Fucosidosis

An autosomal recessive lysosomal oligosaccharidosis (glycoproteinosis) caused by deficiency of tissue alpha-L-fucosidase (FUCA1 gene), with a continuous clinical spectrum between a severe form beginning in the first year of life, historically designated type I, and slowly progressive forms that reach adulthood, historically designated type II. The other oligosaccharidoses (alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, sialidosis, galactosialidosis, Schindler disease) and the mucolipidoses are addressed as differential diagnoses.

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

1. Introduction

1.1 Definition and scope

Fucosidosis is a lysosomal glycoprotein storage disease caused by biallelic loss of function of the FUCA1 gene, which encodes tissue alpha-L-fucosidase [1]. Fucose is a deoxy sugar, an aldohexose in which the terminal CH2OH group is replaced by a methyl group, and it occupies terminal positions in the oligosaccharide chains of glycoproteins and glycolipids, linked to galactose or to N-acetylglucosamine [4]. Lysosomal degradation of these chains is sequential; lack of fucosidase blocks the first step in removing fucosylated residues and leads to generalised accumulation of fucose-rich glycolipids, glycoproteins and oligosaccharides, with excessive urinary excretion of fucosylated oligosaccharides and glycoasparagines [4, 7]. Orphanet defines it as a rare lysosomal disease characterised by generalised tissue accumulation of fucose-rich glycolipids and oligosaccharides, with intellectual disability, psychomotor delay and regression, skeletal changes, visceromegaly, sweating abnormalities and dermatological manifestations [3].

Fucosidosis belongs to the group of oligosaccharidoses, also called glycoproteinoses, which comprises nine lysosomal diseases: alpha-mannosidosis, beta-mannosidosis, aspartylglucosaminuria, fucosidosis, galactosialidosis, mucolipidosis II, mucolipidosis III, sialidosis and Schindler disease [22, 23]. These diseases share features with the mucopolysaccharidoses (MPS), but urinary glycosaminoglycan (GAG) screening is normal or shows only non-specific changes [24]. Saudubray also classifies fucosidosis among the lysosomal disorders of protein deglycosylation, as opposed to cytoplasmic NGLY1 deficiency [25]. This article covers fucosidosis; alpha-mannosidosis, sialidosis and the other oligosaccharidoses enter the differential diagnosis.

1.2 Original description and historical overview

Durand, Borrone and Della Cella published in The Lancet in 1966 a letter entitled “A new mucopolysaccharide lipid-storage disease?”, cited as the first description of the disease [2, 26]. The Atlas of Inherited Metabolic Diseases dates to 1968 the description, by Durand and colleagues, of two Italian siblings [4]. In 1968, Van Hoof and Hers attributed the disease to absence of alpha-fucosidase, in an article entitled “Mucopolysaccharidosis by absence of alpha-fucosidase” [27]. According to OMIM, the deficiency was demonstrated in the liver of the patients with the Hurler-like picture described by Durand’s group, which had presented it in 1967 in an abstract entitled “A new glycolipid storage disease” and named it “fucosidosis” in a 1968 letter to The Lancet [6]. In 1969, Durand’s group published in the Journal of Pediatrics the article “Fucosidosis”, which demonstrated fucose accumulation in all tissues, consolidated the name and described the form later designated type 1; the original patients had decerebrate rigidity and died before the age of 5 years [5, 6, 28]. In the same year, Loeb and colleagues described, in a Belgian patient probably related to Durand’s two Italian patients, the form later designated type 2 [6]. The historical designation “mucopolysaccharidosis type F” reflects the initial resemblance to Hurler syndrome [2].

Heterogeneity was recognised early: the fatal infantile form was joined by descriptions of indolent phenotypes with survival into adulthood, and the disease came to be divided into type I (infantile) and type II, with mention of a type III in some classifications [4]. In 1971, Schafer and colleagues found alpha-L-fucosidase deficiency in a 9-year-old child with an unusual spondylometaepiphyseal dysplasia, and in 1972 Patel and colleagues described a patient without a Hurler appearance, with angiokeratomas from the age of 4 years, anhidrosis with inability to control body temperature, severe intellectual and physical impairment, normal renal function and survival to at least 20 years; urinary and leucocyte alpha-L-fucosidase activity was 10% of normal, and obligate heterozygotes had intermediate values [6]. The division into two types was systematised by Kousseff and colleagues in 1976, and Schoonderwaldt and colleagues proposed in 1980 a juvenile type 3, with slower deterioration than in types 1 and 2, survival into the third decade in some cases and angiokeratomas in all; the two Dutch siblings they described had the type 3 course, but without angiokeratomas and with dry, thin skin [6]. In 1984, Ikeda and colleagues described three sisters with the adult form, with marked psychomotor impairment, gargoyle-like facies and angiokeratomas, and changes in macrophages, endothelial cells, fibroblasts and Schwann cells on rectal biopsy [6]. In 1972 John O’Brien’s group demonstrated alpha-L-fucosidase deficiency in cultured fibroblasts and proposed diagnosis by the serum assay [29, 30]. In 1991, Patrick Willems and colleagues reviewed 77 patients, 19 of them previously unpublished, and found no support for two distinct clinical types, concluding that the disease is a continuous spectrum [5]. There were four arguments: both types occur in the same family; the clinical data show not a separation but a continuum; there is no biochemical heterogeneity, with very low or absent residual activity in both types; and the same variant in the homozygous state occurs in rapidly and slowly progressive forms [5, 6]. That review remains the main source of the frequencies by manifestation used in current sources [1, 2].

1.3 Molecular discovery milestones

The gene was mapped to 1p36 in the early 1980s and the human alpha-L-fucosidase cDNA was cloned in 1985 by Fukushima, de Wet and O’Brien [4, 31]. The localisation resulted from several successive approaches: in 1977, family studies showed close linkage between the alpha-fucosidase locus and the Rh blood group, and a map of the short arm of chromosome 1 built with classical polymorphisms placed it between Rh and the phosphoglucomutase 1 (PGM1) locus; in 1982 and 1986, somatic cell hybrid studies pointed to the distal region of 1p34; and a 1990 linkage map placed FUCA1 about 8 cM distal to Rh [12]. In 1989, Occhiodoro and colleagues constructed a full-length cDNA from liver, placenta and colon libraries, and in 1992 Kretz and colleagues published the structure of the gene and pseudogene [12]. In 1988, Darby and colleagues described two restriction fragment length polymorphisms (RFLPs) in FUCA1 with no recombination with the phenotype, which placed the lesion in the structural gene; in the same year, Willems and colleagues, using Southern blotting in 23 patients, found in 5 the loss of an EcoRI site in the reading frame of the mature enzyme, absent in 80 controls and present in the homozygous state in both type 1 and type 2 patients, and detected no loss of that site, large deletions or insertions in the remaining 18 [6, 32]. The Atlas also attributes to Willems’ group, in 1988, a two-exon deletion with marked reduction of immunoreactive material [4]; the OMIM gene entry records this deletion, which removes two exons at the 3' end, as allele 612280.0002, with negligible activity and greatly reduced immunoreactive protein, but dates it to 1991 [12]. According to the same entry, loss of the EcoRI site is observed in about 20% of families with fucosidosis studied by Southern blotting [12]. In 1989, Guazzi and colleagues found three mRNA patterns in six unrelated Italian patients: absent mRNA in two, greatly reduced mRNA with loss of the EcoRI site in one and a transcript of normal size and amount in three [4, 6]. Also in 1989, Kretz and colleagues characterised the “EcoRI mutation”, a C>T transition that creates a TAA stop codon in the exon 8 reading frame, abolishes the restriction site and served as a molecular test [6, 33]. In 1992, Yang and colleagues described the stop codon E375X (historical numbering, = NM_000147.5:c.1138G>T p.(Glu380Ter)) in a patient whose mother was heterozygous [12]. The history of the pseudogene began in 1986, with Southern blot detection of a homologous site on chromosome 2 in somatic hybrids, and in 1987 it was shown to be a processed pseudogene [12]. The FUCA1P pseudogene was assigned to 2q31–q32 in 1991 by fluorescence in situ hybridisation, a localisation confirmed by linkage to COL3A1, with a maximum LOD score (logarithm of the odds) of 4.03 at 3% recombination [9, 12]. Between 1993 and 1999, the group of O’Brien and Willems sequenced the eight exons in patients of various origins and described 22 mutations, most of them private to one family [14, 34, 35]. In 2022 the cryo-electron microscopy structures of human FucA1 were published [10], and in 2025 the plasma fucosidase FUCA2 was shown not to contribute to lysosomal defucosylation [36].

1.4 Current nomenclature

The disease name remains “fucosidosis” in OMIM, Orphanet and GeneReviews; the terms “type I” and “type II” persist in current sources as descriptors of severity, within a spectrum recognised as continuous [1, 3]. Variants published before 2000 use a numbering that does not follow the HGVS (Human Genome Variation Society) recommendation and differs from the current one by five codons (section 2.5). The first GeneReviews chapter devoted to the disease was published on 2 April 2026, having been submitted on 12 November 2025 [1].

2. Molecular Genetics and Pathophysiology

2.1 The FUCA1 gene and protein

The FUCA1 gene is located at 1p36.11, has 8 exons spread over about 23 kb and lies on the minus strand of chromosome 1, between coordinates 23,845,077 and 23,868,361 of the GRCh38 assembly [2, 8]; OMIM, using NCBI coordinates, ends the gene at 23,868,290, 71 bp earlier, at the 5' boundary (the gene is on the minus strand) [12]. The region upstream of the reading frame lacks a TATA box and contains several transcription factor binding sites, and the 2.3 kb mRNA has been detected in lymphoblasts, testis and epithelial cells [12]. The MANE Select reference transcript is NM_000147.5, which encodes the protein NP_000138.2; part of the literature and HGMD (Human Gene Mutation Database) still use version NM_000147.4, with the same nucleotide numbering for the variants cited [2, 8]. The unprocessed protein has 461 amino acids, of which 22 form the signal peptide and 439 the mature protein [2]. The reference sequence NP_000138.2 has 466 amino acids, and the difference of five matches the five-codon offset between the historical numbering of variants and HGVS numbering [11, 37]. OMIM, summarising the 1989 cloning, describes a 22-amino-acid signal peptide followed by 461 residues of mature protein, a value that matches neither of the two sequences [12]. The active enzyme (EC 3.2.1.51) is a homotetramer with 50 to 60 kDa subunits, whose mass varies with N-glycosylation and proteolytic processing [2]. In fibroblasts, the precursor is 53 kDa and the mature form 50 kDa [4].

The cryo-electron microscopy structures of human FucA1, determined at 2.49 Å resolution without ligand and in complex with the inhibitor deoxyfuconojirimycin, revealed the homotetrameric architecture, the catalytic centre and the position of population and pathogenic variants, and identified aspartate 276 as the catalytic acid/base residue, instead of the canonical glutamate previously proposed [10]. In fucosidosis in Tunisian patients, glycine 332 in historical numbering, altered by the p.(Gly332Glu) variant, lies close to the catalytic nucleophile residue, according to homology modelling [38].

There is an intronless pseudogene, FUCA1P, at 2q31–q32, with 80% identity to FUCA1 and no open reading frame [2, 9, 12]. Plasma fucosidase is encoded by FUCA2 (6q24.2; OMIM 136820), and both human fucosidases are polymorphic [12]. FUCA2 determines plasma fucosidase activity, equivalent to 10–20% of total cellular activity, but not leucocyte activity, and does not cause fucosidosis [2]. In 2025, Bäumges and colleagues showed that FUCA2 is a true lysosomal protein, targeted by the mannose-6-phosphate pathway, but without fucosidase activity against the usual pseudosubstrates, even when purified; FUCA1, and not FUCA2, is solely responsible for lysosomal defucosylation of glycoconjugates [36].

2.2 Molecular and biochemical mechanism

Lysosomal alpha-L-fucosidase hydrolyses fucose in alpha-1,6 linkage to the N-acetylglucosamine at the reducing end of the glycan chains of glycoproteins, and also removes terminal fucoses from glycolipids [1, 7]. Biallelic loss of function causes lysosomal accumulation of fucosylated glycoproteins, glycolipids and oligosaccharides in various tissues, and urinary excretion of these compounds [7]. The urinary glycopeptides contain N-acetylglucosamine linked to asparagine, frequently with fucose in alpha-1,6 linkage, and the disaccharide fucosyl-N-acetylglucosamine is excreted [4]. In the Fuca1-/- mouse model, the compound accumulated in the greatest amount is the glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn, partly excreted in urine [39]. The H and Lewis blood group antigens, which contain terminal fucose, are degraded with difficulty and are found at high concentrations, and the H-antigen glycolipid Fuc-Gal-GlcNAc-Gal-ceramide accumulates [4]. In two siblings of Italian descent, Kousseff and colleagues found markedly raised Lewis A and B antigens on erythrocytes and in saliva, without an increase in H specificity; as the fucose of the Lewis antigens is in alpha-1,4 linkage to N-acetylglucosamine and that of the H antigen in alpha-1,2 linkage to galactose, they postulated a selective loss of substrate specificity, a hypothesis that predates the demonstration that all variants studied abolish activity almost completely [6, 14].

All pathogenic variants studied lead to almost undetectable activity and to cross-reacting immunological material (CRIM) below 6% of the normal mean, indicating that the mutant proteins are unstable and rapidly degraded [2, 14]. In 11 patients with very deficient activity, 8 had no enzyme protein in fibroblasts, 2 had normal amounts of the 53 kDa precursor without the 50 kDa mature form and 1 had a small amount of CRIM (Johnson and Dawson, 1985); in the 1988 study, all patients investigated had fucosidase protein below 6% of normal and negligible activity in fibroblasts and lymphoblastoid lines, despite the heterogeneity observed at DNA level [4, 6]. Complementation studies between patients with different phenotypes did not restore activity, which is consistent with a single locus [2, 4]. The disease mechanism is loss of function [1].

2.3 Tissue and physiological mechanisms

GeneReviews describes the mechanisms linking fucosyl-oligosaccharide accumulation to disease as incompletely understood: lysosomal accumulation causes cellular dysfunction mainly in the central nervous system (CNS), which explains the prominence of neurocognitive and neurological manifestations, and accumulation elsewhere explains the somatic facial and musculoskeletal manifestations [1]. Saudubray stresses that, in the oligosaccharidoses, it is not clear how the metabolic defect produces the neurological manifestations and that the phenotype depends in part on the type and amount of stored material [24]. A 2025 review proposed as mechanisms of neurodegeneration the primary accumulation of fucose-rich substrates, secondary storage defects, microglial activation and neuroinflammation, presenting the inflammatory component as a hypothesis [40].

The Fuca1-/- mouse model reproduces the milder human form: complete absence of activity, storage in liver, kidney, spleen, bladder and CNS, neuroinflammation, progressive loss of Purkinje cells with astrogliosis and psychomotor and memory deficits [39]. In the early phase, the mice show reduced exploration, sensorimotor disintegration and deficits in spatial learning and fear memory, with lysosomal (Lamp1) and inflammatory markers more prominent in the cerebrum than in the cerebellum [41]. The English Springer spaniel dog with naturally occurring fucosidosis is the large-animal model used in studies of transplantation, gene transfer and intrathecal enzyme [42–44]. The canine variant is a deletion of the last 14 bp of exon 1, which shifts the reading frame and introduces a premature stop codon at amino acid 152; its detection by PCR on genomic DNA made it possible to identify carriers and homozygotes in the colony [6].

Histology documents a multisystem disease: vacuolated lymphocytes in peripheral blood, hepatocytes with foamy cytoplasm and vacuoles, some lamellar, foam cells in the bone marrow, vacuoles in sweat glands and conjunctival cells, changes in fibroblasts and Schwann cells on rectal biopsy and storage vacuoles in the brain, which at autopsy is bulky, with atrophic adrenal glands [4]. The endothelium of conjunctival vessels contains two types of vacuoles, clear and reticular, as in the MPS, and dark inclusions of dense granular material [1]. The angiokeratomas correspond to proliferative ectatic vessels in the papillary dermis, with flattened endothelium [1]. Sweat electrolytes are raised in some patients, an observation that historically led to comparison with cystic fibrosis and to the hypothesis of a local defect of mucociliary clearance contributing to respiratory infections [2, 4].

2.4 Inheritance, penetrance and expressivity

Inheritance is autosomal recessive, with frequent consanguinity in the families described [1, 4]. Heterozygotes are asymptomatic [1]. Expressivity is highly variable, even within the same family: in two families with five patients, type I and type II phenotypes coexisted, and the 1991 review observed different phenotypes in homozygotes for the same stop variant, which led the authors to propose environmental factors or modifier genes [5, 45]. In one of these families, whose four parents descended from common ancestors, a patient with angiokeratomas lived almost to the age of 20 years and two cousins died before the age of 5 years; in the other, one patient was alive at about 25 years and a sibling died at 4 years, both with angiokeratomas [6, 45]. A Tunisian series of 10 patients from 6 families showed no intrafamilial variability [46], and in the two British siblings of Puente-Ruiz the severity of cutaneous, neurological and psychiatric manifestations differed [47]. GeneReviews identifies no clinically useful genotype–phenotype correlations [1].

The validity of the FUCA1–fucosidosis association was classified as “Definitive” by ClinGen on 2 August 2022 [13]. No other phenotypes associated with germline FUCA1 variants are known, that is, no allelic disorders have been described [1]. A homozygous 64.5 kb deletion in Turkish patients encompassed exons 1–6 of HMGCL, the whole of FUCA1 and exon 2 of CNR2, constituting the first contiguous gene deletion syndrome with fucosidosis and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency [48].

2.5 Variant spectrum and nomenclature

By 1999, 22 mutations had been described (4 missense, 7 stop codons, 6 small deletions, 2 large deletions, 1 duplication, 1 small insertion and 1 splicing), all with almost absent activity and greatly reduced immunoreactive material [14]. OMIM summarises the same set as 4 missense, 17 “nonsense” (a designation that there groups the stop codons, deletions, duplication and insertion) and 1 splicing [6]. In 2020, HGMD listed 36 pathogenic variants: 6 missense, 11 nonsense, 8 small deletions, 5 large deletions, 3 splicing, 1 stop-loss and others [2]. In October 2026, ClinVar contained 104 pathogenic or likely pathogenic records in FUCA1 [37]. Most variants are private, found in a single family [2, 4]. The OMIM FUCA1 gene entry selects 12 alleles (612280.0001 to .0012): 11 associated with fucosidosis, all described between 1989 and 1998, and the Fu1/Fu2 polymorphism; the designations follow the numbering of the original articles, and correspondence with HGVS is made via the rs identifier and ClinVar [12, 37].

Articles from the 1980s and 1990s numbered codons such that, for variants registered in ClinVar, the historical numbering corresponds to the current HGVS numbering minus five codons. This correspondence was taken from the ClinVar “legacy” designations and VariantValidator conversions, not calculated by hand [8, 37]. The table brings together the historical variants and the most cited recent variants.

Two variants require caution in interpretation. c.998G>A p.(Gly333Asp), described as causal in the Puente-Ruiz siblings in compound heterozygosity with the exon 4 deletion, is classified in ClinVar as of uncertain significance, with a single submitter; the enzyme deficiency confirmed in both siblings supports the diagnosis, but the variant should not be reclassified as pathogenic without a new submission [37, 47]. The designation “W423X” attributed by the Atlas to Gautschi and colleagues, with the notation “c.1295G>A”, is internally inconsistent, because NM_000147.5:c.1295G>A encodes p.(Trp432Ter) in VariantValidator; the c.1295G>A variant is in ClinVar as of uncertain significance, because it affects the last 35 amino acids without triggering nonsense-mediated mRNA decay [4, 8, 37].

2.6 Genotype–phenotype correlations and modifiers

The 1999 review concluded that all mutation types lead to the same virtual absence of activity and protein, and that clinical variability depends on unknown secondary factors [14]. Because most patients are homozygous for private variants, the genotype–phenotype correlation is poorly defined [2]. Stepien and colleagues acknowledge trends: large deletions and truncating variants are associated with severe phenotypes, whereas two variants affecting the splice acceptor site (the deletion including exon 3 and c.1261-1G>A) were associated with normal early development with progression from 2–3 years [2]. The contrary data are numerous: the same c.837_838del variant produced severe and mild phenotypes in an Iranian family, and homozygotes for the Q422X variant (historical numbering, = NM_000147.5:c.1279C>T p.(Gln427Ter)) had different courses [2, 4]. The missense variant L405R (historical numbering, = NM_000147.5:c.1229T>G p.(Leu410Arg)) was associated with survival to 46 years with activity below 1% [4, 51]. In 1997, of 8 patients with a clinical and enzymatic diagnosis, 6 had probably causal variants (5 novel), all with severe forms and very low residual activity and protein, and none had a deletion or gross alteration of the gene [6]. The proposed genetic or environmental modifiers have not been identified [2, 45].

3. Clinical Spectrum and Manifestations by System

3.1 Spectrum and classification

Fucosidosis is a progressive multisystem disease, predominantly neurological, which current sources continue to describe in two severity groups [1]. Type I, the more severe, begins before 1 year, progresses rapidly and typically leads to death before 10 years from respiratory infections and neurological deterioration; type II, the milder, begins in childhood or adolescence, progresses slowly, has more frequent angiokeratomas and allows survival into adulthood, typically into the third decade [1]. The review of 77 patients by Willems and colleagues, which combined published cases and an international survey, found no separate clinical groups, nor differences in residual activity or immunoreactive protein between forms, and described a continuous spectrum [5]. The coexistence of severe and mild forms within the same sibship reinforces this interpretation [4, 45]. The Atlas also mentions cases that do not fit the categories, such as a patient with mild onset and rapidly fatal progression, and a spondyloepiphyseometaphyseal dysplasia with very short stature and normal mental development associated with alpha-fucosidase deficiency, published in 1971 [4]. OrphanAnesthesia, which follows the two-type classification, places the onset of type I between 3 and 18 months and describes the appearance of angiokeratomas at around 10 years as the feature that most distinguishes type II [62].

3.2 Frequency of manifestations

The frequencies derive mainly from the 1991 review (n=77, literature and survey up to 1990) and were taken up by the 2020 Stepien review and the 2026 GeneReviews, which add data from later series [1, 2, 5]. They represent clinically diagnosed patients, with a bias towards more severe forms and published cases, and not treated patients.

Key: +++ frequent; ++ moderately frequent; + less frequent; − not described [1].

Visceromegaly frequencies differ between sources: the summary of the 1991 review gives 44% for visceromegaly, the GeneReviews text gives hepatomegaly in 21 of 53 patients (40%) and splenomegaly in 25%, and the summary table of the same GeneReviews gives 30% for hepatomegaly or splenomegaly [1, 5]. The Orphanet phenotype annotations, based on the HPO (Human Phenotype Ontology), classify as very frequent (80–99%) several manifestations that GeneReviews does not quantify or describes as rare, such as hearing loss, hypothyroidism, hyperhidrosis and “mucopolysacchariduria”, and as frequent (30–79%) hypotonia, spasticity, gallbladder abnormality and corneal opacity; the quantitative frequencies used in this article are those of the 1991 review and GeneReviews [1, 3]. In the Tunisian series, only 3 of 10 patients had visceromegaly [46], and two Turkish families and one US patient published in 2025–2026 had no hepatosplenomegaly [48, 59].

3.3 Natural history by age

Most children are born without signs and have normal early development [1, 4]. In 60 patients with information, the mean age at first symptom was 1.2 ± 0.8 years, ranging from 0 to 5.5 years [2]. Psychomotor, motor, language and cognitive decline began in 60% of patients in one series at a median age of 18 ± 4.5 months [1, 2]. Up to 95% of patients have progressive neurocognitive deterioration and up to 87% motor deterioration [1, 5]. The ability to sit was lost by 41%, to stand by 38%, to walk unaided by 50% and to speak by 67%; 28% had rapid deterioration, with complete loss of walking, standing, sitting or speech before 5 years, 53% slow deterioration, retaining these abilities after 10 years, and 19% an intermediate course [1, 2]. Secondary sources attribute these percentages to the 1991 review, without GeneReviews explicitly identifying the cohort for each value [1, 2].

In the classic infantile Hurler-like form, the child is normal at birth and, by the end of the first year, there is progressive facial coarsening, delayed linear growth and cognitive development, with cerebral degeneration leading to dementia and spasticity, gradual loss of strength, tremor, a protuberant abdomen due to hepatosplenomegaly, sometimes cloudy cornea, dysostosis multiplex, raised sweat chloride and respiratory infections; the terminal phase is one of decerebrate rigidity and death usually occurs in the first decade [4]. In the slowly progressive forms, the first sign may be angiokeratoma, present between 6 months and 4 years, with slower mental deterioration, a stiff broad-based gait, spasticity, hyperreflexia and Babinski sign, and survival into adulthood [4].

In the Tunisian series of 1987–2007 (10 patients from 6 families, diagnosis at 29 ± 10.3 months), 6 patients had a severe phenotype and 4 a slowly progressive one; all had intellectual disability, dysostosis multiplex and recurrent bronchopneumonia, 9 coarse facies, 6 progressive spastic tetraplegia, 4 convulsions, 4 angiokeratoma and 3 visceromegaly; 6 died before 10 years from pulmonary infections and deterioration, which the authors related to restricted access to health care [46]. In the 1991 review, 7 patients (9%) died before 5 years and 36 (64% of those with information) reached the second decade [5].

Adults with attenuated forms accumulate learning difficulties, ataxia, dysostosis multiplex with low back pain, extensive angiokeratomas, retinal vascular changes, valvular disease and, in isolated cases, psychotic episodes and gastrointestinal symptoms [47]. A patient homozygous for the missense variant L405R (historical numbering, = NM_000147.5:c.1229T>G p.(Leu410Arg)), daughter of consanguineous parents, described at 20 years with progressive physical and intellectual impairment, short stature, angiokeratoma corporis diffusum, dysostosis multiplex and generalised muscle atrophy, was alive at 46 years, then presented as the first case to reach the fifth decade: she had lost all verbal and almost all non-verbal communication, could not walk or sit without support, measured 113 cm, had sustained several minor long-bone fractures and one respiratory infection, was rarely seen to sweat and showed discomfort in the heat; the angiokeratomas had progressed little between 20 and 46 years [6, 51]. In survivors beyond 30 years, computed tomography (CT) shows infratentorial and supratentorial volume loss, mainly frontal [1].

3.4 Manifestations by system

3.4.1 Nervous system

Intellectual disability is more severe in type I [1]. With progression, spastic tetraparesis with hyperreflexia, estimated in up to 40% of patients, appears, together with progressive spasticity with unsustained ankle clonus, unsteady gait, femoral anteversion, tibial torsion and in-toeing gait [1, 2]. In type II, spasticity is mild to moderate and some patients remain ambulant [1]. Epileptic seizures affect up to 38% of patients, with variable types, including generalised epilepsy, and are less frequent and milder in type II [1]. Dystonia occurs in about 12% and may be the dominant manifestation: an 8-year-old Indian boy had generalised dystonia with spasticity [57], and a 14-year-old Swiss girl had fixed progressive dystonia with pallidal lesions similar to those of neurodegeneration with brain iron accumulation [61]. In 1995, lower-limb dystonia was described in a 7-year-old boy homozygous for the Q422X variant (historical numbering, = NM_000147.5:c.1279C>T p.(Gln427Ter)), with no alpha-L-fucosidase activity in lymphoblasts; the authors noted that previous families with the same variant in the homozygous state had no dystonia [6]. An Indian series of 22 individuals from 19 families with childhood-onset dystonia included fucosidosis among the genetic causes [63].

Behavioural changes, such as aggressiveness and frustration, accompany psychosocial decline [1]. In a patient with an attenuated form, three psychotic episodes with hallucinations and agitation, at 14, 16 and 21 years, were interpreted as a sign of progression and responded to antipsychotics [47]. Oromotor dysfunction results in hypersalivation and feeding difficulties, with the need for tube feeding in advanced stages; flexion contractures of the limbs cause pain [1].

3.4.2 Neuroimaging

MRI shows hypomyelination, with extensive, confluent, progressive and symmetrical signal change in the periventricular and subcortical white matter [1, 2]. Marked bilateral T2 and FLAIR (fluid-attenuated inversion recovery) hypointensity and T1 hyperintensity of the globi pallidi is described as a feature specific to fucosidosis [1, 2]. The pallidal T2 hypointensity may correspond to raised iron on gradient-echo sequences, and the association with hyperintense curvilinear streaks in the lentiform nuclei produces the “eye-of-the-tiger” sign [1, 64]. Cerebellar volume is increased in early stages, and generalised cerebral and cerebellar atrophy appears with progression, better documented in type II [1, 2]. The thalamus, globus pallidus and internal capsule are involved [4].

Studies from 2025 and 2026 have broadened this picture. In a 4-year-old Spanish boy there was hypoplasia of the corpus callosum, hypomyelination, pallidal change and marked reduction of cortical thickness, showing that cortical atrophy can be early [58]. In a US girl followed with MRI for 15 years, MRI at 23 months showed confluent symmetrical T2 hyperintensity of the supratentorial white matter and subtle hyperintensity of the medial medullary lamina of the globi pallidi; subsequent MRIs showed progressive involvement of the basal ganglia with T1 and T2 shortening and susceptibility changes consistent with mineralisation, extending to the substantia nigra and red nuclei [65]. In a Turkish infant, MRI and spectroscopy showed involvement of the central tegmental tract [66]. MR spectroscopy is described in 5.4.

3.4.3 Skin and mucous membranes

Skin changes are present in 60% of patients; angiokeratoma corporis diffusum appears in about half, mainly in those who live at least 10 years, and the number of lesions increases with age [1, 2]. By 20 years, 85% of patients have angiokeratomas, according to the Atlas, based on the 1991 review [4]. The lesions are pinhead-sized red-purple papules, predominate on the lower abdomen, buttocks and genitalia, and are clinically indistinguishable from those of Fabry disease [1, 4]. Some patients have only telangiectasias [1]. Red gingival streaks, perpendicular to the tooth roots, may precede the angiokeratomas [4]. The skin may be thickened or dry and thin, and acrocyanosis and distal transverse nail bands have been described [2, 4]. One patient had blue-brown patches on the tongue and sclerae, with macroglossia [4].

Sweating is described inconsistently: the Atlas describes hypohidrosis and markedly raised sweat chloride in the infantile form, with sometimes normal chloride and difficulty with thermoregulation in the attenuated forms; Orphanet annotates hyperhidrosis as very frequent; the 2020 review mentions both hyperhidrosis and hypohidrosis; OrphanAnesthesia describes sweat with raised sodium chloride in type I and normal salinity in type II; and OMIM, which follows the Kousseff classification (1976), likewise associates raised sodium chloride with type 1 and normal salinity with type 2, and records anhidrosis with inability to control temperature in Patel’s patient (1972) and hypohidrosis with heat intolerance in Fleming’s 46-year-old patient (1998) [2–4, 6, 62]. Sweat gland dysfunction, documented by vacuoles on skin biopsy, is the common explanation for both changes [4].

3.4.4 Face and growth

Coarse facies, present in 79%, includes prominent supraorbital ridges, full eyelids with ptosis, a broad nose with a flat bridge, long philtrum, thick lips, macroglossia, gingival hypertrophy and prognathism [1]. Saudubray states that patients do not have the facial dysmorphism typical of the other oligosaccharidoses; GeneReviews records that some patients do not develop coarse facies [1, 24]. Short stature is postnatal; adults with the attenuated form remain close to the 5th–6th centile [1]. Head circumference is normal in 79%, with microcephaly in 15% and macrocephaly in 4% [2].

3.4.5 Respiratory system and infections

Recurrent respiratory infections affect up to 78% of patients: otitis media, upper respiratory tract infections and partial upper airway obstruction during sleep [1]. A Chinese patient had an infection every 1–2 months with a normal immunological work-up [1, 54]. Durand’s 1969 article described diffuse emphysema with small atelectases [1, 28]. Infections are less frequent in type II in the second and third decades [1]. A 14-year-old adolescent with type I had a frontal brain abscess due to Streptococcus intermedius, with normal neutrophil oxidative function and normal humoral and innate immunity, according to unpublished data from the GeneReviews authors [1].

3.4.6 Skeleton

Dysostosis multiplex is present in up to 58% of patients and is less severe than in the MPS, closer to that observed in alpha-mannosidosis [1]. It includes small thoracolumbar vertebrae with anterior beaking, a short odontoid (with possible hypoplasia), cervical platyspondyly, broad ribs, scoliosis with partial fusion of lower thoracic vertebrae, lumbar gibbus and absence of the scaphoid, trapezium and trapezoid [1, 2, 4]. The spine, pelvis and hips are the most affected regions: coxa valga, flattening of the femoral heads and widened, scalloped and sclerotic acetabula [4]. The atlas of skeletal dysplasias places fucosidosis in the milder dysostosis group, with intellectual disability, neurological degeneration, mild somatic manifestations and angiokeratoma corporis diffusum [67]. Joint contractures are frequent [1]. Inflammatory joint features, with swelling, synovitis and positive antinuclear antibodies, have been described in a child initially treated as having juvenile idiopathic arthritis [1, 68].

3.4.7 Eye

Blepharospasm is frequent [1]. The 1991 review found dilated and tortuous retinal veins in 54%, dilated and tortuous conjunctival vessels in 53%, conjunctival microaneurysms in 41%, corneal opacities in 11%, pigmentary retinopathy in 7% and visual loss in 6%; severe visual impairment is uncommon [1, 2]. Tortuosity affects the bulbar more than the palpebral conjunctiva and shows saccular dilatations [1]. “Bull’s eye” macular changes have been described, with brown foveal pigmentation surrounded by a hypopigmented zone [1].

3.4.8 Heart and endocrine system

Mild mitral regurgitation was found in 50% of the patients studied in the Tunisian series, and cardiomyopathy is uncommon [1, 2]. Cardiac enlargement with left ventricular hypertrophy, dilatation of the right chambers and incomplete right bundle branch block have been described [1]. In type II, heart disease is milder or absent; in a British adult there was mixed aortic valve disease, with mild stenosis (peak velocity 2.6 m/s, mean gradient 14 mmHg) and mild regurgitation, without progression [1, 47].

GeneReviews describes hypergonadotrophic hypogonadism in the third decade in type II, based on a 2025 conference abstract, but the surveillance and treatment sections of the same chapter mention hypogonadotrophic hypogonadism [1]. In the two adult Puente-Ruiz siblings, gonadotrophins and thyroid function were normal; the sister’s secondary amenorrhoea during the weight loss of the first psychotic episode reversed with weight recovery [47]. Orphanet annotates hypothyroidism as very frequent and OrphanAnesthesia recommends endocrine assessment for that reason, but GeneReviews does not include it among the manifestations [1, 3, 62].

3.4.9 Liver, spleen, hearing and others

Hepatomegaly is generally mild and non-progressive (liver 3–5 cm below the costal margin), transaminases are mildly raised in 25%, regardless of hepatomegaly, and splenomegaly (spleen 1–3 cm below the costal margin) is present in about 25% [1, 2]. Massive splenomegaly is rare and has been associated with portal cavernoma [2, 46]. Hearing is generally preserved, but mild to moderate asymmetrical sensorineural hearing loss, Eustachian tube dysfunction and mild sensorineural hearing loss in adults have been described [1]. Umbilical hernia occurs in 9% [1]. In a British adult there were gastrointestinal symptoms not previously described [47]. OrphanAnesthesia mentions gallbladder and salivary gland dysfunction, with hyper- or hyposalivation [62].

3.5 Treated disease

There is no authorised disease-modifying therapy; data on treated disease are limited to fewer than 10 patients who underwent HSCT, described in section 7.4 [1, 24]. In these cases, transplantation performed before or at the onset of symptoms was associated with donor enzyme activity, reduced urinary oligosaccharides, improved myelination on MRI and better development than that of untreated siblings, with persistence of dysostosis multiplex and coordination delays [22, 69–71]. The frequencies and mortality described above refer to patients without disease-modifying treatment.

4. Clinical Recognition and Warning Signs

4.1 Diagnostic delay

Diagnosis is often late. In the Tunisian series, the mean age at diagnosis was 29 ± 10.3 months, more than one year after the onset of psychomotor decline [46]. In a Turkish boy born at 28 weeks the delay was attributed to prematurity until regression at 3.5 years [60]. A Swiss girl with progressive dystonia from early childhood was only diagnosed at 14 years, when progressive angiokeratoma corporis diffusum raised the hypothesis [61]. In the two British siblings, the elder was referred to genetics at 12 years for learning difficulties and a red retroauricular patch, and the sister was diagnosed at 6 years, after her brother [47]. The absence of organomegaly and angiokeratoma does not exclude the disease: three Turkish patients with severe delay, deafness and coarse facies had none of these signs [48].

4.2 When to suspect, by age and setting

4.3 Warning signs and urgent situations

The clinical warning signs are loss of motor or language milestones after normal early development, the association of progressive neurological disease with angiokeratomas and pallidal hypointensity on MRI [1]. Respiratory distress due to infection or upper airway obstruction, new or prolonged epileptic seizures, dysphagia with aspiration and severe infections, including the brain abscess described in an adolescent, require urgent assessment [1]. Acute psychotic episodes in an adolescent or adult with an attenuated form are a sign of progression and require psychiatric assessment [1, 47]. Poorly localised pain in a person with impaired communication may correspond to contractures, scoliosis or fractures, and pain assessment is part of six-monthly to annual surveillance [1]. Before any anaesthesia, a difficult airway and unstable thermoregulation should be anticipated (section 7.8) [62].

4.4 Newborn screening

There is no newborn screening programme for fucosidosis in the sources consulted [1, 19]. In 2019, Kumar and colleagues developed multiplex tandem mass spectrometry (MS/MS) enzyme assays on dried blood spots, compatible with newborn screening cards, which distinguished untreated patients from random newborns, carriers and a transplanted patient, and which can be combined with a panel of five MPS (II, IIIB, IVA, VI and VII); this is analytical development, without a population study [19]. GeneReviews recommends early testing of the siblings of a patient, which functions as targeted screening in a known family [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no consensus-published clinical diagnostic criteria [1]. GeneReviews defines the diagnosis in two ways: biochemical, by the combination of suggestive clinical and radiological findings, raised urinary oligosaccharides and reduced alpha-L-fucosidase activity in leucocytes; and molecular, by identification of biallelic pathogenic or likely pathogenic variants in FUCA1 [1]. Because of the relatively high sensitivity of molecular testing, it can make the enzyme assay unnecessary and is increasingly the preferred confirmatory test; reduced activity in leucocytes confirms that the variants found are causal and helps to clarify variants of uncertain significance (VUS) [1]. Two VUS, or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis, according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [1].

The suggestive findings listed by GeneReviews are clinical (developmental delay or intellectual disability with regression, postnatal short stature, coarse facies, recurrent respiratory infections, kyphosis, scoliosis or gibbus, telangiectasias and angiokeratoma, dilated and tortuous retinal and conjunctival vessels, conjunctival microaneurysms, corneal opacities, seizures, feeding and swallowing difficulties, flexion contractures, spasticity, loss of walking, mitral regurgitation or cardiomyopathy, hypogonadism and hepatosplenomegaly), laboratory (increased urinary oligosaccharides), radiological (dysostosis multiplex with short odontoid, cervical platyspondyly, thoracolumbar vertebrae with anterior tongue, wedge-shaped lumbar vertebrae, broad ribs, flared iliac wings, bullet-shaped bones of the hands and feet, delayed skeletal maturation and deformed or absent carpal bones), imaging (white matter and globus pallidus changes) and family-related (affected siblings or consanguinity, whose absence does not exclude the diagnosis) [1].

5.2 Testing algorithm

5.3 Enzyme activity

Deficient activity is demonstrated in leucocytes and cultured fibroblasts with artificial substrates and fluorimetric or colorimetric detection; activity is essentially absent in all phenotypes, so the assay does not distinguish the clinical forms [4]. In a 5-year-old Saudi girl, fibroblast activity was 0.05% of control [4]; in a British adult with an attenuated form, activity was 0.22 nmol/mg/h in leucocytes (reference 50–250) and 2.2 nmol/mg/h in fibroblasts (controls 17 and 54 nmol/mg/h) [47]. Reference values depend on the laboratory and substrate; the sources consulted do not provide universal reference intervals.

Activity in serum or plasma is not a reliable diagnostic method. In a series of 422 healthy people, 26 had very low serum activity, inherited as a recessive trait, with a thermolabile enzyme and normal leucocyte activity; this is a common polymorphism that produces false positives [4, 7, 75]. Plasma activity depends mainly on FUCA2, which explains the dissociation between plasma and leucocytes [2, 36]. The attribution of the Wood polymorphism to FUCA1 or FUCA2 is not established in the sources read; the known electrophoretic polymorphism of FUCA1 is c.857A>G p.(Gln286Arg), benign and with preserved activity [37, 75]. In dried blood spots, activity remains linear over 20 hours of incubation, and the optimum pH in serum and plasma is 5.0 [2].

5.4 Oligosaccharides, imaging and other biomarkers

Thin-layer chromatography (TLC) of urinary oligosaccharides stained with orcinol gives diagnostic patterns in fucosidosis, alpha-mannosidosis, sialidosis and aspartylglucosaminuria; stained with ninhydrin and heated to 120 °C, it gives a blue spot in fucosidosis and aspartylglucosaminuria [4]. TLC has limited analytical sensitivity and specificity, does not quantify, is not always available and may miss cases [24, 74]. Mass spectrometry methods have reduced these limitations. At the Greenwood Genetic Center (USA), ultra-performance liquid chromatography with MS/MS (UPLC-MS/MS) of free urinary oligosaccharides, with urine equivalent to 30 µg of creatinine and a 7-minute run, identified 8 lysosomal diseases, including fucosidosis, in 37 patients and more than 100 controls, and showed a reduced response in transplanted patients [74]. At Bambino Gesù (Rome), an underivatised UHPLC-MS/MS method, in urine and dried urine spots, confirmed specific profiles for fucosidosis and six other diseases, with a non-specific profile in mucolipidoses II/III and MPS IVB [76]. At Erasmus MC (Rotterdam), a UHPLC method with high-resolution mass spectrometry and an open algorithm identified fucosidosis and ten other diseases, with occasional “neonatal” profiles in infants, probably of dietary origin, as an interpretation pitfall [77]. Negative urinary oligosaccharides in attenuated phenotypes do not exclude lysosomal disease [2]. In the USA, Mayo Clinic Laboratories offers a urinary oligosaccharide panel by mass spectrometry (OLIGU, code 4889) that detects and relatively quantifies the substrates of several glycoproteinoses in the same assay; Casazza and colleagues note that these urinary assays serve biochemical confirmation, but do not yet have the analytical and longitudinal validation required for trial endpoints [23].

MR spectroscopy shows a reduced N-acetylaspartate/choline ratio, a characteristic abnormal peak at 3.8 ppm and a double peak at 1.2 ppm, and, in the basal ganglia and posterior limb of the internal capsule, a reduced N-acetylaspartate/creatine ratio with a lactate peak at 1.33 ppm [1, 2]. In the 4-year-old Spanish boy, short echo time spectroscopy showed tall, broad double peaks at 3.9 and 1.2 ppm, and long echo time spectroscopy showed bilateral inversion of the 1.2 ppm peak, attributed to fucose [58]. The peripheral blood smear shows vacuolated lymphocytes, weakly positive on periodic acid–Schiff (PAS) staining [2, 4, 72]. Urinary GAG screening does not detect fucosidosis [2].

5.5 Molecular testing and its limitations

According to HGMD, FUCA1 sequencing detects 96% of known pathogenic variants and targeted deletion/duplication analysis detects 4% [1]. These values are proportions of variant type among those published, not the clinical sensitivity of the test in a patient. Sequencing detects missense, nonsense, canonical splice site variants and small insertions and deletions; exon and whole-gene deletions require MLPA, CMA or copy number analysis of exome or genome data [2]. Deep intronic variants and balanced structural rearrangements are beyond the reach of exon sequencing. Apparent homozygosity may correspond to a deletion on the other allele (false homozygosity) or to uniparental isodisomy, and should be clarified by parental testing [1]. The FUCA1P pseudogene, with 80% identity and no introns, may interfere with poorly designed amplification methods [2]. A large deletion including FUCA1 should prompt analysis of the neighbouring genes, particularly HMGCL, because of the possibility of concomitant 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, with a risk of hypoketotic hypoglycaemia [48]. A negative result does not exclude the disease when leucocyte enzyme deficiency has been demonstrated.

The report should state the gene, the transcript with version (NM_000147.5), HGVS nomenclature at cDNA and protein level, zygosity, the ACMG/AMP classification of each variant, the method and its limitations, and the recommendation for parental testing [1, 8]. Variants published in the historical numbering should be converted using the ClinVar designations or tools such as VariantValidator before being compared with the result (section 2.5) [8, 37]. When the laboratory returns a VUS, leucocyte alpha-L-fucosidase activity and family segregation help to interpret it [1].

5.6 Characterisation investigations after diagnosis

Characterisation includes brain and spine MRI, electroencephalogram (EEG) if seizures are suspected, skeletal radiographs, echocardiogram and electrocardiogram (ECG), abdominal ultrasound, ophthalmological and audiological assessment, polysomnography if sleep apnoea is suspected, and chest radiograph or CT as clinically indicated; urinary oligosaccharides serve as a baseline value [1]. The full list is in section 7.2.

5.7 Prenatal and preimplantation diagnosis

Prenatal diagnosis was historically performed by enzyme assay in cultured amniocytes, in families from Calabria [4]. Currently, once the two familial variants have been identified, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing for monogenic disorders (PGT-M) are performed by molecular testing; biochemical testing is not recommended for this purpose, because of the overlap between carrier and non-carrier activities [1, 2]. The options are detailed in section 8.

6. Differential Diagnosis

6.1 Principles

The differential diagnosis of fucosidosis is organised along three axes. The first is that of the other oligosaccharidoses and the mucolipidoses, which share coarse facies, mild dysostosis multiplex, vacuolated lymphocytes and neurological regression, and which are distinguished by the urinary oligosaccharide profile and the deficient enzyme [22, 24, 74]. The second is that of the diseases with angiokeratoma corporis diffusum, of which Fabry disease is the main cause and in which the lesions are clinically indistinguishable [4, 72]. The third is that of neurological diseases with hypomyelination, pallidal lesions or dystonia, in which fucosidosis may be confused with hypomyelinating leukodystrophies or with neurodegeneration with brain iron accumulation (NBIA) [61, 64, 73]. The urinary GAG assay is normal or non-specific in all oligosaccharidoses and does not distinguish between them [24].

6.2 Comparative table

6.3 Main differential diagnoses

Alpha-mannosidosis is the closest differential: it has coarse facies, intellectual disability, hearing loss, recurrent infections and dysostosis multiplex of similar severity, and the Minnesota review recalls that it was classified as an MPS (Hurler-like syndrome) before the defect was identified [1, 22]. It is distinguished by early and almost constant hearing loss, immunodeficiency, destructive arthropathy of the large joints and mannose-rich oligosaccharides; it has an authorised enzyme replacement therapy [1, 24]. Aspartylglucosaminuria shares with fucosidosis the blue spot on ninhydrin-stained TLC and angiokeratomas, but has a slower course, joint laxity and geographical concentration in Finland [4, 22, 72]. Sialidosis is distinguished by the cherry-red spot and myoclonus; galactosialidosis adds beta-galactosidase deficiency [22, 24].

Comparison with the OMIM entries for the other glycoproteinoses adds details useful for discrimination. Alpha-mannosidosis was described by Ockerman in 1967 in a boy with a Hurler-like picture whose stored material was not mucopolysaccharide, a historical course parallel to that of fucosidosis; the 2019 expert panel recommends, up to 10 years, investigation in the presence of language delay, hearing loss, developmental delay and facial dysmorphism, and, after 10 years, in the presence of hearing loss, ataxia, psychiatric disorders and skeletal changes, with enzyme assay in dried blood spots or leucocytes as the first step [78]. Beta-mannosidosis was described first in goats (1981) and only in 1986 in humans; in one of the first patients, a 44-year-old Indian man with intellectual disability without other neurological signs, there were angiokeratomas of the scrotum and penis and marked tortuosity of the conjunctival vessels, without dysmorphism, visceromegaly or radiological changes, a combination also seen in attenuated fucosidosis and distinguished by the abnormal disaccharide band on urinary oligosaccharide chromatography and by beta-mannosidase assay [79]. The phenotype is highly variable, even among patients with null MANBA variants, ranging from pictures with dysmorphism and skeletal involvement to pictures with neither; isolated progressive angiokeratoma has been described in a 22-year-old woman, and demyelinating peripheral neuropathy and a picture of motor and vocal tics consistent with Gilles de la Tourette syndrome have been described [79].

Aspartylglucosaminuria belongs to the Finnish disease heritage: the estimated frequency in Finland was 1/26,000 in 1980, and a study in school-age children in the east of the country found 1/3,643, consistent with a carrier frequency of 1/30, which made it the third genetic cause of intellectual disability there after trisomy 21 and fragile X syndrome [80]. Most patients are diagnosed after 5 years, and the abundant urinary excretion of aspartylglucosamine makes urinary chromatography sufficient for detection; outside Finland, the disease has been described in Italian, Palestinian, Puerto Rican, Japanese and North American families, several of them consanguineous, with angiokeratomas in some patients, macro-orchidism, oral mucosal hyperplasia and facial angiofibromas [80]. Follow-up of 19 young patients, 5 of whom received bone marrow transplants between 1991 and 1997, showed that the first two transplanted patients had, after 5 and 7 years, more severe intellectual disability than the non-transplanted ones, and that the transplanted patients had complications; the authors advised against transplantation outside infancy, a small observational finding that contrasts with the EBMT “Option” classification for aspartylglucosaminuria and fucosidosis and that reinforces the importance of age at transplantation [15, 80].

In sialidosis, the stored material is sialic acid bound to oligosaccharides and glycoproteins, which separates it from the sialurias and Salla disease, in which sialic acid is free and neuraminidase is normal or raised; the Lowden and O’Brien classification (1979) distinguishes normosomatic type I (cherry-red spot–myoclonus syndrome) from dysmorphic type II, with infantile and juvenile forms, also called mucolipidosis I [81]. Durand and colleagues proposed in 1977 the term “sialidosis” for two siblings with progressive visual loss, cherry-red spot and minimal neurological signs [81]. In 2014, 6 patients from 2 families were described with cortical action myoclonus beginning between 22 and 32 years, without a cherry-red spot and with little or no increase in urinary sialic acid, diagnosed by exome sequencing; isolated action myoclonus in adults justifies NEU1 testing even without the classic findings [81]. In galactosialidosis, the combined beta-galactosidase and neuraminidase deficiency results from lack of protective protein/cathepsin A, and the three subtypes differ in the amount of precursor and mature protein; in a series of 20 patients, the 12 with the early infantile form had no cathepsin A activity and the 8 with later forms had 2–5%, an assay also applicable to chorionic villi and amniocytes [82]. The angiokeratomas and conjunctival telangiectasias of galactosialidosis have been described mainly in Japanese patients with the juvenile/adult form, and galactosialidosis is a recognised cause of non-immune fetal hydrops [82].

Type I alpha-N-acetylgalactosaminidase deficiency was described in two German siblings with psychomotor regression from 9 months, without organomegaly, coarse facies or skeletal dysplasia, and with neuropathology of neuroaxonal dystrophy; one of the siblings, a blood group A secretor, excreted in urine the group A determinant trisaccharide in amounts five times above normal [84]. The relationship between genotype and phenotype is inconsistent: the same homozygous variant, E325K (= NAGA NM_000262.3:c.973G>A p.(Glu325Lys)), was found in a Moroccan boy with neuromotor delay and congenital cataracts and in a 7-year-old sibling without clinical signs, and the intermediate type III includes an asymptomatic sibling with the same genotype as the proband; it has also been suggested that the original German patients might have had a second disease, an independent neuroaxonal dystrophy [8, 84]. This dissociation, like that of fucosidosis, prevents prediction of the clinical course from the genotype [5, 84].

Fabry disease causes angiokeratomas indistinguishable from those of fucosidosis, but does not cause neurocognitive impairment or dysostosis multiplex; neuropathic pain and proteinuria are specific to Fabry disease [1, 4]. OMIM records that angiokeratomas may be absent even in patients with severe visceral involvement and that identical lesions occur in other lysosomal diseases, citing as an example the patient with alpha-L-fucosidase deficiency described in 1972; for that reason it prefers the eponym to the designation “angiokeratoma corporis diffusum” [86]. The two conditions also share reduced sweating, of autonomic origin in Fabry disease, and tortuosity of the retinal vessels, described in a young heterozygous woman with Fabry disease [1, 86]. Fabry disease is distinguished by cornea verticillata, present to a similar extent in men and women, X-linked inheritance with frequently symptomatic heterozygous women, cardiomyopathy and nephropathy, and raised plasma lyso-Gb3 [86]. The frequency of Fabry disease is much higher than that of fucosidosis: 1/55,000 male births according to the classic estimate and about 1/3,100 boys in newborn screening of 37,104 male newborns, with a predominance of late-onset forms [86]. A pair of twins with a clinical picture of Fabry disease and normal alpha-galactosidase and alpha-L-fucosidase activities, described in 1977, illustrates that the diagnosis of both requires enzymatic or molecular confirmation [86]. Saudubray’s list of causes of angiokeratosis includes aspartylglucosaminuria, beta-mannosidosis, fucosidosis, Fabry disease, galactosialidosis, the adult form of Schindler disease and, outside metabolic diseases, Kawasaki disease [72]. Kanzaki disease, type II alpha-N-acetylgalactosaminidase deficiency (NAGA, 22q13.2), is the differential with adult-onset angiokeratomas: the original Japanese patient, daughter of first cousins, had angiokeratomas from 28 years, telangiectasias of the gastric mucosa, dilated conjunctival vessels and corkscrew tortuous fundus vessels, mild intellectual disability and, at 59 years, distal axonal sensory neuropathy, recurrent vertigo, bilateral sensorineural hearing loss and white matter changes on MRI; another Japanese patient had a normal IQ and Ménière syndrome, and two Spanish siblings had angiokeratomas and lymphoedema without neurological signs [83]. In the original patient, enzyme studies excluded fucosidosis and the urine contained sialylated glycoamino acids with a predominance of an O-linked glycoamino acid, which guides the urinary profile and alpha-N-acetylgalactosaminidase assay [83]. In mucolipidoses II and III, serum alpha-L-fucosidase is raised, unlike in fucosidosis, because mistargeting of lysosomal hydrolases raises them in body fluids and leaves them normal or low in leucocytes and fibroblasts [85].

On the neurological axis, fucosidosis appears among the causes of hypomyelination alongside sialidosis, Salla disease and the 4H group leukodystrophies [72, 73]. The combination of hypomyelination with pallidal T2 hypointensity and T1 hyperintensity is the most useful imaging clue [1, 2]. The “eye-of-the-tiger” sign leads to the hypothesis of NBIA; in two patients with fucosidosis, the NBIA panel was negative and the diagnosis came from the angiokeratomas or the exome [58, 61, 64]. Childhood-onset dystonia with spasticity and regression should include FUCA1 in the panels [57, 63]. Inflammatory joint signs may lead to a diagnosis of juvenile idiopathic arthritis, revised when dysostosis and neurological signs appear [68].

7. Treatments and Risk Management Strategies

7.1 General principles

Fucosidosis has no cure and no authorised medicine [1, 16]. Management rests on HSCT, considered only in children diagnosed very early, before CNS deterioration, and on supportive treatment of each manifestation, coordinated by a multidisciplinary team in a centre specialising in lysosomal diseases, with access to ENT, orthopaedic and neurosurgical surgery, experienced anaesthesia and palliative care [1, 2, 24]. GeneReviews states that there are no published clinical practice guidelines for fucosidosis and that its recommendations for assessment, treatment and surveillance are based on the authors’ experience [1]. The 2020 review lists as the core team paediatric and adult metabolic medicine, physiotherapy, ophthalmology, orthopaedics and cardiology, with neurology, neuropsychiatry and full neuropsychological assessment when complications arise [2].

7.2 Initial assessment after diagnosis

7.3 Regulatory status

There is no authorised medicine for fucosidosis at the FDA or in the European Union (EU), and JCR Pharmaceuticals stated in February 2026 that “There is no approved therapy available for this disease” [16, 88]. The EMA orphan designation register consulted in October 2026 contains no designation for fucosidosis [17]. A search for the term “fucosidosis” in the designation field of the FDA orphan designations and approvals database (OOPD, Office of Orphan Products Development), with all designations and all dates, on 27 and 28 October 2026, returned no records; as the search depends on the text of the designation, this result does not exclude a designation worded in other terms [18]. All drugs used are supportive or conditioning agents, and their use in fucosidosis is outside the disease-specific indication, by extrapolation from analogous indications.

7.4 Haematopoietic stem cell transplantation

7.4.1 Rationale and animal evidence

In the Springer spaniel dog with fucosidosis, bone marrow transplantation normalised enzyme activity in leucocytes and plasma, increased it in neural and visceral tissues, reduced storage and improved the clinical picture [4, 22, 42]. The first study, in 1986, used allogeneic bone marrow transplantation after total lymphoid irradiation and showed increased enzyme activity in visceral and nervous tissues with reduction of storage lesions [6]. Transplantation performed before clinical signs delayed onset and reduced severity, and that performed after symptom onset was not effective [22, 42]. The assumed mechanism is cross-correction: donor cells, which engraft in the marrow, blood and, presumably as brain macrophages or microglia-like cells, in the CNS, produce enzyme bearing mannose-6-phosphate that is taken up by neighbouring deficient cells [22, 87].

7.4.2 Published human cases

A review of 89 cases published between 1991 and 2019 found only 3 transplanted patients (3.37%) [57]. Saudubray counts fewer than 10 transplants, with experimental outcome and better results in very young patients with unrelated donors [24]. A 1999 review of more than 400 transplants in lysosomal and peroxisomal diseases included fucosidosis among the diseases with CNS benefit, without specific numbers [102]. Urinary oligosaccharides decrease after transplantation and can be used for monitoring [74].

7.4.3 Recommendations on the indication

For the other oligosaccharidoses, Saudubray records 20–30 transplants in alpha-mannosidosis (indicated in young, neuronopathic cases with a good donor, alongside ERT), fewer than 10 in aspartylglucosaminuria and fewer than 5 in beta-mannosidosis and sialidosis, all experimental, and considers HSCT not indicated in free sialic acid storage disease, Schindler disease and mucolipidoses II/III [24]. The Minnesota review summarises the results as positive in fucosidosis when transplantation precedes symptoms, positive in alpha-mannosidosis when early, mixed in aspartylglucosaminuria, preventive of encephalopathy but not of renal disease in sialidosis, and absent or unknown in the others [22]. The sources agree in limiting HSCT to presymptomatic or minimally symptomatic children, typically siblings of an index case diagnosed in the first year. They differ in degree: the EBMT and NMDP treat it as an established option to be discussed at diagnosis, whereas Saudubray classifies it as experimental. No source recommends transplantation in patients with established neurological deterioration, and experience in symptomatic patients is limited to isolated cases [1, 15, 24, 87].

7.4.4 Conditioning and doses

The conditioning recommended by the EBMT for lysosomal diseases is myeloablative, with fludarabine and busulfan at a pharmacokinetically guided dose, without ex vivo T-cell depletion; cyclophosphamide has fallen out of use because of cardiac toxicity and hepatic veno-occlusive disease (VOD) [15]. UCB is associated with more frequent full chimerism, greater tolerance of HLA mismatch and greater enzyme delivery, but with relatively high rates of aplastic graft failure and immune cytopenias [15]. The reference cited by the EBMT is the 2014 Utrecht study [15, 103]. The doses below refer to protocols for non-malignant diseases and not to trials in fucosidosis; the published fucosidosis cases used busulfan with cyclophosphamide, with or without thiotepa, whose doses are not given in the abstracts [69, 70].

The EU label of the original busulfan product recommended case-by-case pharmacokinetic monitoring in children weighing less than 9 kg, because only 60% reached the target window of 900–1500 µmol/L·min with 1 mg/kg [91]. The FDA label carries a boxed warning on severe and prolonged myelosuppression, which makes HSCT mandatory, and in the paediatric pharmacokinetic study (24 patients aged 5 months to 16 years, 9 of them with non-malignant diseases) the target was reached with the first dose in 71% and mortality was 17% (4/24) [89]. The EBMT stresses that HSCT is not curative and that transplant outcomes should be distinguished from disease outcomes, with long-term multidisciplinary follow-up [15].

7.5 Supportive treatment by manifestation

7.6 Supportive drugs: doses and extrapolation

None of the following drugs has been studied in fucosidosis, and GeneReviews gives no doses [1]. The doses come, in this order, from a trial or guideline in the analogous condition, from official labels in the analogous condition and, for adults with an attenuated form, from adult labels; the analogous condition used is sialorrhoea or spasticity in chronic neurological disorders of childhood, such as cerebral palsy.

7.6.1 Sialorrhoea

The randomised DRI trial (Drooling Reduction Intervention), in 90 treatment-naive children with chronic neurological disease (median age 4 years; 14 with genetic disorders), compared transdermal hyoscine with oral glycopyrronium and found similar reductions in the drooling impact scale at 4 weeks (25.0 and 26.6 points); at 12 weeks, 55% of children in the hyoscine group and 82% in the glycopyrronium group were continuing treatment (ratio 1.42; 95% confidence interval [CI] 1.04 to 1.95), because of more adverse effects with hyoscine [104]. Skin reactions to the transdermal system (redness, blisters, oedema, skin damage) led to discontinuation in 11 children; constipation was more frequent with glycopyrronium (31.6% vs 10.6%) [104].

7.6.2 Spasticity and dystonia

7.6.3 Epilepsy, psychosis and pain

GeneReviews recommends standard antiseizure medications, chosen by an experienced neurologist according to seizure type, and records that many may be effective, none having been studied specifically in fucosidosis [1]; the dose follows the SmPC of the chosen drug. In patients who are to receive busulfan, anticonvulsant prophylaxis is mandatory (section 7.4.4) [89, 90]. Interactions between cytochrome P450-inducing antiseizure medications and anaesthetic drugs should be considered perioperatively [62].

In the British patient with three psychotic episodes, the third, at 21 years, was treated with antipsychotics and temporary diazepam and zopiclone, and stability was maintained with quetiapine 50 mg/day [47]. This is a single case, not a drug or dose recommendation; the choice of antipsychotic rests with psychiatry, considering interactions and seizure risk. Pain should be treated with stepwise analgesia and palliative care support [1].

7.7 Agents and procedures to use with caution

No drugs are specifically contraindicated in fucosidosis in the sources consulted [1, 62]. The precautions arise from the manifestations: anticholinergics (hyoscine, glycopyrronium) reduce sweating and may worsen hyperthermia in a disease in which sweat gland dysfunction impairs thermoregulation, and hyoscine may precipitate psychosis in children [4, 62, 101]; baclofen may lower the seizure threshold and its abrupt discontinuation may cause seizures [99]; botulinum toxin increases the risk of dysphagia and aspiration in patients with oromotor dysfunction [96]; and tizanidine requires hepatic assessment, because transaminases may already be mildly raised in 25% of patients [1, 100]. In OrphanAnesthesia, the choice and doses of anaesthetic drugs should be adjusted to cardiac, hepatic and renal involvement [62].

7.8 Anaesthesia and surgery

The OrphanAnesthesia recommendation (Abdallah, December 2018 revision), based on two published anaesthesia reports, describes patients as candidates for MRI, CT, bone marrow transplantation, and dental, ophthalmological, orthopaedic and urological procedures [62]. The airway may be difficult, owing to difficult laryngoscopy and poor visualisation of the vocal cords secondary to facial and mandibular dysmorphism and macroglossia; planning for difficult airway management and inducing anaesthesia while maintaining spontaneous ventilation are recommended [62]. Preoperative assessment should document cardiomegaly, hepatosplenomegaly and renal, urological, endocrine and metabolic function (including hypothyroidism), baseline neurological and mental status, skeletal deformities, spasticity, visual and hearing deficits, seizure type and frequency (with prior optimisation of treatment) and angiokeratomas [62]. Hydration and normothermia should be maintained, with temperature monitoring, because of sweat gland dysfunction; positioning should be adapted to bone deformities and spasticity; hyper- or hyposalivation should be anticipated [62]. Intravenous and inhalational techniques are suitable; there are no reports of regional anaesthesia, which may be considered once neurological or anatomical abnormalities such as kyphoscoliosis have been excluded [62]. Postoperatively, monitor airway patency (macroglossia, obstructive sleep apnoea), haemodynamic stability and seizures; day-case anaesthesia should only be performed in an institution able to manage a difficult airway and cardiac and hepatic dysfunction [62]. In patients who have undergone or are awaiting transplantation, strict sterile techniques apply [62].

Saudubray adds, based on experience in the MPS and in oligosaccharidoses with dysostosis multiplex, the risk of atlanto-occipital instability and of peri- and postoperative spinal cord injury (due to low mean arterial pressure, compromised spinal cord circulation or positioning), and recommends careful positioning, monitoring of motor and somatosensory evoked potentials and avoidance of hypotension; it notes that these considerations are generally less serious in the oligosaccharidoses than in the MPS [24]. The short or hypoplastic odontoid described in fucosidosis makes assessment of the cervical spine before anaesthesia relevant [1, 4].

7.9 Pregnancy, contraception and breastfeeding

The sources consulted do not describe pregnancies in women with fucosidosis, and GeneReviews records that patients usually do not reproduce, because of the severity of the disease [1]. OrphanAnesthesia recommends that obstetric anaesthesia take place in an institution able to manage a difficult airway, cardiac and hepatic dysfunction, hypothyroidism and seizures [62]. Women with attenuated forms may have secondary amenorrhoea associated with weight loss, as in the British patient [47]. Contraception and breastfeeding are not addressed in the sources consulted; the choice of drugs during pregnancy follows the respective SmPCs.

7.10 Transition to adulthood

GeneReviews recommends preparing realistic plans for adult life from the age of 10 years [1]. The British siblings were transferred to an adult metabolic service (Salford), where follow-up included neurology, cardiology, ophthalmology, dermatology, psychiatry and neurocognitive assessment; the brother worked under supervision [47]. The 2020 review stresses the need for adult multidisciplinary teams for patients surviving beyond the second decade [2].

7.11 Guidelines, consensus and divergences

No fucosidosis-specific guideline from SSIEM (Society for the Study of Inborn Errors of Metabolism), MetabERN, ACMG or ASTCT was found in the searches performed, which does not prove that none exists; GeneReviews states that there are no published guidelines [1]. The applicable recommendations are partial:

7.12 Registered clinical studies

There are no interventional trials of specific therapy (enzyme, gene therapy, small molecule) in patients with fucosidosis on ClinicalTrials.gov [16, 88]. The registered studies that include fucosidosis are natural history studies and HSCT protocols open to several diseases.

ClinicalTrials.gov also lists other HSCT protocols open to several metabolic diseases with fucosidosis among the eligible conditions: three from the University of Minnesota (NCT00176904, phase 2/3, n=135, 1995–2010, completed; NCT01043640, phase 2, n=46, 2009–2017, completed; NCT00668564, n=18, terminated in 2010), a study of UCB adjuvant cells (NCT00654433, phase 3, n=40, terminated in 2011), a Los Angeles study (NCT00730314, phase 1/2, n=25, completed), a placental cell study (NCT01586455, phase 1, n=43, completed in 2022) and an observational study of pulmonary complications (NCT00005900, status unknown), without separate results for fucosidosis [108]. The limitations are those of a disease with about 120 to 200 known patients: HSCT data amount to isolated cases, with no comparison group other than untreated siblings, with short follow-up and publication bias; there are no registered negative trials, because there have been no specific interventional trials; and the multi-disease studies have not published separate results for fucosidosis [22, 57, 107]. The review by Casazza and colleagues, of April 2026, identifies as the main obstacle to clinical development in the glycoproteinoses the lack of outcome measures accepted by regulators and of biomarkers of CNS progression, and proposes a harmonised cross-disease framework, with standardised functional assessments and biochemical profiling, for natural history studies and trials [23]. The argument rests on the clinical convergence of the group: neurocognitive regression, dysostosis multiplex, motor impairment and reduced survival recur across the nine diseases, and early mortality is concentrated in mucolipidosis II and severe fucosidosis. The authors propose instruments already used in other rare neurological diseases, such as the SARA ataxia scale (Scale for the Assessment and Rating of Ataxia) and its modified versions, the 6-minute walk test, forced vital capacity (FVC) as a percentage of predicted and developmental and adaptive behaviour batteries (Bayley, Vineland), assigned by an age and ability algorithm, with centralised rater training and components compatible with teleconsultation; they note that none of these instruments has been validated in glycoproteinosis cohorts and that no biomarker for these diseases has been qualified in the FDA Biomarker Qualification Program [23]. In fucosidosis, they point to cognition, epileptic seizures, angiokeratoma burden, mobility and urinary fucosylated oligosaccharides as a pharmacodynamic marker as candidate endpoints, and stress that the link between substrate reduction and clinical benefit has not been demonstrated; the lesson of alpha-mannosidosis, in which velmanase alfa corrected circulating oligosaccharides and some somatic endpoints without relevant effect on neurological decline, steers development towards modalities with CNS access (enzymes fused to anti-transferrin receptor antibodies, intrathecal or intracerebroventricular gene therapy, small molecules that cross the blood–brain barrier) [23].

7.13 Investigational therapies and recent developments (October 2025 to October 2026)

Earlier preclinical approaches include intracisternal recombinant canine enzyme in the dog, given as three monthly injections from 8 weeks of age: activity reached 39–73% of normal in the brainstem and adjacent spinal cord, 8.5–20% in the superficial cortex and 2.6–5.5% in deep regions, with a reduction of fucosylated oligosaccharides in the CNS, liver and ganglia, a 79–80% reduction in the lumbar spinal cord, absence of antibodies and of inflammatory reaction and a mean weight gain of 16% [43]. In the same cohort (3 treated dogs, 3 untreated, 3 controls), there was a trend towards less vacuolation, neuronal loss, astrocytosis, microgliosis, perivascular storage, apoptosis, oligodendrocyte loss and hypomyelination, with no effect on spheroids or Purkinje cell loss, and the authors concluded that more complete and sustained correction is needed [110]. Correction of human fibroblasts with a retroviral vector and retroviral transfer into haematopoietic stem cells in the dog were demonstrated in the 1990s [44, 111]. None of these approaches has reached human trials, and the statement that they are promising is a review opinion [23, 40].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

Fucosidosis is autosomal recessive, and the parents of a patient are, in principle, asymptomatic heterozygotes [1]. GeneReviews recommends molecular testing of the parents to confirm heterozygosity and allow a reliable estimate of the recurrence risk [1].

8.2 Carrier detection and cascade testing

Carrier detection is performed by molecular testing and requires prior identification of the familial variants [1]. Enzyme activity in the leucocytes or fibroblasts of heterozygotes is intermediate, as already observed in the obligate heterozygotes of the family described in 1972, but overlaps with that of non-carriers enough to make biochemical detection and screening in at-risk populations unreliable [2, 4, 6]. In a London family, three heterozygous siblings had activity below the reference range, an example of this overlap [52]. The low serum activity polymorphism makes serum activity even less useful for this purpose [4, 75]. When the variants are not known, GeneReviews accepts alpha-L-fucosidase activity to clarify the status of siblings, to be confirmed clinically and by molecular testing [1]. If the molecular diagnosis has not been confirmed, storing the patient’s DNA is recommended [1].

8.3 Prenatal diagnosis and preimplantation genetic testing

Once the two familial variants have been identified, prenatal diagnosis and PGT-M are possible by molecular testing, which is the only recommended method [1, 2]. The enzyme assay in cultured amniocytes was used historically in families from Calabria, before the molecular era [4]. GeneReviews acknowledges that professionals and families may have different perspectives on the use of these tests, and recommends that the discussion ideally take place before pregnancy [1]. Saudubray recommends that all families with oligosaccharidoses be referred for genetic counselling, carrier detection and information on prenatal and preimplantation diagnosis [24].

8.4 Particular situations

A contiguous gene deletion including FUCA1 and HMGCL has consequences for counselling: carriers transmit both deficiencies together, and affected individuals may have 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, with a risk of hypoketotic hypoglycaemia, in addition to fucosidosis [48]. A homozygous variant within an extensive region of homozygosity, such as the 17.2 Mb at 1p36.21p35.2 in the patient of Wang and Xing, suggests consanguinity or isodisomy and may justify parental testing to estimate recurrence [1, 59].

8.5 Minors and young adults

Testing of asymptomatic minor siblings is recommended because early detection allows HSCT to be discussed before neurological deterioration; this is diagnostic testing with direct medical benefit, not predictive testing for a late-onset condition [1, 15]. Carrier testing in unaffected minor siblings has no medical benefit in childhood; GeneReviews recommends offering genetic counselling to young adults who are carriers or at risk of being carriers [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Global frequency and what each estimate measures

These estimates rest on clinical ascertainment of a rare and severe disease and probably underestimate attenuated forms and patients who die undiagnosed. The allele frequency of pathogenic variants in gnomAD is very low: 0.0044% for c.1279C>T and 0.006% for c.1138G>T [37].

9.2 Europe and founder populations

Fucosidosis was first described in Italy, and the highest relative frequency in Europe remains the Italian one [2, 14]. The allele of the infantile form is common in Reggio Calabria, in southern Italy, where the first prenatal diagnosis was made [4]. Most of the first Italian cases came from two neighbouring villages in that province, Grotteria and Mammola, whose genetic and demographic structure was characterised in 1982 [6]. The Italian variants include c.437del (p.Pro146ArgfsTer41), present in 8 Italian patients in HGMD, c.194G>A (p.Gly65Asp), shared with Cajun patients, and c.203C>T (p.Ser68Leu) [2, 35, 50]. Outside Italy, European cases are sporadic: a Belgian patient, an Austrian patient, two adult British siblings, a Spanish boy and a Swiss girl [2, 34, 47, 58, 61]. The Salford and Warsaw case series (United Kingdom and Poland) added European patients to the 2020 review [2].

In Portugal, the only reference in the sources consulted is a patient homozygous for the c.810del p.(Cys271ValfsTer59) variant (historical designation S265fs), described in 1993 [34]. A 1990 study described the formal and population genetics of the FUCA1 polymorphism in northern Portugal; this is an isoenzyme polymorphism, not cases of disease [113]. The sources consulted provide no Portuguese incidence or national patient registry.

9.3 The Americas

In the USA, cases are concentrated in the south-west, in the Hispanic American population of New Mexico and Colorado, in which 8 patients were homozygous for the variant NM_000147.5:c.1138G>T p.(Glu380Ter) (historical numbering E375X), described in ClinVar as frequent in people of Hispanic American descent [4, 35, 37]. Three related Franco-American (Cajun) patients shared the Italian p.Gly65Asp variant [35]. An Indo-Canadian patient had the c.661del variant [34]. Cuba is mentioned as a region of increased frequency by the 1999 and 2020 reviews, but the Orphanet numerical estimate for Cuba has no verifiable source [2, 3, 14]. Recent US cases include a girl followed for 15 years in Orange County (California) and a patient from Loma Linda with a novel variant within a region of homozygosity [59, 65]. The sources consulted contain no data from Brazil.

9.4 North Africa, the Middle East and Asia

Recent series come mainly from populations with consanguinity. In Tunisia, 10 patients from 6 families were diagnosed between 1987 and 2007, and three families were studied molecularly, with homozygous truncating variants in the severe phenotypes [38, 46]. In Turkey, the published patients have no distinctive clinical or radiological findings, and a novel variant p.(Trp79Ter) and the contiguous FUCA1–HMGCL deletion have been described [48, 60, 66]. The 2026 natural history study has five centres in Turkey and two in Tunisia [88]. Patients have been described from Saudi Arabia, Iran, Algeria, India, China (at most 10 cases published up to 2022), Taiwan and Thailand [2, 4, 35, 54–57, 114].

9.5 Special populations

In patients with a severe phenotype and restricted access to health care, mortality before 10 years was 6 in 10 in Tunisia, a figure the authors attributed in part to the care available [46]. Adults with attenuated forms are a poorly described population, with specific needs (psychiatry, valvular cardiology, supported employment) [47]. Children born prematurely or with other apparent causes of delay may have their diagnosis delayed [60].

9.6 European network and patient organisations

The relevant European reference network is MetabERN, the European network for hereditary metabolic disorders [20]. ISMRD, an international organisation devoted to the glycoproteinoses, and the MPS Society of the United Kingdom (telephone 0345 389 9901, mps@mpssociety.org.uk) support patients with fucosidosis and collaborated on GeneReviews [1, 21]. Orphanet maintains the ORPHA:349 entry, which links to reference centres and patient organisations [3, 62]. The sources consulted do not identify Portuguese or Brazilian organisations specific to fucosidosis.

10. Illustrative Clinical Case

10.1 Two adult siblings with an attenuated form (Puente-Ruiz et al., 2023)

Puente-Ruiz and colleagues described two white British siblings with an attenuated form (type II), followed for 19 years, first in paediatric services and then in the Salford adult metabolic service [47].

The brother was born at 36 weeks (3.005 kg) with normal developmental milestones, underwent umbilical hernia repair and had red skin lesions from early childhood, increasing in number [47]. At primary school he was about one year behind his peers, and at 12 years he was referred to genetics for learning difficulties and a red retroauricular patch [47]. Lysosomal enzyme screening showed deficient alpha-L-fucosidase activity in leucocytes (0.22 nmol/mg/h; reference 50–250), confirmed in fibroblasts (2.2 nmol/mg/h; controls 17 and 54) [47]. A lysosomal disease panel identified the c.998G>A p.(Gly333Asp) variant in the heterozygous state, and genome sequencing, years later, identified the exon 4 deletion on the other allele [47]. At 20 years low back pain appeared, and spine MRI showed dysostosis multiplex with a normal craniocervical junction (Fig. 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC10694746/figure/f0005/) [47]. At 31 years he had a blood pressure of 100/70 mmHg, a grade 2/4 aortic ejection murmur, a broad-based gait with ataxia (score of 16/40 on the SARA, Scale for the Assessment and Rating of Ataxia) and a tendency to scissor gait, improved by orthoses [47]. The echocardiogram showed mixed aortic valve disease, with mild stenosis (peak velocity 2.6 m/s, mean gradient 14 mmHg) and mild regurgitation, without progression on subsequent examinations and without left ventricular hypertrophy [47]. He had mild dilatation and tortuosity of the retinal veins with stable vision (Fig. 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC10694746/figure/f0010/), no organomegaly, occasional diarrhoea after meals and neurocognitive assessment below the 5th centile in most domains; he held paid employment under supervision [47].

The sister was born at term (2.95 kg) with a small ventricular septal defect, surgically closed, had speech delay and was diagnosed at 6 years, after her brother [47]. She had diffuse and confluent angiokeratomas on the limbs, trunk and buttocks, with a migratory pattern, which bled on trauma (Fig. 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC10694746/figure/f0015/), mild unilateral hearing loss, no epileptic seizures and no skeletal problems [47]. At 14 years, after an infection, she had cognitive decline with weight loss, sleep disturbance, hallucinations and agitation, with partial recovery over months without specific treatment; EEG and biochemistry were normal, and the weight loss was accompanied by amenorrhoea that reversed with weight recovery [47]. A second psychotic episode, at 16 years, resolved completely. The third, at 21 years, lasted about 12 months and was treated with antipsychotics, diazepam and zopiclone; the patient stabilised on quetiapine 50 mg per day [47]. At 22 years, the verbal comprehension and perceptual reasoning indices and the full-scale intelligence quotient were below the 1st centile; ataxia was mild (SARA 6/40) and she walked without support [47]. Both siblings had normal urinary GAG, abnormal urinary oligosaccharides at diagnosis and in adulthood (Fig. 4, https://pmc.ncbi.nlm.nih.gov/articles/PMC10694746/figure/f0020/), and normal gonadotrophins and thyroid function [47].

The case illustrates intrafamilial variability with the same genotype, diagnostic delay in attenuated forms, psychosis and aortic valve disease as adult manifestations, and the interpretation of a variant classified in ClinVar as of uncertain significance in the light of demonstrated enzyme deficiency [37, 47]. Quetiapine was the treating team’s choice in an isolated case and does not constitute a recommendation. The figures were identified from the captions of the PMC version.

10.2 Paediatric case with early cortical involvement (de la Peña et al., 2025)

A Spanish boy of non-consanguineous parents, with a birth weight of 3.3 kg, length of 52 cm and head circumference of 31 cm, sat at 9 months, crawled at 15 months and stood with support at 18 months, with language regression at 14 months [58]. At 3 years, MRI showed non-specific white matter change and the pallidal “eye-of-the-tiger” sign; karyotype, fragile X testing, the 850,000-probe microarray and the NBIA panel were normal [58]. Trio exome sequencing identified c.856C>T p.(Gln286Ter) (published on NM_000147.4; = NM_000147.5:c.856C>T, same numbering) in exon 5, of paternal origin, and c.539_546delinsTTTAAGGAA p.(Gly180ValfsTer2) in exon 2, of maternal origin [58]. At 4 years he had axial hypotonia, distal hypertonia, hyperreflexia, spasticity predominating in the lower limbs, dystonic-dyskinetic postures of the upper limbs and moderate bilateral sensorineural hearing loss, with a weight of 19.5 kg (95th centile), height of 105 cm (75th centile), head circumference of 54 cm (95th centile), mild hypertelorism and thick lips [58]. 3 T MRI showed hypoplasia of the corpus callosum and changes in the corona radiata, periventricular white matter and globi pallidi, with cortical thickness of 2.27 mm on the left and 2.53 mm on the right, below the 0.5th centile (Fig. 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC11761451/figure/mgg370070-fig-0001/); spectroscopy showed double peaks at 3.9 and 1.2 ppm (Fig. 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC11761451/figure/mgg370070-fig-0002/) [58]. 24-hour urinary oligosaccharides were consistent and fucosidase activity was absent; abdominal ultrasound, cardiological assessment and visual evoked potentials were normal [58]. The case shows that cortical atrophy can be early and that a negative NBIA panel does not exclude fucosidosis when there is a pallidal sign. The figures were identified from the captions of the PMC version.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Without disease-modifying treatment, life expectancy is reduced and varies with severity [1]. In the 1991 review and the reviews citing it, 43% of patients died before 10 years and 41% after 20 years; about 60% of deaths resulted from respiratory infections and neurological deterioration [1, 2]. In the same set of 77 patients, 7 (9%) died before 5 years and 36 (64% of those with information) reached the second decade [5]. Early onset is associated with faster neurological deterioration and death at a younger age [1]. The severe form typically leads to death before 10 years, and the attenuated form may reach adulthood, typically into the third decade [1]. In the Tunisian series, 6 of 10 patients died before 10 years [46]. There are survivors into the fourth and fifth decades, such as the patient with the L405R variant (historical numbering, = NM_000147.5:c.1229T>G p.(Leu410Arg)), alive at 46 years with severe muscle atrophy and unable to walk [6, 47, 51]. Patients transplanted early had a better course than their untreated siblings, with a maximum published follow-up of about 4 years [69, 70]; there are no long-term survival data after HSCT in fucosidosis.

11.2 Surveillance table

The intervals follow GeneReviews, which bases them on the authors’ experience; post-transplant follow-up follows the EBMT [1, 15].

11.3 Assessment of at-risk relatives

The older and younger siblings of a patient, even if asymptomatic, should be tested to identify early those who may benefit from HSCT and preventive measures: by molecular testing if the familial variants are known, or by alpha-L-fucosidase activity if they are not [1]. The transplanted cases with the best outcomes were precisely younger siblings diagnosed because of an affected sibling [69, 70].

11.4 Transition and palliative care

Preparation for adult life begins at around 10 years, and patients who survive the second decade need adult services with metabolic medicine, neurology, cardiology, ophthalmology, psychiatry and rehabilitation [1, 2, 47]. The need for palliative care and home nursing should be assessed continuously, especially in the severe forms [1].

12. Summary and Final Considerations

Fucosidosis is an autosomal recessive lysosomal oligosaccharidosis caused by biallelic loss-of-function variants in FUCA1 (1p36.11), which encodes tissue alpha-L-fucosidase; the deficiency leads to accumulation of fucosylated glycoproteins, glycolipids and glycoasparagines, mainly in the CNS [1, 39]. It is rare, with about 120 published patients and an estimated incidence below 1/200,000, and has clusters in Italy, in the Hispanic American population of the south-western USA, in Cuba and in consanguineous populations of Tunisia and Turkey [1, 14, 46, 60].

The clinical picture is a continuous spectrum: in the severe form, normal early development is followed by regression in the second year, with coarse facies, short stature, respiratory infections, dysostosis multiplex and death before 10 years; in the attenuated forms, angiokeratomas, learning difficulties, ataxia, spasticity, dystonia, conjunctival and retinal vascular changes and, in adulthood, psychosis and valvular disease dominate a slow course [1, 5, 47]. Hypomyelination with pallidal T2 hypointensity is the most useful imaging clue, and angiokeratomas associated with neurological disease are the clinical clue that distinguishes fucosidosis from the other oligosaccharidoses [1, 72].

Diagnosis is based on urinary oligosaccharides, alpha-L-fucosidase activity in leucocytes and FUCA1 sequencing with deletion analysis; serum activity is misleading because of a common low-activity polymorphism and the contribution of FUCA2 [1, 36, 75]. Variants published before 2000 differ from the current HGVS numbering by five codons and should be converted with validated tools [8, 37].

There is no authorised medicine. HSCT, with fludarabine and pharmacokinetically guided busulfan, is an option for children diagnosed before neurological deterioration, usually siblings of an index case, on the basis of isolated cases and data from the canine model [1, 15, 22]. Supportive treatment (rehabilitation, control of sialorrhoea, spasticity and seizures, nutrition, airway clearance, palliative care) uses drugs outside the specific indication, with doses taken from trials and labels in chronic neurological disorders of childhood [1, 99, 104]. Anaesthesia requires preparation for a difficult airway and temperature control [62]. In 2026 the first natural history study devoted to the disease began, sponsored by the company developing an enzyme designed to cross the blood–brain barrier, still at the preclinical stage [16, 88]. Early testing of a patient’s siblings is the condition for HSCT to be discussed in time, and genetic counselling allows families to use prenatal diagnosis and preimplantation genetic testing [1, 2].

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