RARE DISEASE
Fucosidosis
Fucosidosis
Fucosidosis
Synonyms: Alpha-L-fucosidase deficiency
Synonyms: Alpha-L-fucosidase deficiency
Synonyms: Alpha-L-fucosidase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Fucosidosis is a rare autosomal recessive lysosomal storage disorder caused by FUCA1 gene mutations, resulting in α-L-fucosidase deficiency. This leads to systemic accumulation of fucose-rich glycoconjugates, causing progressive neurodegeneration, developmental regression, coarse facial features, dysostosis multiplex, angiokeratomas, and recurrent infections. Clinical severity ranges from rapid infantile decline (type I) to slower-progressing forms (type II) [1][2][6].
Categories: rare bone diseases, rare cardiac diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
67 drug discovery papers about Fucosidosis, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
67 drug discovery papers about Fucosidosis, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-14 | An Essential Parameters of Fucosidosis Include History of the Disease, Other Lysosomal Storage Disease, Symptoms as well as Clinical Features, Treatment as well as Therapeutic Options
Fucosidosis is a rare lysosomal storage disease occurred by α-L-fucosidase deficiency because of mutation especially in the FUCA1 gene. This enzyme plays an important role regarding catabolism of fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Fucose-rich substrates are deposited in lysosomes as a result of mutations in FUCA1, which cause either reduced enzyme activity or complete loss of function. Undigested substrates cause lysosomes to swell, leading to secondary storage problems that affect other metabolic pathways. The central nervous system is especially vulnerable,along with lysosomal dysfunction creating microglial activation, inflammation, and neuronal loss, resulting in the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, along with neuronal apoptosis, axonal degeneration, and synaptic dysfunction, enhancing the disease process. Chronic neuroinflammation disrupts synaptic plasticity as well as neuronal survival, resulting in progressive intellectual disability, learning difficulties, and loss of previously acquired skills. Inflammatory cytokines and lysosomal burden in motor neurons and associated pathways contribute to ataxia, spasticity, and hypotonia, which are common motor symptoms in fucosidosis. Raised neuroinflammatory markers can enhance neuronal excitability, resulting in the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is manifested by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients generally die at an early age. Treatment of fucosidosis is a great challenge, and there is currently no definitive effective treatment. Hematopoietic cell transplantation studies are ongoing regarding the treatment of fucosidosis. Whatever it may be, early diagnosis of this disease and treatment shows an effectiveness. In addition, the body’s immune system reduces because of chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is more along with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is enhancing because of their easy integration, high cell efficiency, and safety. Preclinical research is being conducted for fucosidosis using an alternative treatment strategy called enzyme replacement therapy; nevertheless, a significant disruption in lysosomal storage illnesses affecting the central nervous system is the blood–brain barrier. Due to the rapid advancement of fucosidosis, a rare disease, and the delay in diagnosing patients who have been identified thus far, early identification is crucial. Furthermore, the less dangerous enzyme replacement therapy shows promise.
2026-02-04 | Novel FUCA1 variants in two families, including the first report of a contiguous gene deletion syndrome involving FUCA1 and HMGCL.
Fucosidosis is a rare, autosomal recessive lysosomal storage disorder caused by deficiency of an alpha-L-fucosidase due to pathogenic variants in the FUCA1 gene, leading to the accumulation of fucoglyco-conjugates in the lysosomes of the liver, brain, skin and other organs. Its main clinical features include progressive neurological deterioration, seizures, coarse facies, visceromegaly, angiokeratoma, growth retardation, recurrent sinopulmonary infections and dysostosis multiplex. Three patients with fucosidosis from two unrelated families with severe developmental delay, hearing loss, coarse facies but no hepatosplenomegaly and angiokeratoma are presented. A homozygous, novel nonsense mutation c.236G>A (p.Trp79*) in exon 1 of the FUCA1 gene was identified in one family, and a homozygous novel 64.5 kb deletion, including HMGCL (exons 1-6), FUCA1, and CNR2 (exon 2) genes in the other. Fucosidosis should be considered in patients with delayed motor and cognitive development followed by progressive neurological deterioration, even in the absence of common features such as organomegaly and angiokeratoma. The pathogenic variants identified in both families were novel and consistent with fucosidosis type 1. To our knowledge, this is the first reported case of fucosidosis accompanied by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency resulting from a contiguous gene deletion involving the HMGCL gene at the 1p36.11 locus.
2025-11-07 | Recovery of α-L-fucosidase in fucosidosis nonsense variants by readthrough stimulation and release factor degradation.
Fucosidosis is an ultra-rare and fatal lysosomal storage disease caused by the impaired lysosomal degradation of fucosylated glycoconjugates due to a deficiency in the lysosomal tissue α-L-fucosidase (FUCA1). The accumulation of fucosylated metabolites within lysosomes leads to a range of severe, primarily neurological, symptoms, including cognitive impairment and progressive motor dysfunction. In this study, we explored a therapeutic approach using translational readthrough (TR) for patients with premature termination codons resulting from nonsense mutations in the FUCA1 gene. We ectopically expressed several clinically identified FUCA1 nonsense variants in a cell line with low endogenous FUCA1 expression. Treatment with the aminoglycoside G418 induced TR, leading to partial recovery of the full-length enzyme and FUCA1 activity. Moreover, combining aminoglycoside treatment with CC-885-induced degradation of the eukaryotic release factor subunit eRF3a further enhanced FUCA1 restoration in two variants (p.Q82X and p.W188X). This study lays the groundwork for individualized TR therapy for patients with fucosidosis with FUCA1 nonsense variants.
2025-09-24 | Recombinant Production and Characterization of a Novel α-L-Fucosidase from Bifidobacterium castoris
α-L-fucosidases (EC 3.2.1.51) are of particular interest due to their ability to cleave terminal α-L-fucose residues from glycoconjugates, a property associated with numerous biological and therapeutic effects. They have also been investigated for their potential use in glycan remodeling, disease biomarker analysis, and particularly as therapeutic agents in the context of fucosidosis, a rare lysosomal storage disorder, caused by a deficiency in α-L-fucosidase activity. However, limitations in enzyme availability, stability, and substrate specificity highlight the need for novel and more efficient enzyme sources. Bifidobacterium castoris (B. castor is) is a newly identified species first discovered in the beaver gut microbiota in 2019. Phylogenetic studies have revealed its advanced metabolic capacity, and genomic analyses have demonstrated its extensive carbohydrate metabolism potential. This research article focuses on the recombinant production and biochemical characterization of a novel α-L-fucosidase from B. castoris LMG (Laboratorium voor Microbiologie Gent) 30937, predicted to belong to glycoside hydrolase family 29 (GH29) according to Universal Protein Resource (UniProt) annotation. Under optimized reaction conditions the recombinant α-L-fucosidase exhibited a specific activity of 0.264 U/mg to pNP-Fuc (4-Nitrophenyl-α-L-fucopyranoside). The results indicate that the enzyme is active in the pH range of 3.0–8.0 and temperatures of 24–42 °C, but its optimum conditions are the slightly acidic pH of 5.5 and the elevated temperature of 42 °C. This profile suggests that the enzyme is adapted to acidic intestinal-like environments. This novel enzyme expands the GH29 α-L-fucosidase repertoire and offers a promising new candidate for future biotechnological applications.
2025-03-17 | P406: A novel UBA2 variant causing aplasia cutis congenita with ectrodactyly skeletal (ACCES) syndrome in a family with variable expressivity
Discussion: Fucosidosis is a progressive neurodegenerative disorder characterized by relentless symptom progression.It is classified into two types: Type I, presenting within the first year of life and associated with rapid disease progression and a life expectancy of 5-10 years, and Type II, which presents after age two with a slower progression and longer survival.Our patient aligns with Type I, displaying severe and progressive symptoms.However, diagnostic delays due to the diverse spectrum of clinical features associated with fucosidosis illustrate the ongoing challenges in early diagnosis and the need for increased awareness. Conclusion:The FUCA1 gene, located on chromosome 1p36.11,contains eight exons spanning 23 kb.To date, only 36 pathogenic variants in FUCA1 have been reported.The identification of this novel variant expands the mutation spectrum.This case highlights the importance of considering rare forms of LSD in patients presenting with a broad array of multisystemic symptoms.Further research is needed to develop therapies, including enzyme replacement, stem cell transplantation, and gene therapy.Introduction: Fucosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) with an incidence of less than 1 in 200,000.It is caused by pathogenic variants in the FUCA1 gene, resulting in a deficiency of the lysosomal enzyme -L-fucosidase.This enzyme deficiency disrupts the degradation of fucose-containing glycoconjugates, leading to their accumulation in various tissues and causing a range of neurodegenerative symptoms.Clinical manifestations of fucosidosis vary widely and include coarse facial features, growth retardation, recurrent respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum.The broad spectrum of presentations complicates early diagnosis, with approximately 120 cases reported globally to date.Case Presentation: We report the case of a two-year-old boy presenting with global developmental delay, nonverbal status, and inability to walk.He was born at 36 weeks to a 23-year-old mother via spontaneous vaginal delivery and experienced neonatal jaundice treated with phototherapy.Initial symptoms included significant hypotonia, dysphagia, exotropia, lumbar kyphosis, gibbus deformity, lower extremity spasticity, and in-toeing gait.Family history was unremarkable.Diagnostic Workup: Brain MRI revealed diffuse white matter abnormalities and signal changes in the bilateral globus pallidi, suggesting a lysosomal storage disorder or leukodystrophy.However, MPS enzyme screening, urine analysis, and ophthalmologic examination yielded no conclusive results.Chromosomal microarray analysis identified a 17.2 Mb region of homozygosity at 1p36.21, suggestive of consanguinity and possible autosomal recessive disorders.Exome sequencing could not be completed due to the family's relocation and the COVID-19 pandemic.At age six, the patient was admitted to the hospital with fever and hand, foot, and mouth lesions, which prompted further genetic investigation.Physical examination revealed muscle atrophy, hypotonia, and lower extremity spasticity with ankle contractures.A leukodystrophy panel revealed a novel homozygous pathogenic variant, c.557T>A (p.Leu186*) in the FUCA1 gene.Subsequent enzyme testing confirmed a complete absence of alpha-fucosidase activity, leading to a definitive diagnosis of fucosidosis.
2026-04-14 | An Essential Parameters of Fucosidosis Include History of the Disease, Other Lysosomal Storage Disease, Symptoms as well as Clinical Features, Treatment as well as Therapeutic Options
Fucosidosis is a rare lysosomal storage disease occurred by α-L-fucosidase deficiency because of mutation especially in the FUCA1 gene. This enzyme plays an important role regarding catabolism of fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Fucose-rich substrates are deposited in lysosomes as a result of mutations in FUCA1, which cause either reduced enzyme activity or complete loss of function. Undigested substrates cause lysosomes to swell, leading to secondary storage problems that affect other metabolic pathways. The central nervous system is especially vulnerable,along with lysosomal dysfunction creating microglial activation, inflammation, and neuronal loss, resulting in the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, along with neuronal apoptosis, axonal degeneration, and synaptic dysfunction, enhancing the disease process. Chronic neuroinflammation disrupts synaptic plasticity as well as neuronal survival, resulting in progressive intellectual disability, learning difficulties, and loss of previously acquired skills. Inflammatory cytokines and lysosomal burden in motor neurons and associated pathways contribute to ataxia, spasticity, and hypotonia, which are common motor symptoms in fucosidosis. Raised neuroinflammatory markers can enhance neuronal excitability, resulting in the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is manifested by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients generally die at an early age. Treatment of fucosidosis is a great challenge, and there is currently no definitive effective treatment. Hematopoietic cell transplantation studies are ongoing regarding the treatment of fucosidosis. Whatever it may be, early diagnosis of this disease and treatment shows an effectiveness. In addition, the body’s immune system reduces because of chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is more along with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is enhancing because of their easy integration, high cell efficiency, and safety. Preclinical research is being conducted for fucosidosis using an alternative treatment strategy called enzyme replacement therapy; nevertheless, a significant disruption in lysosomal storage illnesses affecting the central nervous system is the blood–brain barrier. Due to the rapid advancement of fucosidosis, a rare disease, and the delay in diagnosing patients who have been identified thus far, early identification is crucial. Furthermore, the less dangerous enzyme replacement therapy shows promise.
2026-02-04 | Novel FUCA1 variants in two families, including the first report of a contiguous gene deletion syndrome involving FUCA1 and HMGCL.
Fucosidosis is a rare, autosomal recessive lysosomal storage disorder caused by deficiency of an alpha-L-fucosidase due to pathogenic variants in the FUCA1 gene, leading to the accumulation of fucoglyco-conjugates in the lysosomes of the liver, brain, skin and other organs. Its main clinical features include progressive neurological deterioration, seizures, coarse facies, visceromegaly, angiokeratoma, growth retardation, recurrent sinopulmonary infections and dysostosis multiplex. Three patients with fucosidosis from two unrelated families with severe developmental delay, hearing loss, coarse facies but no hepatosplenomegaly and angiokeratoma are presented. A homozygous, novel nonsense mutation c.236G>A (p.Trp79*) in exon 1 of the FUCA1 gene was identified in one family, and a homozygous novel 64.5 kb deletion, including HMGCL (exons 1-6), FUCA1, and CNR2 (exon 2) genes in the other. Fucosidosis should be considered in patients with delayed motor and cognitive development followed by progressive neurological deterioration, even in the absence of common features such as organomegaly and angiokeratoma. The pathogenic variants identified in both families were novel and consistent with fucosidosis type 1. To our knowledge, this is the first reported case of fucosidosis accompanied by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency resulting from a contiguous gene deletion involving the HMGCL gene at the 1p36.11 locus.
2025-11-07 | Recovery of α-L-fucosidase in fucosidosis nonsense variants by readthrough stimulation and release factor degradation.
Fucosidosis is an ultra-rare and fatal lysosomal storage disease caused by the impaired lysosomal degradation of fucosylated glycoconjugates due to a deficiency in the lysosomal tissue α-L-fucosidase (FUCA1). The accumulation of fucosylated metabolites within lysosomes leads to a range of severe, primarily neurological, symptoms, including cognitive impairment and progressive motor dysfunction. In this study, we explored a therapeutic approach using translational readthrough (TR) for patients with premature termination codons resulting from nonsense mutations in the FUCA1 gene. We ectopically expressed several clinically identified FUCA1 nonsense variants in a cell line with low endogenous FUCA1 expression. Treatment with the aminoglycoside G418 induced TR, leading to partial recovery of the full-length enzyme and FUCA1 activity. Moreover, combining aminoglycoside treatment with CC-885-induced degradation of the eukaryotic release factor subunit eRF3a further enhanced FUCA1 restoration in two variants (p.Q82X and p.W188X). This study lays the groundwork for individualized TR therapy for patients with fucosidosis with FUCA1 nonsense variants.
2025-09-24 | Recombinant Production and Characterization of a Novel α-L-Fucosidase from Bifidobacterium castoris
α-L-fucosidases (EC 3.2.1.51) are of particular interest due to their ability to cleave terminal α-L-fucose residues from glycoconjugates, a property associated with numerous biological and therapeutic effects. They have also been investigated for their potential use in glycan remodeling, disease biomarker analysis, and particularly as therapeutic agents in the context of fucosidosis, a rare lysosomal storage disorder, caused by a deficiency in α-L-fucosidase activity. However, limitations in enzyme availability, stability, and substrate specificity highlight the need for novel and more efficient enzyme sources. Bifidobacterium castoris (B. castor is) is a newly identified species first discovered in the beaver gut microbiota in 2019. Phylogenetic studies have revealed its advanced metabolic capacity, and genomic analyses have demonstrated its extensive carbohydrate metabolism potential. This research article focuses on the recombinant production and biochemical characterization of a novel α-L-fucosidase from B. castoris LMG (Laboratorium voor Microbiologie Gent) 30937, predicted to belong to glycoside hydrolase family 29 (GH29) according to Universal Protein Resource (UniProt) annotation. Under optimized reaction conditions the recombinant α-L-fucosidase exhibited a specific activity of 0.264 U/mg to pNP-Fuc (4-Nitrophenyl-α-L-fucopyranoside). The results indicate that the enzyme is active in the pH range of 3.0–8.0 and temperatures of 24–42 °C, but its optimum conditions are the slightly acidic pH of 5.5 and the elevated temperature of 42 °C. This profile suggests that the enzyme is adapted to acidic intestinal-like environments. This novel enzyme expands the GH29 α-L-fucosidase repertoire and offers a promising new candidate for future biotechnological applications.
2025-03-17 | P406: A novel UBA2 variant causing aplasia cutis congenita with ectrodactyly skeletal (ACCES) syndrome in a family with variable expressivity
Discussion: Fucosidosis is a progressive neurodegenerative disorder characterized by relentless symptom progression.It is classified into two types: Type I, presenting within the first year of life and associated with rapid disease progression and a life expectancy of 5-10 years, and Type II, which presents after age two with a slower progression and longer survival.Our patient aligns with Type I, displaying severe and progressive symptoms.However, diagnostic delays due to the diverse spectrum of clinical features associated with fucosidosis illustrate the ongoing challenges in early diagnosis and the need for increased awareness. Conclusion:The FUCA1 gene, located on chromosome 1p36.11,contains eight exons spanning 23 kb.To date, only 36 pathogenic variants in FUCA1 have been reported.The identification of this novel variant expands the mutation spectrum.This case highlights the importance of considering rare forms of LSD in patients presenting with a broad array of multisystemic symptoms.Further research is needed to develop therapies, including enzyme replacement, stem cell transplantation, and gene therapy.Introduction: Fucosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) with an incidence of less than 1 in 200,000.It is caused by pathogenic variants in the FUCA1 gene, resulting in a deficiency of the lysosomal enzyme -L-fucosidase.This enzyme deficiency disrupts the degradation of fucose-containing glycoconjugates, leading to their accumulation in various tissues and causing a range of neurodegenerative symptoms.Clinical manifestations of fucosidosis vary widely and include coarse facial features, growth retardation, recurrent respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum.The broad spectrum of presentations complicates early diagnosis, with approximately 120 cases reported globally to date.Case Presentation: We report the case of a two-year-old boy presenting with global developmental delay, nonverbal status, and inability to walk.He was born at 36 weeks to a 23-year-old mother via spontaneous vaginal delivery and experienced neonatal jaundice treated with phototherapy.Initial symptoms included significant hypotonia, dysphagia, exotropia, lumbar kyphosis, gibbus deformity, lower extremity spasticity, and in-toeing gait.Family history was unremarkable.Diagnostic Workup: Brain MRI revealed diffuse white matter abnormalities and signal changes in the bilateral globus pallidi, suggesting a lysosomal storage disorder or leukodystrophy.However, MPS enzyme screening, urine analysis, and ophthalmologic examination yielded no conclusive results.Chromosomal microarray analysis identified a 17.2 Mb region of homozygosity at 1p36.21, suggestive of consanguinity and possible autosomal recessive disorders.Exome sequencing could not be completed due to the family's relocation and the COVID-19 pandemic.At age six, the patient was admitted to the hospital with fever and hand, foot, and mouth lesions, which prompted further genetic investigation.Physical examination revealed muscle atrophy, hypotonia, and lower extremity spasticity with ankle contractures.A leukodystrophy panel revealed a novel homozygous pathogenic variant, c.557T>A (p.Leu186*) in the FUCA1 gene.Subsequent enzyme testing confirmed a complete absence of alpha-fucosidase activity, leading to a definitive diagnosis of fucosidosis.
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