Galactosialidosis: historic aspects and overview of investigated and emerging treatment options

Abstract

Introduction Galactosialidosis is a glycoprotein storage disease caused by mutations in the CTSA gene, encoding lysosomal protective protein/cathepsin A (PPCA). The enzyme’s catalytic activity is distinct from its protective function towards β-galactosidase (β-GAL) and neuraminidase 1 (NEU1), with which PPCA forms a complex. In this configuration the two glycosidases acquire their full activity and stability in lysosomes. Deficiency of PPCA results in combined NEU1/β-GAL deficiency. Because of its low incidence, galactosialidosis is considered an orphan disorder with no therapy yet available. Areas covered This review gives a historic overview on the discovery of PPCA, which defined galactosialidosis as a new clinical entity; the evidence for the existence of the PPCA/NEU1/β-GAL complex; the clinical forms of galactosialidosis and disease-causing CTSA mutations. Ppca−/− mice have proven to be a suitable model to test different therapeutic approaches, paving the way for the development of clinical trials for patients with galactosialidosis. Expert opinion Improved understanding of the molecular bases of disease has sparked renewed incentive from clinicians and scientists alike to develop therapies for rare conditions, like GS, and has increased the willingness of biotech companies to invest in the manufacturing of new therapeutics. Both ERT and gene therapy may become available to patients in the near future.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…To date, four LSDs are known to be caused by inactivating mutations in CTS genes. Defects in CTSA, CTSD, CTSF, and CTSK result in galactosialidosis, neuronal ceroid lipofuscinoses (NCLs) type 10 and type 13, and pycnodysostosis, respectively [13,43, (Table 2). Table 2.…”

“…Galactosialidosis #256540 CTSA Accumulation of sialylated oligosaccharides and glycoproteins in lysosomes due to complete deficiency in neuraminidase-1 and partial deficiency in beta-galactosidase. [13,43,119,121,122] Neuronal ceroid lipofuscinosis 10 #610127 CTSD Impaired lysosomal degradation and aberrant autophagy. [42,43,130,131] Neuronal ceroid lipofuscinosis 13 #615362 CTSF Impaired lysosomal degradation and aberrant autophagy.…”

Dental Management of a Young Child Affected by Galactosialidosis and a Gigantic Abdominal Growth

“…LSDs can be very rare individually; however, as a group, these anomalies comprise around 70 pathologic conditions with an incidence of 1 : 5000 live births [1, 2]. Galactosialidosis (GS) is an uncommon lysosomal storage condition, which belongs to the glycoproteinosis subgroup of LSDs, inherited as an autosomal recessive trait [3]. The prevalence of the disease is, to our knowledge, unknown.…”

“…Based on the age of onset of the disease during childhood and disease severity, GS is classified into three subtypes [3]. The early infantile type initiates between 0 and 3 months of age.…”

“…It is characterized primarily by absent or mild neurological/cognitive disability and mental deterioration. This condition consists of dysostosis multiplex, especially of the spine, growth retardation-associated muscular atrophy, hepatosplenomegaly, cardiac involvement (thickening of the heart valves), macroglossia, and hearing loss [1, 3, 9]. Additionally, there is a third subtype of GS, the juvenile/adult type.…”