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 about Galactosialidosis, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
55 drug discovery papers about Galactosialidosis, with 3 first-in-class emerging drug candidates 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.
2024-08-28 | Neuraminidase-1 (NEU1): Biological Roles and Therapeutic Relevance in Human Disease.
Neuraminidases catalyze the desialylation of cell-surface glycoconjugates and play crucial roles in the development and function of tissues and organs. In both physiological and pathophysiological contexts, neuraminidases mediate diverse biological activities via the catalytic hydrolysis of terminal neuraminic, or sialic acid residues in glycolipid and glycoprotein substrates. The selective modulation of neuraminidase activity constitutes a promising strategy for treating a broad spectrum of human pathologies, including sialidosis and galactosialidosis, neurodegenerative disorders, cancer, cardiovascular diseases, diabetes, and pulmonary disorders. Structurally distinct as a large family of mammalian proteins, neuraminidases (NEU1 through NEU4) possess dissimilar yet overlapping profiles of tissue expression, cellular/subcellular localization, and substrate specificity. NEU1 is well characterized for its lysosomal catabolic functions, with ubiquitous and abundant expression across such tissues as the kidney, pancreas, skeletal muscle, liver, lungs, placenta, and brain. NEU1 also exhibits a broad substrate range on the cell surface, where it plays hitherto underappreciated roles in modulating the structure and function of cellular receptors, providing a basis for it to be a potential drug target in various human diseases. This review seeks to summarize the recent progress in the research on NEU1-associated diseases and highlight the mechanistic implications of NEU1 in disease pathogenesis. An improved understanding of NEU1-associated diseases should help accelerate translational initiatives to develop novel or better therapeutics.
2024-01-16 | Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent.
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.
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.
2024-08-28 | Neuraminidase-1 (NEU1): Biological Roles and Therapeutic Relevance in Human Disease.
Neuraminidases catalyze the desialylation of cell-surface glycoconjugates and play crucial roles in the development and function of tissues and organs. In both physiological and pathophysiological contexts, neuraminidases mediate diverse biological activities via the catalytic hydrolysis of terminal neuraminic, or sialic acid residues in glycolipid and glycoprotein substrates. The selective modulation of neuraminidase activity constitutes a promising strategy for treating a broad spectrum of human pathologies, including sialidosis and galactosialidosis, neurodegenerative disorders, cancer, cardiovascular diseases, diabetes, and pulmonary disorders. Structurally distinct as a large family of mammalian proteins, neuraminidases (NEU1 through NEU4) possess dissimilar yet overlapping profiles of tissue expression, cellular/subcellular localization, and substrate specificity. NEU1 is well characterized for its lysosomal catabolic functions, with ubiquitous and abundant expression across such tissues as the kidney, pancreas, skeletal muscle, liver, lungs, placenta, and brain. NEU1 also exhibits a broad substrate range on the cell surface, where it plays hitherto underappreciated roles in modulating the structure and function of cellular receptors, providing a basis for it to be a potential drug target in various human diseases. This review seeks to summarize the recent progress in the research on NEU1-associated diseases and highlight the mechanistic implications of NEU1 in disease pathogenesis. An improved understanding of NEU1-associated diseases should help accelerate translational initiatives to develop novel or better therapeutics.
2024-01-16 | Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent.
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.
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