Free Sialic Acid Storage Disorder

Abstract

CLINICAL CHARACTERISTICS The allelic disorders of free sialic acid metabolism – 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. DIAGNOSIS/TESTING 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. MANAGEMENT Treatment of manifestations: Management is symptomatic and supportive: rehabilitation to optimize mobility and communication; provision of adequate nutrition; standard treatment of seizures. Surveillance: Regular evaluation by a rehabilitation specialist to identify potentially helpful interventions. GENETIC COUNSELING The free sialic acid storage disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing for pregnancies at increased risk is possible by measuring free sialic acid either in chorionic villus biopsy specimens (obtained by chorionic villus sampling at ~10-12 weeks' gestation) or in amniocytes (obtained by amniocentesis usually performed at ~15-18 weeks' gestation). Carrier testing for relatives at increased risk and prenatal testing for pregnancies at increased risk is an option if both causing pathogenic variants have been identified in a family.