic counselling should be offered to at-risk couples (both individuals carry a mutation) informing them there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is no approved therapy for FSASD. Management is symptomatic and supportive and includes the provision of adequate nutrition, supplementation of calcium and vitamin D, the use of anticonvulsants (for seizures), physical therapy, speech therapy and adapted education.
Prognosis
Life expectancy fluctuates according to the severity of the disease, from 1 day for patients presenting symptoms before birth, to over 70 years for the least severe forms. Free sialic acid concentration correlates with the severity of the disease.

                            Last update: 
                            October 2023


                            - Expert reviewer(s): 
                            Dr David ADAMS  - Dr Marjan HUIZING  - Dr Melissa WASSERSTEIN