RARE DISEASE
Fucosidosis
Fucosidosis
Fucosidosis
Synonyms: Alpha-L-fucosidase deficiency
Synonyms: Alpha-L-fucosidase deficiency
Synonyms: Alpha-L-fucosidase deficiency
Drug discovery
67
papers
On emerging therapies
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:
categories:
Small molecules
proteins
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.
2025-09-24 | 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.
2025-01-11 | Fucosidosis: A Review of a Rare Disease.
Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following a mutation in the FUCA1 gene. This enzyme is responsible for breaking down fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Mutations in FUCA1 result in either reduced enzyme activity or complete loss of function, leading to the accumulation of fucose-rich substrates in lysosomes. Lysosomes become engorged with undigested substrates, which leads to secondary storage defects affecting other metabolic pathways. The central nervous system is particularly vulnerable, with lysosomal dysfunction causing microglial activation, inflammation, and neuronal loss, leading to the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, including neuronal apoptosis, axonal degeneration, and synaptic dysfunction, exacerbating the disease process. Chronic neuroinflammation impairs synaptic plasticity and neuronal survival, leading to 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. Elevated neuroinflammatory markers can increase neuronal excitability, leading to the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually 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 in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body's immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is promising due to their easy integration, high cell efficiency, and safety. In another treatment approach, enzyme replacement therapy, preclinical studies are ongoing for fucosidosis, but the blood-brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is important in fucosidosis, a rare disease, due to the delay in the diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising.
2023-02-07 | Characterization of l-fucose isomerase from Paenibacillus rhizosphaerae to produce l-fuculose from hydrolyzed fucoidan and commercial fucose.
l-Fuculose is a valuable rare sugar that is used to treat a variety of ailments, including HIV, cancer, Hepatitis B, human lysosomal disease (fucosidosis), and cardio-protective medications. The enzymatic approach for the production of l-fuculose using l-fucose as a substrate would be an advantageous method with a wide range of industrial applications. The objective of this study is the characterization of recombinant l-fucose isomerase from Paenibacillus rhizosphaerae (Pa-LFI) for the production of l-fuculose from an inexpensive and natural source (fucoidan) as well as its comparison with commercial l-fucose (Sigma-Aldrich). Fucoidan, a fucose-containing polysaccharide (FPs), was isolated from Undaria pinnatifida, subsequently hydrolyzed, and characterized before the enzymatic production of l-fuculose. The results elaborate that FPs contain 35.9% of fucose along with other kinds of monosaccharides. The purified Pa-LFI exhibited a single band at 65 kDa and showed it as a hexamer with a native molecular mass of 396 kDa. The highest activity of 104.5 U mg-1 of Pa-LFI was perceived at a temperature of 50°C and pH 6.5 in the presence of 1 mM of Mn2+. The Pa-LFI revealed a melting temperature (Tm) of 75°C and a half-life of 12.6 h at 50°C. It exhibited that Pa-LFI with aldose substrate (l-fucose), has a stronger isomerizing activity, disclosing Km,kcat, and kcat/Km 86.2 mM, 32 831 min-1, and 335 min-1 mM-1, respectively. After reaching equilibrium, Pa-LFI efficiently catalyzed the reaction to convert l-fucose into l-fuculose and the conversion ratios of l-fuculose from 100 g L-1 of FPs and commercial fucose were around 6% (5.6 g L-1) and 30% (30.2 g L-1), respectively. According to the findings of the current study, the Pa-LFI will be useful in the manufacturing of l-fuculose using an effective and easy approach that produces no by-products.
cell therapies
2022-08-25 | Fucosidosis: clinical and molecular findings of turkish patients
Fucosidosis is a rare, autosomal recessive lysosomal storage disease caused by alpha L- fucosidase enzyme deficiency in all tissues. Here, we identify a patient with a novel homozygous pathogenic variant and atypical clinical findings and summarized the clinical and molecular features of Turkish patients reported in the literature and present.The patient was born to consangineous parents at the 28th week of gestation. He had developmental delay that was attributed to prematurity. At he age of 2.5 years, brain magnetic resonans imaging revealed hyperintensities of symmetrical periventricular, subcortical, centrum semiovale and corona radiata regions on T2 and FLAIR weighted images. He developed seizures and showed developmental regression at he age of 3,5 years. Beside, coarse facial features and hepatomegaly were detected on phsyical examination. Lysosomal enzyme analysis revelaed alfa fucosidase deficiency and molecular genetic analysis identified a novel homozygous pathogenic p. Lys431 fs variant in FUCA1 gene.In Turkish patients no distinguishable clinical and radiologic finding could be established. Molecular analysis was performed in few patients. Increasing of molecular and biochemical facilities might enable to make diagnosis and increase the prevalence of the disease in countries with high rate of consanguineous marriages. Moreover, it will provide genetic counseling, and enlighten the therapeutic effects of hematopoietic stem cell transplantation.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
2021-01-06 | Fucosidosis in a Chinese boy: a case report and literature review.
Fucosidosis is a rare lysosomal storage disease, resulting from a deficiency in an alpha-l-fucosidase enzyme. There are fewer than 120 cases of this disease worldwide and very few reported in Chinese children. Here, we report a Chinese boy presenting with psychomotor regression, dermatological abnormality, dysostosis multiplex, and classic changes observed with head magnetic resonance imaging. He was diagnosed with fucosidosis, with a previously reported homozygous mutation of c.393(exon2)T > A, p.Tyr131Stop, in the FUCA1 gene. Increasing awareness of fucosidosis will help in the early diagnosis of this disease and could shed light on the therapeutic role of hematopoietic stem cell transplantation, which may be effective in early stages of the disease.
2019-05-07 | A Novel Homozygous Mutation in the FUCA1 Gene Highlighting Fucosidosis as a Cause of Dystonia: Case Report and Literature Review
Background Fucosidosis is a rare lysosomal disorder caused by mutations in the FUCA1 gene. We describe here a novel homozygous mutation in FUCA1 in an Indian fucosidosis case. Furthermore, we summarize the clinical and genetic findings in the most recently reported individuals with fucosidosis. Case The proband is an 8-year-old boy born to consanguineous parents. He had generalized dystonia and bilateral spasticity as well as coarse facies, dysostosis multiplex, recurrent infections, angiokeratoma corporis diffusum, and visceromegaly. Whole exome sequencing analysis detected a homozygous canonical splice variant in the FUCA1 gene [Chr1(GRCh37):g.24172346C > T; NM_000147.4:c.1261–1G > A], not previously reported as causative of a human phenotype. Low levels of α-fucosidase in patient leukocytes and a positive qualitative urine based thin layer chromatography test for fucosidosis confirmed the diagnosis. Our literature review identified 89 cases of fucosidosis since the last major review. We show that dystonia is a rare manifestation (12%) and that only a small minority of cases receive treatment with transplantation (3.37%). Conclusion We report a novel homozygous mutation in FUCA1 as the cause of severe neurological phenotype including generalized dystonia. Early recognition of fucosidosis may be important for consideration of promising treatment options, such as bone marrow transplantation.
2018-01-05 | Brain abnormalities in fucosidosis: transplantation or supportive therapy?
Fucosidosis is a rare lysosomal storage disease caused by α-fucosidase deficiency, which leads to progressive neurological deterioration and death. Hematopoietic stem cell transplantation is the best curative therapy if performed during the early stages of disease. We report two fucosidosis patients with brain abnormalities and the challenge faced in their management. The first patient received supportive therapy and the second one firstly underwent unrelated donor umbilical cord blood transplantation. After a period of follow-up, we found neurological symptoms were worsening day by day on patient1. By contrast, patient2 who received cord blood transplantation acquired clinical neurologic improvement in response to normalization of deficient enzymatic activity. This report indicates that hematopoietic transplant could reduce the severity and retard the progression of clinical neurological deterioration. Umbilical cord blood transplantation is a novel approach for treating fucosidosis patients who lack suitable bone morrow donors.
small molecules
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.
2022-10-11 | The long-awaited structure of human fucosidase FucA1 opens novel avenues for the treatment of fucosidosis.
In this issue of Structure, Armstrong and colleagues probe the structure of human fucosidase FucA1. Their work resolves an ongoing debate around the enzyme's catalytic mechanism and provides a valid structural template to guide the design of drugs alleviating the rare, yet severe, lysosomal storage disease fucosidosis.
2022-08-26 | Dual role of fucosidase in cancers and its clinical potential
Glycosidases and glycosyltransferases greatly impact malignant phenotype of tumors though genetics and epigenetics mechanisms.As the member of glycoside hydrolase (GH) families 29A, α-L-fucosidases (AFUs) are involved in the hydrolysis of terminal L-fucose residues linked via α-1,2, α-1,3, α-1,4 or α-1,6 to the reducing end of N-acetyl glucosamine (GlcNAc) of oligosaccharide chains.The defucosylation process mediated by AFUs contributes to the development of various diseases, such as chronic inflammatory diseases, immune disorders, and autoimmune diseases by reducing the interaction between fucosylated adhesion molecules supporting leukocyte extravasation.AFUs also impair crucial cell-extracellular matrix (ECM) interactions and presumably subsequent cell signaling pathways, which lead to changes in tumor function and behavior.There are two isoforms of AFUs in human, namely α-L-fucosidase 1 (FUCA1) and α-L-fucosidase 2 (FUCA2), respectively.FUCA1 is a p53 target gene and can hydrolyze different fucosylation sites on epidermal growth factor receptor (EGFR), thereby determining the activation of EGFR.FUCA2 mediates the adhesion between Helicobacter pylori and gastric mucosa and is upregulated in 24 tumor types.Besides, based on the participation of AFU in signaling pathways and tumor progression, we discuss the prospect of AFU as a therapeutic target.
2019-04-17 | Development of a UHPLC-MS method for inhibitor screening against α-L-1,3-fucosidase.
α-L-Fucosidase (AFU) is a promising therapeutic target for the treatment of inflammation, cancer, cystic fibrosis, and fucosidosis. Some of the existing analytical methods for the assessment of AFU activity are lacking in sensitivity and selectivity, since most of them are based on spectrofluorimetric methods. More recently, mass spectrometry (MS) has evolved as a key technology for enzyme assays and inhibitor screening as it enables accurate monitoring of the conversion of substrate to product in enzymatic reactions. In this study, UHPLC-MS has been utilized to develop a simple, sensitive, and accurate assay for enzyme kinetics and inhibition studies of AFU3, a member of the AFU family. A reported method for analyzing saccharide involving a porous graphitic carbon column, combined with reduction by NaBH4/CH3OH, was used to improve sensitivity. The conversion of saccharide into alditol could reach nearly 100% in the NaBH4 reduction reaction. In addition, the bioanalytical quantitative screening method was validated according to US-FDA guidance, including selectivity, linearity, precision, accuracy, stability, and matrix effect. The developed method displayed a good accuracy, high sensitivity (LOD = 0.05 mg L-1), and good reproducibility (RSD < 15%). The assay accurately measured an IC50 value of 0.40 μM for the known AFU inhibitor, deoxyfuconojirimycin, which was consistent with results reported in the literature. Further validation of the assay was achieved through the determination of a high Z'-factor value of 0.89. The assay was applied to screen a marine-derived chemical library against AFU3, which revealed two marine-oriented pyrimidine alkaloids as potential AFU3 inhibitors. Graphical abstract.
2018-05-01 | Harnessing pyrrolidine iminosugars into dimeric structures for the rapid discovery of divalent glycosidase inhibitors
The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one β-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (Ki = 0.15 nM) and Homo sapiens (Ki = 60 nM), and dimer 2e as the best inhibitor of β-galactosidase from bovine liver (Ki = 5.8 μM). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver β-galactosidase by dimer 2e.
gene therapies
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.
2024-12-11 | Fucosidosis: Review of a Rare Disease
Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following mutation in the FUCA1 gene, in which fucose-bound glycoconjugates accumulate in the lysosomes of different tissues of the body. Fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or an-giokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually 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 in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body's immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors is promising due to their easy inte-gration, high cell efficiency and safety. In another treatment approach, enzyme replacement ther-apy, preclinical studies are ongoing for fucosidosis, but the blood-brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is im-portant in fucosidosis, a rare disease, due to the delay in diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising.
2002-02-21 | Non-viral, integrin-mediated gene transfer into fibroblasts from patients with lysosomal storage diseases.
Non-viral vectors consisting of Lipofectin/integrin-targeting peptide/DNA (LID) complexes have great potential for gene therapy, as they are safe, simple, and able to package large DNA molecules. In this study, these vectors were evaluated in vitro for the therapy of lysosomal storage disorders. Non-viral vectors were designed to deliver therapeutic genes by integrin-mediated uptake into fibroblasts from patients with the lysosomal storage disorders fucosidosis and Fabry disease, which result from deficiencies of alpha-L-fucosidase and alpha-galactosidase A, respectively. The vectors consisted of a complex (LID) of Lipofectin and a peptide containing an integrin-targeting domain and a poly-lysine domain to which was bound plasmid DNA, containing alpha-L-fucosidase (LID-alpha-Fuc) or alpha-galactosidase A (LID-alpha-Gal). Patients' fibroblasts transfected with LID-alpha-Fuc and LID-alpha-Gal produced the corresponding enzyme at levels which were 10-40% of the total activity in cultures of normal fibroblasts. However, 95-98% of this activity was secreted. Transfection of endothelial cells, the main target cells in Fabry disease, with an LID-alpha-Gal produced a total alpha-galactosidase activity 65% higher than that in untransfected cultures after 6 days, 67% of the activity being secreted. Although transfection of fibroblasts with LID complexes also caused small changes in the distribution of endogenous lysosomal enzymes, it did not appear to affect the viability of the cells. The integrin-mediated transfer of genes encoding lysosomal enzymes into cells results in the secretion of large amounts of normal enzyme that could be taken up by other cells. This could be a useful strategy for enzyme-replacement therapy.
1997-07-01 | Canine fucosidosis: a model for retroviral gene transfer into haematopoietic stem cells
Severe progressive fatal neurological degeneration occurs in fucosidosis, a storage disease. Bone marrow transplantation into affected dogs has shown that haematopoietic stem cells can provide enzyme producing daughter cells to the central nervous system, altering disease course. This makes canine fucosidosis an ideal large animal model for gene therapy. Fucosidosis affected allogeneic or autologous canine marrow was transduced ex vivo by cocultivation, then transplanted into fucosidosis affected dogs conditioned with total lymphoid irradiation. The vectors were Moloney murine leukaemia virus based. Transduction efficiency was increased with multiple cytokines in short term marrow culture. Despite high levels of transduction, proviral sequence was detected 2 months post transplant in only one dog. Early or total graft failure occurred in all transplants. We believe lack of engraftment could be caused by differentiation or change of repopulating ability of marrow cells occurring with multiple cytokine mixes in culture media.
1992-10-20 | Correction of alpha-L-fucosidase deficiency in fucosidosis fibroblasts by retroviral vector-mediated gene transfer.
A full-length cDNA clone encoding the lysosomal hydrolase alpha-L-fucosidase was cloned into two retroviral vectors, one using the human cytomegalovirus immediate-early promoter for expression, and the other, the retroviral long terminal repeat (LTR). High-titer amphotropic virus was produced for both constructs by infection of PA317 cells, and used to efficiently transduce the alpha-L-fucosidase gene into both human and canine fucosidosis fibroblasts. This resulted in correction of the alpha-L-fucosidase enzyme deficiency characteristic of these fibroblasts. The high levels of recombinant enzyme produced corrected the degradative defect normally seen in these cells, enabling them to catabolize efficiently the accumulated storage product present in lysosomes. Therefore, these retroviral constructs should allow us to start evaluating the value of gene therapy in treating the central nervous system pathology associated with fucosidosis and other lysosomal storage disorders in humans, using a canine model of fucosidosis.
proteins
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.
2025-09-24 | 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.
2025-01-11 | Fucosidosis: A Review of a Rare Disease.
Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following a mutation in the FUCA1 gene. This enzyme is responsible for breaking down fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Mutations in FUCA1 result in either reduced enzyme activity or complete loss of function, leading to the accumulation of fucose-rich substrates in lysosomes. Lysosomes become engorged with undigested substrates, which leads to secondary storage defects affecting other metabolic pathways. The central nervous system is particularly vulnerable, with lysosomal dysfunction causing microglial activation, inflammation, and neuronal loss, leading to the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, including neuronal apoptosis, axonal degeneration, and synaptic dysfunction, exacerbating the disease process. Chronic neuroinflammation impairs synaptic plasticity and neuronal survival, leading to 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. Elevated neuroinflammatory markers can increase neuronal excitability, leading to the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually 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 in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body's immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is promising due to their easy integration, high cell efficiency, and safety. In another treatment approach, enzyme replacement therapy, preclinical studies are ongoing for fucosidosis, but the blood-brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is important in fucosidosis, a rare disease, due to the delay in the diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising.
2023-02-07 | Characterization of l-fucose isomerase from Paenibacillus rhizosphaerae to produce l-fuculose from hydrolyzed fucoidan and commercial fucose.
l-Fuculose is a valuable rare sugar that is used to treat a variety of ailments, including HIV, cancer, Hepatitis B, human lysosomal disease (fucosidosis), and cardio-protective medications. The enzymatic approach for the production of l-fuculose using l-fucose as a substrate would be an advantageous method with a wide range of industrial applications. The objective of this study is the characterization of recombinant l-fucose isomerase from Paenibacillus rhizosphaerae (Pa-LFI) for the production of l-fuculose from an inexpensive and natural source (fucoidan) as well as its comparison with commercial l-fucose (Sigma-Aldrich). Fucoidan, a fucose-containing polysaccharide (FPs), was isolated from Undaria pinnatifida, subsequently hydrolyzed, and characterized before the enzymatic production of l-fuculose. The results elaborate that FPs contain 35.9% of fucose along with other kinds of monosaccharides. The purified Pa-LFI exhibited a single band at 65 kDa and showed it as a hexamer with a native molecular mass of 396 kDa. The highest activity of 104.5 U mg-1 of Pa-LFI was perceived at a temperature of 50°C and pH 6.5 in the presence of 1 mM of Mn2+. The Pa-LFI revealed a melting temperature (Tm) of 75°C and a half-life of 12.6 h at 50°C. It exhibited that Pa-LFI with aldose substrate (l-fucose), has a stronger isomerizing activity, disclosing Km,kcat, and kcat/Km 86.2 mM, 32 831 min-1, and 335 min-1 mM-1, respectively. After reaching equilibrium, Pa-LFI efficiently catalyzed the reaction to convert l-fucose into l-fuculose and the conversion ratios of l-fuculose from 100 g L-1 of FPs and commercial fucose were around 6% (5.6 g L-1) and 30% (30.2 g L-1), respectively. According to the findings of the current study, the Pa-LFI will be useful in the manufacturing of l-fuculose using an effective and easy approach that produces no by-products.
cell therapies
2022-08-25 | Fucosidosis: clinical and molecular findings of turkish patients
Fucosidosis is a rare, autosomal recessive lysosomal storage disease caused by alpha L- fucosidase enzyme deficiency in all tissues. Here, we identify a patient with a novel homozygous pathogenic variant and atypical clinical findings and summarized the clinical and molecular features of Turkish patients reported in the literature and present.The patient was born to consangineous parents at the 28th week of gestation. He had developmental delay that was attributed to prematurity. At he age of 2.5 years, brain magnetic resonans imaging revealed hyperintensities of symmetrical periventricular, subcortical, centrum semiovale and corona radiata regions on T2 and FLAIR weighted images. He developed seizures and showed developmental regression at he age of 3,5 years. Beside, coarse facial features and hepatomegaly were detected on phsyical examination. Lysosomal enzyme analysis revelaed alfa fucosidase deficiency and molecular genetic analysis identified a novel homozygous pathogenic p. Lys431 fs variant in FUCA1 gene.In Turkish patients no distinguishable clinical and radiologic finding could be established. Molecular analysis was performed in few patients. Increasing of molecular and biochemical facilities might enable to make diagnosis and increase the prevalence of the disease in countries with high rate of consanguineous marriages. Moreover, it will provide genetic counseling, and enlighten the therapeutic effects of hematopoietic stem cell transplantation.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
2021-01-06 | Fucosidosis in a Chinese boy: a case report and literature review.
Fucosidosis is a rare lysosomal storage disease, resulting from a deficiency in an alpha-l-fucosidase enzyme. There are fewer than 120 cases of this disease worldwide and very few reported in Chinese children. Here, we report a Chinese boy presenting with psychomotor regression, dermatological abnormality, dysostosis multiplex, and classic changes observed with head magnetic resonance imaging. He was diagnosed with fucosidosis, with a previously reported homozygous mutation of c.393(exon2)T > A, p.Tyr131Stop, in the FUCA1 gene. Increasing awareness of fucosidosis will help in the early diagnosis of this disease and could shed light on the therapeutic role of hematopoietic stem cell transplantation, which may be effective in early stages of the disease.
2019-05-07 | A Novel Homozygous Mutation in the FUCA1 Gene Highlighting Fucosidosis as a Cause of Dystonia: Case Report and Literature Review
Background Fucosidosis is a rare lysosomal disorder caused by mutations in the FUCA1 gene. We describe here a novel homozygous mutation in FUCA1 in an Indian fucosidosis case. Furthermore, we summarize the clinical and genetic findings in the most recently reported individuals with fucosidosis. Case The proband is an 8-year-old boy born to consanguineous parents. He had generalized dystonia and bilateral spasticity as well as coarse facies, dysostosis multiplex, recurrent infections, angiokeratoma corporis diffusum, and visceromegaly. Whole exome sequencing analysis detected a homozygous canonical splice variant in the FUCA1 gene [Chr1(GRCh37):g.24172346C > T; NM_000147.4:c.1261–1G > A], not previously reported as causative of a human phenotype. Low levels of α-fucosidase in patient leukocytes and a positive qualitative urine based thin layer chromatography test for fucosidosis confirmed the diagnosis. Our literature review identified 89 cases of fucosidosis since the last major review. We show that dystonia is a rare manifestation (12%) and that only a small minority of cases receive treatment with transplantation (3.37%). Conclusion We report a novel homozygous mutation in FUCA1 as the cause of severe neurological phenotype including generalized dystonia. Early recognition of fucosidosis may be important for consideration of promising treatment options, such as bone marrow transplantation.
2018-01-05 | Brain abnormalities in fucosidosis: transplantation or supportive therapy?
Fucosidosis is a rare lysosomal storage disease caused by α-fucosidase deficiency, which leads to progressive neurological deterioration and death. Hematopoietic stem cell transplantation is the best curative therapy if performed during the early stages of disease. We report two fucosidosis patients with brain abnormalities and the challenge faced in their management. The first patient received supportive therapy and the second one firstly underwent unrelated donor umbilical cord blood transplantation. After a period of follow-up, we found neurological symptoms were worsening day by day on patient1. By contrast, patient2 who received cord blood transplantation acquired clinical neurologic improvement in response to normalization of deficient enzymatic activity. This report indicates that hematopoietic transplant could reduce the severity and retard the progression of clinical neurological deterioration. Umbilical cord blood transplantation is a novel approach for treating fucosidosis patients who lack suitable bone morrow donors.
small molecules
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.
2022-10-11 | The long-awaited structure of human fucosidase FucA1 opens novel avenues for the treatment of fucosidosis.
In this issue of Structure, Armstrong and colleagues probe the structure of human fucosidase FucA1. Their work resolves an ongoing debate around the enzyme's catalytic mechanism and provides a valid structural template to guide the design of drugs alleviating the rare, yet severe, lysosomal storage disease fucosidosis.
2022-08-26 | Dual role of fucosidase in cancers and its clinical potential
Glycosidases and glycosyltransferases greatly impact malignant phenotype of tumors though genetics and epigenetics mechanisms.As the member of glycoside hydrolase (GH) families 29A, α-L-fucosidases (AFUs) are involved in the hydrolysis of terminal L-fucose residues linked via α-1,2, α-1,3, α-1,4 or α-1,6 to the reducing end of N-acetyl glucosamine (GlcNAc) of oligosaccharide chains.The defucosylation process mediated by AFUs contributes to the development of various diseases, such as chronic inflammatory diseases, immune disorders, and autoimmune diseases by reducing the interaction between fucosylated adhesion molecules supporting leukocyte extravasation.AFUs also impair crucial cell-extracellular matrix (ECM) interactions and presumably subsequent cell signaling pathways, which lead to changes in tumor function and behavior.There are two isoforms of AFUs in human, namely α-L-fucosidase 1 (FUCA1) and α-L-fucosidase 2 (FUCA2), respectively.FUCA1 is a p53 target gene and can hydrolyze different fucosylation sites on epidermal growth factor receptor (EGFR), thereby determining the activation of EGFR.FUCA2 mediates the adhesion between Helicobacter pylori and gastric mucosa and is upregulated in 24 tumor types.Besides, based on the participation of AFU in signaling pathways and tumor progression, we discuss the prospect of AFU as a therapeutic target.
2019-04-17 | Development of a UHPLC-MS method for inhibitor screening against α-L-1,3-fucosidase.
α-L-Fucosidase (AFU) is a promising therapeutic target for the treatment of inflammation, cancer, cystic fibrosis, and fucosidosis. Some of the existing analytical methods for the assessment of AFU activity are lacking in sensitivity and selectivity, since most of them are based on spectrofluorimetric methods. More recently, mass spectrometry (MS) has evolved as a key technology for enzyme assays and inhibitor screening as it enables accurate monitoring of the conversion of substrate to product in enzymatic reactions. In this study, UHPLC-MS has been utilized to develop a simple, sensitive, and accurate assay for enzyme kinetics and inhibition studies of AFU3, a member of the AFU family. A reported method for analyzing saccharide involving a porous graphitic carbon column, combined with reduction by NaBH4/CH3OH, was used to improve sensitivity. The conversion of saccharide into alditol could reach nearly 100% in the NaBH4 reduction reaction. In addition, the bioanalytical quantitative screening method was validated according to US-FDA guidance, including selectivity, linearity, precision, accuracy, stability, and matrix effect. The developed method displayed a good accuracy, high sensitivity (LOD = 0.05 mg L-1), and good reproducibility (RSD < 15%). The assay accurately measured an IC50 value of 0.40 μM for the known AFU inhibitor, deoxyfuconojirimycin, which was consistent with results reported in the literature. Further validation of the assay was achieved through the determination of a high Z'-factor value of 0.89. The assay was applied to screen a marine-derived chemical library against AFU3, which revealed two marine-oriented pyrimidine alkaloids as potential AFU3 inhibitors. Graphical abstract.
2018-05-01 | Harnessing pyrrolidine iminosugars into dimeric structures for the rapid discovery of divalent glycosidase inhibitors
The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one β-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (Ki = 0.15 nM) and Homo sapiens (Ki = 60 nM), and dimer 2e as the best inhibitor of β-galactosidase from bovine liver (Ki = 5.8 μM). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver β-galactosidase by dimer 2e.
gene therapies
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.
2024-12-11 | Fucosidosis: Review of a Rare Disease
Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following mutation in the FUCA1 gene, in which fucose-bound glycoconjugates accumulate in the lysosomes of different tissues of the body. Fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or an-giokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually 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 in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body's immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors is promising due to their easy inte-gration, high cell efficiency and safety. In another treatment approach, enzyme replacement ther-apy, preclinical studies are ongoing for fucosidosis, but the blood-brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is im-portant in fucosidosis, a rare disease, due to the delay in diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising.
2002-02-21 | Non-viral, integrin-mediated gene transfer into fibroblasts from patients with lysosomal storage diseases.
Non-viral vectors consisting of Lipofectin/integrin-targeting peptide/DNA (LID) complexes have great potential for gene therapy, as they are safe, simple, and able to package large DNA molecules. In this study, these vectors were evaluated in vitro for the therapy of lysosomal storage disorders. Non-viral vectors were designed to deliver therapeutic genes by integrin-mediated uptake into fibroblasts from patients with the lysosomal storage disorders fucosidosis and Fabry disease, which result from deficiencies of alpha-L-fucosidase and alpha-galactosidase A, respectively. The vectors consisted of a complex (LID) of Lipofectin and a peptide containing an integrin-targeting domain and a poly-lysine domain to which was bound plasmid DNA, containing alpha-L-fucosidase (LID-alpha-Fuc) or alpha-galactosidase A (LID-alpha-Gal). Patients' fibroblasts transfected with LID-alpha-Fuc and LID-alpha-Gal produced the corresponding enzyme at levels which were 10-40% of the total activity in cultures of normal fibroblasts. However, 95-98% of this activity was secreted. Transfection of endothelial cells, the main target cells in Fabry disease, with an LID-alpha-Gal produced a total alpha-galactosidase activity 65% higher than that in untransfected cultures after 6 days, 67% of the activity being secreted. Although transfection of fibroblasts with LID complexes also caused small changes in the distribution of endogenous lysosomal enzymes, it did not appear to affect the viability of the cells. The integrin-mediated transfer of genes encoding lysosomal enzymes into cells results in the secretion of large amounts of normal enzyme that could be taken up by other cells. This could be a useful strategy for enzyme-replacement therapy.
1997-07-01 | Canine fucosidosis: a model for retroviral gene transfer into haematopoietic stem cells
Severe progressive fatal neurological degeneration occurs in fucosidosis, a storage disease. Bone marrow transplantation into affected dogs has shown that haematopoietic stem cells can provide enzyme producing daughter cells to the central nervous system, altering disease course. This makes canine fucosidosis an ideal large animal model for gene therapy. Fucosidosis affected allogeneic or autologous canine marrow was transduced ex vivo by cocultivation, then transplanted into fucosidosis affected dogs conditioned with total lymphoid irradiation. The vectors were Moloney murine leukaemia virus based. Transduction efficiency was increased with multiple cytokines in short term marrow culture. Despite high levels of transduction, proviral sequence was detected 2 months post transplant in only one dog. Early or total graft failure occurred in all transplants. We believe lack of engraftment could be caused by differentiation or change of repopulating ability of marrow cells occurring with multiple cytokine mixes in culture media.
1992-10-20 | Correction of alpha-L-fucosidase deficiency in fucosidosis fibroblasts by retroviral vector-mediated gene transfer.
A full-length cDNA clone encoding the lysosomal hydrolase alpha-L-fucosidase was cloned into two retroviral vectors, one using the human cytomegalovirus immediate-early promoter for expression, and the other, the retroviral long terminal repeat (LTR). High-titer amphotropic virus was produced for both constructs by infection of PA317 cells, and used to efficiently transduce the alpha-L-fucosidase gene into both human and canine fucosidosis fibroblasts. This resulted in correction of the alpha-L-fucosidase enzyme deficiency characteristic of these fibroblasts. The high levels of recombinant enzyme produced corrected the degradative defect normally seen in these cells, enabling them to catabolize efficiently the accumulated storage product present in lysosomes. Therefore, these retroviral constructs should allow us to start evaluating the value of gene therapy in treating the central nervous system pathology associated with fucosidosis and other lysosomal storage disorders in humans, using a canine model of fucosidosis.
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