Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created.

Sialidosis is a rare lysosomal storage disease caused by an α-N-acetyl neuraminidase-1 deficiency due to mutations of the NEU1 gene (6p21). Disease severity varies among patients and is linked to the level of residual neuraminidase activity in vivo. At least 40 disease-causing mutations in the NEU1 gene have been reported. Sialidosis occurs in two main clinical variants: type I, the milder form of the disease, and type II, which is subdivided into congenital, infantile, and juvenile forms. We report the clinical, biochemical, and molecular characterization of a patient with infantile sialidosis type II. The abnormal urinary oligosaccharide profile is described for the first time. The genetic characterization of the patient showed two previously unreported missense mutations in the NEU1 gene: p.R78C (c.232C>T) and p.R290Q (c.869G>A).

Sialidosis is a rare lysosomal storage disorder characterized by deficiency of alpha-N-acetyl neuraminidase. The macular cherry-red spot, which could be important for diagnosis, is a distinctive feature of its ocular manifestation. We evaluated the fundus autofluorescence (FAF) and optical coherence tomography (OCT) images of a juvenile patient who presented with vision decrease and was later confirmed with genetic sialidosis. A 13-year-old Chinese male presented with bilateral decreased vision over the past 2 years before his initial visit. Funduscopic examination revealed a macular cherry-red bilateral spot. FAF showed hyperreflective areas surrounding a central hyporeflective fovea in both eyes. OCT revealed increased reflectivity in the ganglion cell layer in both maculae without a definite boundary between the hyperreflective and normal areas. These findings suggested that lipofuscin had accumulated in the retinal ganglion cells, which is a distinctive ocular feature in metabolic central nervous system (CNS) disorders. He was later confirmed with genetic sialidosis. FAF and OCT images are very sensitive and useful techniques for diagnosing lysosomal storage disease of the CNS, and are helpful in evaluating the extent of damage in retinal ganglion cells.