RARE DISEASE
Galactosialidosis
Galactosialidosis
Galactosialidosis
Synonyms: Goldberg syndrome, Neuraminidase deficiency with beta-galactosidase deficiency
Synonyms: Goldberg syndrome, Neuraminidase deficiency with beta-galactosidase deficiency
Synonyms: Goldberg syndrome, Neuraminidase deficiency with beta-galactosidase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Galactosialidosis is an autosomal recessive lysosomal storage disorder caused by CTSA gene mutations, leading to deficient protective protein/cathepsin A (PPCA). This results in secondary deficiencies of β-galactosidase and neuraminidase, causing accumulation of sialyl-oligosaccharides. Clinical forms include early infantile (severe visceral/organ involvement), late infantile, and juvenile/adult types (neurological decline, myoclonus, ataxia). Hallmarks include coarse facial features, cherry-red macular spots, and dysostosis multiplex. Diagnosis relies on enzyme assays and genetic testing. Management is supportive, targeting symptoms such as seizures and organ complications [1][6][14].
Burden
Morbidity: Progressive neurodegeneration, vision/hearing loss, skeletal deformities, and renal/cardiac complications [2][6].
Infantile forms: High caregiving demands due to rapid progression and early mortality [1][6].
Healthcare utilization: Requires lifelong specialist care, frequent monitoring, and adaptive interventions for disability [17][19].
Therapies
Symptomatic care: Anticonvulsants, physical therapy, and multidisciplinary monitoring (ophthalmology, neurology, etc.) [1][18].
Experimental approaches: Enzyme replacement therapy (ERT) with recombinant PPCA shows preclinical efficacy in restoring enzyme activity [3][14], while AAV-mediated gene therapy is under investigation [15].
Bone marrow transplant: Limited evidence; no long-term benefit confirmed [1][18].
Categories: rare bone diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
55 drug discovery papers related to Galactosialidosis, with 3 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
55 drug discovery papers related to Galactosialidosis, with 3 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-01 | Lysosomal Neuraminidase 1 (NEU1): Its Unique Molecular Characters and Therapeutic Approaches for Deficiencies.
Neuraminidase 1 (NEU1) is a lysosomal sialidase that removes terminal α-bound sialic acid from sialylglycoconjugates and contributes to ubiquitous catabolism of sialylglycoconjugates and immunoregulatory functions. Different from other human sialidases, including NEU2 to NEU4, NEU1 is first produced as an N-glycosylated precursor protein, which binds to its protective protein/cathepsin A (CTSA) and then forms a lysosomal multienzyme complex (LMC) with β-galactosidase 1 (GLB1) in the rough endoplasmic reticulum (RER) lumen. NEU1 trafficking to lysosomes and intralysosomal activation under acidic pH conditions essentially requires association with CTSA, which carries terminal mannose 6-phosphate (M6P)-type N-glycan to bind with cation-dependent (CD) M6P receptor (CD-M6PR) in the Golgi apparatus via endosomes. In contrast, the single NEU1 gene overexpression in mammalian cells results in NEU1 protein crystallization in the RER owing to self-aggregation at a relatively low intrinsic CTSA level. Two NEU1 deficiencies, sialidosis (SiD) and galactosialidosis (GS), are caused by autosomal recessive NEU1 and CTSA gene mutations, respectively. These untreatable disorders are associated with excessive storage of sialylglycans in neurovisceral organs and systemic symptoms. We produced a new GS model mouse by introducing a homozygous Ctsa IVS6+1g/a mutation into the murine gene locus, leading to partial exon 6 skipping and simultaneous deficiency of Ctsa and Neu1. The GS mice exhibited clinical symptoms similar to those seen in juvenile/adult GS patients, including myoclonic seizures, suppressed behavior, a gargoyle-like face, edema, proctoptosis owing to Neu1 deficiency, and sialylglycan accumulation related to neurovisceral inflammation. Evaluating the efficacy of a novel therapy utilizing GS and SiD model mice and overcoming the human NEU1 gene product shortage will be necessary for a novel, effective treatment for NEU1 deficiencies.
2025-09-27 | Juvenile/adult-type galactosialidosis with a homozygous CTSA variant without consanguinity.
Here we report a Japanese patient with juvenile/adult-type galactosialidosis carrying a homozygous c.692+3A>G CTSA variant. Comprehensive genetic analyses including exome sequencing, chromosomal microarray and homozygosity mapping supported biallelic inheritance of this variant and suggested a founder effect in the Japanese population. Clinically, the patient exhibited typical features of the juvenile/adult-type galactosialidosis, with growth impairment noted during adolescence as a less conspicuous but relevant observation.
2024-11-20 | Lysosomal storage diseases. Mucolipidosis
The epidemiology, clinical, biochemical and molecular genetic characteristics of mucolipidoses — autosomal recessive lysosomal storage diseases that combine the clinical manifestations of mucopolysaccharidoses and sphingolipidoses — are presented. In accordance with the modern classification, types I, II and III mucolipidoses are classified as glycoproteinoses, and type IV mucolipidoses are classified as gangliosidoses. Mucolipidoses type I, or sialidosis, is caused by the presence of inactivating mutations in the α-neuraminidase gene NEU1, and a related disease is galactosialidosis, accompanied by secondary deficiency of α-neuraminidase and β-galactosidase in the CTSA gene of the protective protein cathepsin A. Both diseases are characterized by early progressive delay in psychomotor development, muscle myoclonus, severe ophthalmopathy and early death of patients. The pathogenesis of diseases is associated with excessive accumulation of sialocontaining glycoproteins and oligosaccharides in lysosomes. Hereditary deficiency of N-acetylglucosaminyl-1-phosphotransferase, necessary for the addition of mannose-6-phosphate to the oligosaccharides of lysosomal enzymes, underlies the development of two allelic diseases caused by mutations in the GNPTAB gene mucolipidoses type II, or “I-cell” disease and mucolipidoses type III, alpha/beta or pseudopolydystrophy of Hurler. Mutations in the GNPTG gene, which encodes the gamma subunit of this enzyme, are responsible for the development of the milder type III mucolipidoses (gamma). All these diseases are characterized by impaired phosphorylation and transport of lysosomal enzymes, which is accompanied by severe growth retardation, skeletal abnormalities and early death of patients. Pathogenesis of mucolipidoses type IV, or sialolipidosis, associated with the simultaneous accumulation of phospholipids, sphingolipids, mucopolysaccharides and gangliosides, which occurs as a result of mutations in the MCOLN1 gene, encoding mucolipin 1, which forms a channel localized on the membranes of lysosomes and endosomes, involved in the regulation of lipid and protein transport. The article presents a description of clinical cases of mucolipidosis types II and IIIA. Preclinical trials have shown promise for enzyme replacement therapy, chaperone therapy, and gene therapy for the treatment of sialidosis and galactosialidosis. However, pathogenetic methods of therapy for mucolipidoses have not been described in clinical practice to date.
2026-04-01 | Lysosomal Neuraminidase 1 (NEU1): Its Unique Molecular Characters and Therapeutic Approaches for Deficiencies.
Neuraminidase 1 (NEU1) is a lysosomal sialidase that removes terminal α-bound sialic acid from sialylglycoconjugates and contributes to ubiquitous catabolism of sialylglycoconjugates and immunoregulatory functions. Different from other human sialidases, including NEU2 to NEU4, NEU1 is first produced as an N-glycosylated precursor protein, which binds to its protective protein/cathepsin A (CTSA) and then forms a lysosomal multienzyme complex (LMC) with β-galactosidase 1 (GLB1) in the rough endoplasmic reticulum (RER) lumen. NEU1 trafficking to lysosomes and intralysosomal activation under acidic pH conditions essentially requires association with CTSA, which carries terminal mannose 6-phosphate (M6P)-type N-glycan to bind with cation-dependent (CD) M6P receptor (CD-M6PR) in the Golgi apparatus via endosomes. In contrast, the single NEU1 gene overexpression in mammalian cells results in NEU1 protein crystallization in the RER owing to self-aggregation at a relatively low intrinsic CTSA level. Two NEU1 deficiencies, sialidosis (SiD) and galactosialidosis (GS), are caused by autosomal recessive NEU1 and CTSA gene mutations, respectively. These untreatable disorders are associated with excessive storage of sialylglycans in neurovisceral organs and systemic symptoms. We produced a new GS model mouse by introducing a homozygous Ctsa IVS6+1g/a mutation into the murine gene locus, leading to partial exon 6 skipping and simultaneous deficiency of Ctsa and Neu1. The GS mice exhibited clinical symptoms similar to those seen in juvenile/adult GS patients, including myoclonic seizures, suppressed behavior, a gargoyle-like face, edema, proctoptosis owing to Neu1 deficiency, and sialylglycan accumulation related to neurovisceral inflammation. Evaluating the efficacy of a novel therapy utilizing GS and SiD model mice and overcoming the human NEU1 gene product shortage will be necessary for a novel, effective treatment for NEU1 deficiencies.
2025-09-27 | Juvenile/adult-type galactosialidosis with a homozygous CTSA variant without consanguinity.
Here we report a Japanese patient with juvenile/adult-type galactosialidosis carrying a homozygous c.692+3A>G CTSA variant. Comprehensive genetic analyses including exome sequencing, chromosomal microarray and homozygosity mapping supported biallelic inheritance of this variant and suggested a founder effect in the Japanese population. Clinically, the patient exhibited typical features of the juvenile/adult-type galactosialidosis, with growth impairment noted during adolescence as a less conspicuous but relevant observation.
2024-11-20 | Lysosomal storage diseases. Mucolipidosis
The epidemiology, clinical, biochemical and molecular genetic characteristics of mucolipidoses — autosomal recessive lysosomal storage diseases that combine the clinical manifestations of mucopolysaccharidoses and sphingolipidoses — are presented. In accordance with the modern classification, types I, II and III mucolipidoses are classified as glycoproteinoses, and type IV mucolipidoses are classified as gangliosidoses. Mucolipidoses type I, or sialidosis, is caused by the presence of inactivating mutations in the α-neuraminidase gene NEU1, and a related disease is galactosialidosis, accompanied by secondary deficiency of α-neuraminidase and β-galactosidase in the CTSA gene of the protective protein cathepsin A. Both diseases are characterized by early progressive delay in psychomotor development, muscle myoclonus, severe ophthalmopathy and early death of patients. The pathogenesis of diseases is associated with excessive accumulation of sialocontaining glycoproteins and oligosaccharides in lysosomes. Hereditary deficiency of N-acetylglucosaminyl-1-phosphotransferase, necessary for the addition of mannose-6-phosphate to the oligosaccharides of lysosomal enzymes, underlies the development of two allelic diseases caused by mutations in the GNPTAB gene mucolipidoses type II, or “I-cell” disease and mucolipidoses type III, alpha/beta or pseudopolydystrophy of Hurler. Mutations in the GNPTG gene, which encodes the gamma subunit of this enzyme, are responsible for the development of the milder type III mucolipidoses (gamma). All these diseases are characterized by impaired phosphorylation and transport of lysosomal enzymes, which is accompanied by severe growth retardation, skeletal abnormalities and early death of patients. Pathogenesis of mucolipidoses type IV, or sialolipidosis, associated with the simultaneous accumulation of phospholipids, sphingolipids, mucopolysaccharides and gangliosides, which occurs as a result of mutations in the MCOLN1 gene, encoding mucolipin 1, which forms a channel localized on the membranes of lysosomes and endosomes, involved in the regulation of lipid and protein transport. The article presents a description of clinical cases of mucolipidosis types II and IIIA. Preclinical trials have shown promise for enzyme replacement therapy, chaperone therapy, and gene therapy for the treatment of sialidosis and galactosialidosis. However, pathogenetic methods of therapy for mucolipidoses have not been described in clinical practice to date.
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