Alpha-Mannosidosis

An autosomal recessive lysosomal glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (MAN2B1 gene), with a continuous clinical spectrum between a severe infantile-onset form and attenuated forms surviving into adulthood. Beta-mannosidosis (MANBA) is addressed only as a differential diagnosis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1 Definition and scope

Alpha-mannosidosis is a lysosomal storage disease (LSD) in the oligosaccharidosis group, also called glycoproteinoses, caused by deficiency of lysosomal acid alpha-mannosidase, the hydrolase that removes terminal mannose residues from asparagine-linked oligosaccharides released during glycoprotein degradation [1, 18]. Failure of this step interrupts the sequential degradation pathway and causes accumulation of mannose-rich oligosaccharides in almost all tissues, with cytoplasmic vacuolation predominant in the central nervous system (CNS) and parenchymal organs [1, 2]. The disease is inherited in an autosomal recessive manner and results from biallelic variants in MAN2B1, located at 19p13.13 [1]. The Orphanet definition summarises the phenotype as an inherited lysosomal disease characterised by immunodeficiency, facial and skeletal abnormalities, hearing impairment and intellectual disability [5].

This article treats alpha-mannosidosis as a lysosomal storage disease; the ophthalmological (cataract and corneal opacities) and visceral (hepatosplenomegaly) perspectives are integrated into sections 3 and 4 [19, 20]. Beta-mannosidosis, deficiency of another lysosomal glycosidase (MANBA gene), is a distinct entity and is addressed in the differential diagnosis [18, 21].

1.2 Original description and historical overview

The disease was described by Öckerman in 1967 in a patient with a generalised storage disorder resembling Hurler syndrome [21]. In the same year, I-cell disease (mucolipidosis II) was delineated; both entities emerged from recognition of patients with a mucopolysaccharidosis (MPS) phenotype without increased urinary mucopolysaccharide excretion [21]. In 1976, Desnick and colleagues proposed division into type I, severe infantile disease, fatal between 3 and 8 years, and type II, with later onset and slower progression [3]. In 1977, Champion and Shows assigned the gene to chromosome 19 [21]. The three-clinical-type classification, introduced by Chester in 1982 and subsequently used by Malm and Nilssen, distinguishes type 1 (mild, recognised after 10 years, without skeletal abnormalities, very slow progression), type 2 (moderate, recognised before 10 years, with skeletal abnormalities and ataxia between 20 and 30 years), and type 3 (severe, recognised immediately, with rapid progression and early death from primary CNS involvement or myopathy) [3].

The first bone marrow transplant, performed by Will and colleagues in 1987, ended with the child's death at 18 weeks from procedural complications; autopsy showed reversal of somatic abnormalities without reversal of cerebral storage, in the context of a carrier maternal donor, corticosteroid therapy and short observation [3]. In 1994, Walkley and colleagues showed in the feline model that early transplantation prevents neurological deterioration, and in 1998 Wall described resolution of infections and organomegaly, skeletal improvement and neurocognitive stabilisation over two years after transplantation in a child [3]. Grewal and colleagues reported the Minnesota series of four transplant recipients in 2004 [22], and Mynarek and colleagues assembled the first multicentre analysis of 17 patients in 2012 [23].

1.3 Molecular discovery milestones

In 1997, Nilssen and colleagues functionally cloned lysosomal alpha-mannosidase complementary DNA from human placenta and identified the first pathogenic variant, a histidine-to-leucine substitution at a conserved residue, in two siblings of Palestinian origin [7]. In 1999, Berg and colleagues published the first mutational spectrum, with 43 patients from 39 families, and identified the recurrent p.Arg750Trp variant [24]. In 2012, Riise Stensland and colleagues studied 130 unrelated patients from 30 countries, described 83 novel variants, expanded the spectrum from 42 to 125 variants, and documented the origin of p.Arg750Trp in a few ancestral haplotypes [25]. In 2015, the relational database amamutdb.no was published, bringing together genotypes, phenotypes and biochemical and structural data [26], and Borgwardt and colleagues described the first correlation between genotype, subcellular localisation of the mutant protein and phenotype [8].

1.4 Therapeutic milestones and current nomenclature

Recombinant human alpha-mannosidase (velmanase alfa) was developed by a European academic consortium with Community funding and subsequently by Chiesi; the phase I–II trial in ten children was published in 2013 and the phase III trial in 2018 [27, 28]. The European Commission authorised velmanase alfa (Lamzede®) on 23 March 2018 under exceptional circumstances [12], and the United States Food and Drug Administration (FDA) approved it on 16 February 2023 [13]. In 2019 an international working group published an age-based clinical recognition algorithm [11], and in 2024 the first international monitoring consensus, developed using the Delphi method, was published [4].

Type 1 to 3 terminology remains useful for prognosis and management but describes untreated patients and is based on a continuous spectrum, with marked intrafamilial variability [1, 21]. Beck and colleagues questioned the division into three types in light of the variability observed [29], and the 2024 Delphi consensus adopts a distinction between a severe rapidly progressive form, with prenatal loss or early death from CNS involvement or infection, and mild-to-moderate attenuated forms [4]. The unqualified term “mannosidosis”, used in some skeletal dysplasia tables, groups alpha- and beta-mannosidosis and should be avoided in clinical communication [30].

2. Molecular Genetics and Pathophysiology

2.1 The MAN2B1 gene and protein

The MAN2B1 gene is located at 19p13.13, has 24 exons and is transcribed into a single messenger RNA of about 3.5 kb expressed in all tissues [1, 7, 8]. The MANE Select reference transcript is NM_000528.4, encoding the protein NP_000519.2; GeneReviews and some recent reports use the previous version NM_000528.3 [1, 6, 10]. The chromosome 9 location that appears in one passage of the Atlas of Inherited Metabolic Diseases is a typographical error in the book itself, which on another page and in the original reference by Champion and Shows (1977) assigns the gene to chromosome 19 [21]. The 2024 French PNDS (National Diagnosis and Care Protocol) repeats the location 19p13.2-q12, which does not match the current position 19p13.13 [1, 9].

Lysosomal alpha-mannosidase (LAMAN) is a family 38 glycosyl hydrolase synthesised as a single-chain precursor, with a putative 48-amino-acid signal peptide followed by 962 amino acids, for a total of 1011 residues [7, 8]. In the lysosome, the precursor is proteolytically processed into 70, 42 and 15 kDa glycopeptides linked by disulphide bridges, and in human liver forms assemble that are separable by chromatography and electrophoresis but immunologically indistinguishable, all encoded by the same gene [2, 21]. The enzyme removes non-reducing terminal alpha-D-mannose residues, cleaving alpha-1,2, alpha-1,3 and alpha-1,6 linkages in oligosaccharides generated by N-glycoprotein degradation; the Atlas figure depicts only the alpha-1,3 and alpha-1,6 linkages of the trimannosyl core [2, 21]. The active site coordinates a zinc ion, and the first described variant affects a histidine residue involved in this coordination [3].

2.2 Molecular mechanism

The disease mechanism is loss of function [1]. Almost all secreted and membrane proteins, and the acid hydrolases themselves, are glycosylated, and asparagine-linked chains have a core of N-acetylglucosamine and mannose [18]. In lysosomal degradation of these chains, each enzyme acts at a sequential step; lack of alpha-mannosidase compromises the whole pathway and leads to accumulation of mannose-rich oligosaccharides and glycopeptides [1]. The main oligosaccharide excreted in urine is the trisaccharide Man-alpha(1,3)Man-beta(1,4)GlcNAc, corresponding to the M2GN fraction in liquid chromatography and to GlcNAc(Man)2 in current mass spectrometry methods [21, 31]. Cross-reacting material (CRM) is present in most patients [21]. Serum dolichol may be elevated, as in aspartylglucosaminuria, reflecting transfer of the oligosaccharide precursor from dolichol to asparagine [21].

Activity measured in affected individuals' leucocytes is not zero: it corresponds to 5–10% of normal in GeneReviews and 5–15% in other series, and is attributed to mannosidases from other compartments (MAN2A1 in the Golgi apparatus, MAN2C1 in the cytosol and MAN1B1 in the endoplasmic reticulum) retaining some activity at acidic pH; after immunoprecipitation of the lysosomal enzyme, true residual activity falls to 0.1–1.3% [1, 3, 32]. The Atlas reports values of 3–5%, with rare variants showing 15–20% residual activity, and the current reference value follows GeneReviews [1, 21].

2.3 Tissue and physiological mechanisms

Oligosaccharide accumulation appears to impair lysosomal function at several levels, including vesicle maturation, endocytosis, exocytosis and calcium homeostasis, but does not alone explain the disease [1]. Histopathology shows vacuolated foamy hepatocytes, vacuoles in histiocytes, lymphocytes, muscle and fibroblasts and, in the CNS, diffuse neuronal changes with ballooning and ultrastructural storage vacuoles [21]. Cerebral pathogenic cascades remain poorly understood, and the phenotype depends partly on the type and amount of stored material [18]. Secondary mitochondrial dysfunction has been proposed for psychiatric episodes [1].

Immunodeficiency has several components: reduced ability to produce specific antibodies, inadequate leucocyte phagocytosis due to disease-induced serum blocking agents or lack of antibodies, reduced intracellular killing capacity and, in older studies, defective chemotaxis, reduced lymphocyte transformation and sometimes low immunoglobulin G (IgG) [1, 21]. Binding of oligomannosides with five and six mannose residues to interleukin 2 receptors has been proposed as a mechanism, without definitive demonstration [3]. The increase in serum IgG during ERT, reversing hypogammaglobulinaemia when present, supports the link between storage and immune dysfunction [33].

Hearing loss has a sensorineural component, attributed to storage material in the ear, and a conductive component, linked to otitis with effusion favoured by immunodeficiency and skull bone abnormalities that impair Eustachian tube drainage [1, 21]. Diarrhoea is related at least partly to the laxative effect of D-mannose, which accelerates intestinal transit in these patients [1]. Myopathy may worsen through an immune-mediated mechanism, including after HSCT, and in one patient strength improved after a single plasma exchange [1].

2.4 Inheritance, penetrance and expressivity

Inheritance is autosomal recessive, with both sexes affected [1, 21]. Heterozygotes are asymptomatic and are not at risk of developing the disease [1]. Expressivity is highly variable: siblings with the same genotype may have different severities, suggesting as-yet-unidentified expression modifiers [1, 21, 25]. The sources consulted do not describe specific modifier genes or allelic diseases; GeneReviews states that no other phenotypes are known to be associated with germline pathogenic MAN2B1 variants [1].

2.5 Variant spectrum

GeneReviews counts more than 130 pathogenic variants, and Hennermann and colleagues reported 162 variants in the Human Gene Mutation Database (HGMD) in 2021, including missense, nonsense, small frameshift insertions and deletions, in-frame duplications, splicing variants and large deletions [1, 8, 32]. Most variants are private to a family [25]. Sequencing identified 72% of alleles in the 1999 series and 98.5% (256/260 alleles) in the 2012 series; these proportions describe alleles detected in patients with an enzyme-based diagnosis, not the clinical sensitivity of a test applied to a patient with suspected disease [24, 25]. Deletions of one or more exons account for less than 2% of alleles [1]. Of the missense variants expressed in cells, most were inactive and ten had activity above background, with pathogenicity unresolved [25].

The c.2248C>T p.(Arg750Trp) variant is the most frequent. Berg and colleagues found it in 13 patients from several European countries, accounting for 21% of alleles; Malm and Nilssen's review cites the same study with a figure above 30%, and the value from the original abstract is used [3, 24]. In the 2012 series it was present in 50 patients from 16 countries and accounted for 27.3% of alleles; it occurs on four haplotypes, one accounting for 95% of alleles, indicating spread from a few ancestral haplotypes through a founder effect, with less frequent recurrent mutational events [3, 25]. A common haplotype shared by Finnish, Polish and Italian homozygotes and a different haplotype in a Turkish patient were described [3]. Next in frequency are the splicing variant c.1830+1G>C, at approximately 5% of alleles, and c.2426T>C p.(Leu809Pro), at approximately 3% [8].

The following table presents the variants cited in the article normalised according to Human Genome Variation Society (HGVS) nomenclature on the MANE Select transcript, their historical designation where available, and ClinVar classification. Correspondence between the historical designations R760X and Q639X and the variants c.2278C>T and c.1915C>T was established from amino acid position without reading the original 1998 articles [6]. The historical designation “212A>T” for the first variant does not match the current reference sequence, whose base at position c.212 is cytosine; the cloning variant corresponds to c.215A>T p.(His72Leu), consistent with the structural description of the active-site histidine residue [3, 6]. The historical designations “IVS-2A>G” (exon 21 skipping) and “322-323insA” (frameshift with a termination codon at position 160), described by Beccari in two Italian patients, were not normalised because the original article was unavailable [21].

The splicing variants c.2356-2A>G and c.1929-2A>G (the latter in a Syrian family) have also been described in the United Arab Emirates, and deceased patients in Hennermann's series included, in the published nomenclature, homozygous c.1831-2A>G p.(His611Glyfs*3) and c.2175_2177delins11 p.(Trp725Cysfs*4), and c.1816delA p.(Thr606Profs*18) and c.685C>T p.(Arg229Trp) in compound heterozygosity with c.1830+1G>C [32, 36]. The sources consulted do not describe enzyme pseudodeficiency or common hypomorphic variants producing low activity without disease, nor documented cases of mosaicism; parental postzygotic mosaicism and uniparental isodisomy are considered possibilities when only one parent is a carrier (section 8) [1, 3].

2.6 Genotype–phenotype correlations

Until 2015, genotype and phenotype were considered uncorrelated, and GeneReviews retains this formulation [1, 3]. Berg and colleagues found no relationship between variant type and phenotype, and patients with two null alleles may have mild or moderate forms [3, 24]. It had already been observed that missense proteins divide into those correctly targeted to the lysosome and those retained in the endoplasmic reticulum [3].

Borgwardt and colleagues studied 66 patients with attenuated disease (57 unrelated, aged 5–42 years; 60 Europeans, 4 North Africans and 2 Pakistanis), with complete genotypes in all and 28 homozygotes among the 57 unrelated patients, and divided them into three subgroups: two null variants (n=21), at least one missense or in-frame variant with protein retained in the endoplasmic reticulum (n=32), and at least one missense variant with protein reaching the lysosome (n=13) [8]. The lysosomal subgroup had significantly higher cognitive scores (Leiter-R), fewer oligosaccharides in cerebrospinal fluid (CSF), better upper limb coordination and balance on the Bruininks–Oseretsky scale (BOT-2), and higher forced vital capacity (FVC) [8]. p.Arg750Trp was classified as retained in the endoplasmic reticulum [8]. In a series of 25 patients diagnosed after 16 years, compound heterozygosity was more frequent in mildly affected patients (64%) than in those with moderate-to-severe disease (9%) [10]. These are group-level associations and do not allow prediction of severity in a patient or fetus [1, 3].

Genotypic subgroup also relates to ERT immunogenicity: treatment-emergent antidrug antibodies occurred in 3/7 patients with two null alleles (43%), 1/17 with protein retained in the endoplasmic reticulum (6%) and 0/9 with lysosomal protein [38].

3. Clinical Spectrum and Manifestations by System

3.1 Spectrum and classification

Alpha-mannosidosis forms a continuous spectrum, and division into three types describes mainly untreated patients [1, 3]. Type 1 is recognised after 10 years, includes myopathy and slow progression, and has no skeletal abnormalities; type 2 is recognised before 10 years, with myopathy, skeletal abnormalities and ataxia developing between 20 and 30 years; type 3 shows evident progression from an early age and early death from primary CNS involvement or infection [1, 3]. Most described patients have the moderate type [1, 21]. Even at the time of the Atlas, with more than 90 published patients, separation into a severe infantile form and an indolent form was considered simplistic, given intrafamilial heterogeneity documented since 1981 in two siblings with different severities [21]. ERT and HSCT may modify this natural history, and the following data distinguish untreated from treated patients wherever the sources permit [1].

The 2024 French PNDS (National Diagnosis and Care Protocol) retains the three types with different age criteria: the triad of hearing loss, coarse facies and intellectual disability is present in 90% of patients; type 3 begins between 3 months and 1 year; type 2 presents between 1 and 4 years, and always before 10, with language delay and hearing loss, with survival into adulthood; type 1, diagnosed after 10 years, presents with cognitive or psychiatric disturbances in a patient who already had hearing loss [9]. Because patients with onset after the first year are difficult to classify, the PNDS in practice separates the rare severe form, with prenatal or early death from neurological involvement or severe infections, from the attenuated forms, which are more heterogeneous, in line with the Delphi consensus [4, 9]. It also distinguishes the early signs of the attenuated forms (almost constant and often revealing hearing loss, strabismus and hypermetropia, coarse facies with moderate dysostosis and genu valgum, ENT and respiratory infections in the first decade with IgG deficiency, sometimes severe asthma, usually normal early development, clumsiness with hypotonia, weakness and sometimes hyperlaxity, school difficulties) from the later signs (osteonecrosis, destructive polyarthropathy, osteoporosis, carpal tunnel syndrome, valvulopathy and cardiomyopathy, cerebellar-spastic syndrome, psychiatric episodes in 25%, corneal opacities, glaucoma, adult retinopathy, restrictive respiratory failure and sleep apnoea) [9].

3.2 Severe infantile-onset form

In the classic infantile form, onset is very early and the picture resembles a severe MPS: hernias may be among the first findings, the facies is very coarse, the teeth are widely spaced, the skin is thickened and hepatosplenomegaly is prominent [21]. Breathing is noisy, with rhinorrhoea and frequent respiratory infections; there is macrocephaly with frontal bossing, severe intellectual disability and speech delay aggravated by hearing loss, a wide-based gait and extreme dysostosis multiplex, with a J-shaped sella turcica, thickened calvarium, hypoplastic, flattened and ovoid vertebral bodies with anterior beaking, gibbus, metacarpals with proximal tapering and flared iliac wings [21]. Pulmonary infiltrates, corneal opacities and spoke-like posterior lenticular cataracts are frequent [21]. Deterioration is rapid and, in older series, most children died between 3 and 10 years of age, often from pneumonia [21]. In Hennermann's literature review, the seven published deaths occurred at a median age of 4.3 years (2.2–41), four of them in the first decade [32]. The French PNDS adds that equinus foot may be present from birth, that bacterial infections dominate the picture, favoured by defective neutrophil chemotaxis and phagocytosis and by IgG deficiency, that there is skin infiltration, gingival hypertrophy with macroglossia and hepatosplenomegaly, and that hydrocephalus may complicate the course from the first year; death occurs in most cases in the first decade, mainly from bacterial infection or respiratory failure [9].

The Atlas illustrates this form with a 20-month-old Saudi boy who could stand and walk with support but neither walk independently nor speak, with fibroblast alpha-mannosidase activity at 10% of control, lips and nose suggestive of storage, a protuberant abdomen with hepatomegaly and splenomegaly, foamy marrow histiocytes, fifth-finger clinodactyly and proximally placed thumbs (Figs. 96.2–96.5 in the book) [21].

3.3 Attenuated forms: course by age

Children appear normal at birth; some have equinus foot or hydrocephalus in the first year [3]. In the first decade, recurrent infections (colds, pneumonias, gastroenteritis and, more rarely, urinary tract infections) and serous otitis media, usually non-bacterial and associated with hearing loss, predominate [1]. Infections decrease in the second and third decades, when ataxia and muscle weakness become more apparent; many patients can ski, cycle or play football until the third decade [1]. From the second to the fourth decade, destructive polyarthropathy develops, particularly hip and knee osteoarthritis, often requiring surgery [3]. Acute necrotising arthritis or acute hydrocephalus may occur at any age, both requiring surgery [1]. Progression is slow, over decades; most adult patients eventually become wheelchair-dependent, and none in the Norwegian series was fully socially independent [3]. In a series of 35 patients with a type 2 phenotype, all were socially dependent and unable to care for themselves, and degeneration over time appeared to be the rule regardless of phenotype [21].

3.4 Manifestations by system

Facial features and skull. Regardless of family and ancestry, untreated patients have Hurler-like or coarse facial features, macrocephaly with a prominent forehead, highly arched eyebrows, a depressed nasal bridge, spaced teeth, macroglossia and prognathism [1]. In mild forms, these features may be so subtle that an inexperienced observer misses them [1]. In the European longitudinal cohort, coarse facial features were present in 13 of 43 patients with mild disease [29]. Mild strabismus is common [3]. Gingival hyperplasia is a clue distinguishing alpha-mannosidosis from other oligosaccharidoses with coarse facial features and vacuolated lymphocytes [19]. Three cases with craniosynostosis have been described, potentially extending the spectrum [39].

Hearing. Most untreated patients have hearing loss beginning in early childhood, usually non-progressive and, in many cases, mixed, with conductive and sensorineural components [1]. In the European longitudinal cohort, all patients over 3 years had significant hearing loss and used hearing aids, and hearing remained stable or improved slightly over 24 months [29]. Malm and Nilssen describe moderate-to-severe sensorineural hearing loss as apparently inevitable, aggravated by the conductive component of otitis with effusion [3]. The Atlas describes it as progressive, and this divergence partly reflects superimposed recurrent otitis and the observation period of each series [1, 21]. Untreated otitis in early childhood contributes to speech and cognitive impairment [1]. In one mildly affected patient in the Atlas, middle ear surgery at 19 years revealed extensive mannoside deposits [21].

Immunity and infections. Frequent infections result from the immunodeficiency described in section 2, and bacterial infections are often severe [1]. Bronchitis and otitis media are the most typical infections in older series, and pancytopenia has been described [21]. In the European cohort, eight of 43 patients had otitis during observation [29].

Autoimmunity. Systemic lupus erythematosus (SLE) is frequently observed in untreated patients, and increased autoimmunity forms part of the presentation [1, 3]. In a United Arab Emirates series, three of nine patients had autoimmune diseases [36]. One death in Hennermann's series was due to SLE-associated renal failure [32].

Development and cognition. Early psychomotor development may appear normal, but intellectual disability has been described in all patients [1]. In patients diagnosed in adulthood, impairment is mild to moderate, with intelligence quotient (IQ) between 60 and 80 and better performance on non-verbal tests [1, 3]. Some authors describe slow progression of impairment, others stabilisation after puberty, and in one study general intelligence, language and visuospatial and adaptive abilities remained stable over two years [1]. Natural history information rests on a limited number of observations [1].

Speech and language. Speech develops late, sometimes only in the second decade, with restricted vocabulary and pronunciation that is difficult to understand, partly because of hearing loss [1, 3]. In a 25-year longitudinal study of a brother and sister, speech ability declined in one but not the other [1].

Motor and neurological system. Walking is somewhat delayed and follow-up suggests progressive motor deterioration with age [1]. Ataxia is the most characteristic motor disturbance: children are described as “clumsy” [1]. Muscular hypotonia is common; communicating hydrocephalus may appear at any age; spastic paraplegia has been described, but spasticity, rigidity and dyskinesia are not usual [1, 21]. In three adult siblings, progressive cerebellar ataxia beginning in late adolescence was the presenting manifestation, with nystagmus, dysarthria and Babinski sign [21]. In the European cohort, 71% of minors and 79% of adults had an abnormal neurological examination, with ataxia in 12 of the minors [29]. Over time, pyramidal involvement may be added to the ataxia, producing a cerebellar-spastic syndrome [9].

Neuroimaging. The most common findings, particularly in untreated patients, are white matter changes compatible with dysmyelination and progressive cortical and cerebellar atrophy, particularly of the vermis [1]. A thin corpus callosum, prominent Virchow-Robin spaces and perioptic CSF, a partially empty sella turcica and T2 hyperintensity of the basal ganglia, thalami, dentate nuclei or cerebellum have also been described [1]. A Portuguese group from Porto described bilateral hyperintensity of the thalami and dentate nuclei as a new presentation of the disease [40]. In adulthood, leukoencephalopathy with a periventricular and posterior pattern is among the presentations that should lead to consideration of the diagnosis [41]. Cranial magnetic resonance imaging (MRI) also shows brachycephaly, a thick calvarium and poor pneumatisation of the sphenoid body [1]. On brain and spinal MRI, the French PNDS adds diploic thickening, a narrow foramen magnum and sometimes cervical syringomyelia; hydrocephalus is typical of the infantile forms and cerebellar atrophy of advanced adult forms [9].

Psychiatric manifestations. These may affect 25% or more of untreated patients, with typical onset between late puberty and early adulthood, as recurrent episodes of limited duration that may require medication; psychosis appears more common in adults [1, 3]. In nine patients with psychiatric symptoms, a physical or psychological stressor preceded rapid development of confusion, delusions, hallucinations, anxiety and frequently depression, with severe loss of function for 3 to 12 weeks, followed by somnolence, asthenia and prolonged sleep; in four of the nine no organic cause was found [1]. In the European cohort, psychological or psychiatric abnormalities increased from 52% to 79% of patients over two years [29]. One death in Hennermann's series was due to dehydration during catatonia [32].

Skeleton. Bone disease ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis [1]. Mild-to-moderate clinical or radiological dysostosis multiplex occurs in 90% of diagnosed patients, with intrafamilial variation and a tendency to become less pronounced with age [1, 3]. Scoliosis and sternal deformity are the most frequent abnormalities, and genu valgum is common and contributes to gait disturbance [1, 3]. Radiographs show a thickened calvarium, ovoid, flattened and hooked vertebral bodies, hypoplasia of the lower portions of the ilia and mild expansion of the short tubular bones of the hands [1]. The skeletal dysplasia atlas illustrates, at 9 years, sclerosis of the skull base and mastoid with a thick calvarium lacking differentiation between tables; at 5 years, flattened vertebral bodies with L1 set back owing to absent anterior ossification; and at 10 months and 12 years, hypoplastic lower ilia, flared wings, shallow acetabula and valgus femoral necks [42]. In the European cohort, musculoskeletal examination was abnormal in 62% of minors and 92% of adults, and in 94% after two years, with macrocephaly, contractures, scoliosis, genu valgum, hip dysplasia and foot deformities [29].

Joints. In the hip, osteoarthritis, dysplasia, subarticular cystic changes in the femoral head and acetabulum with loss of joint space and mild flattening of the femoral head have been described, a degenerative picture with possible ischaemic changes that may lead to joint destruction if not surgically corrected [1, 43]. Destructive synovitis of the knees, bilateral patellar dislocation, synovial hypertrophy, Charcot elbow and bilateral avascular necrosis of the hip and elbow have also been described [3, 21]. The PNDS also lists proximal stiffness of the shoulders and hips, inflammatory arthropathy with deformity or destruction of the knees, hips, elbows and wrists, aseptic osteonecrosis, kyphoscoliosis, beaked vertebrae, carpal tunnel syndrome and slowly progressive spinal cord compression [9].

Growth. Children grow slowly after birth, without an adolescent growth spurt, and final height may be at or below the 3rd centile [1]. In the European cohort of 45 patients, only four children were below −2 standard deviations, and mean adult height was 162 ± 9 cm (145–179) [1, 29]. Some patients have shorter lower limbs with a normal trunk; narrow shoulders and a convex chest are characteristic, and head circumference does not differ from that of peers, although the head tends to be shorter and wider [1]. Two adult women in the European cohort had severe obesity, and hyperphagia has been described [21, 29]. The French PNDS follow-up sheet instructs clinicians to look for growth slowing after a phase of acceleration, a pattern different from the absence of an adolescent spurt described in GeneReviews [1, 9].

Eyes. In a review of 32 patients, tapetoretinal degeneration and optic atrophy appeared frequent, and retinal dystrophy may lead to visual loss [1]. Other findings are hypermetropia (more frequent than myopia), strabismus, lens changes, superficial corneal opacities and poorly defined optic discs, many of them correctable [1, 3]. In the European cohort there was corneal opacity in two patients, cataract in two, near-blindness due to pigmentary retinal degeneration in two (aged 15 and 34 years) and a pale optic disc in one; low vision affected 2/20 minors and 3/23 adults [29]. The PNDS adds glaucoma, which is rare, and photophobia associated with corneal opacities [9]. In the severe form, cataract may be detectable before 1 year, and corneal opacities appear between the end of the first year and 6 years [19, 21].

Digestive system and liver. Gastrointestinal dysfunction is common, with increased stool frequency or diarrhoea; in a 13-year-old boy, HSCT resolved diarrhoea and recurrent infections [1, 22]. Swallowing and aspiration problems occur, and some patients require gastrostomy [1]. Hepatosplenomegaly is frequent in more severely affected untreated patients, with normal or soft liver consistency, usually normal liver function and hepatocyte vacuoles on biopsy [1, 19]. Dental caries are frequent because of poor tooth quality, bruxism and reflux [3].

Heart. Cardiac involvement is more frequent in adults: aortic regurgitation or stenosis and mitral stenosis or regurgitation appear more common than in the general population and may require surgery, and some patients have dilated cardiomyopathy [1]. Ventricular extrasystoles and a short PR interval have been described [21]. In the European cohort, the cardiovascular examination was abnormal in 24% of minors and 17% of adults, mainly murmurs, and five echocardiograms showed valvular insufficiency or reduced ejection fraction [29]. The French PNDS follow-up sheet also includes hypertrophic cardiomyopathy [9].

Lungs. In a series of five patients, computed tomography (CT) showed parenchymal lung disease in three, and pulmonary function tests were abnormal in all five, with an obstructive or restrictive pattern and air trapping [1]. In the European cohort, FVC ranged from 30% to 90% of predicted, and no patient needed nocturnal ventilation [29]. The French PNDS distinguishes an obstructive component, linked to tracheal, laryngeal and bronchial infiltration with hyperreactivity and sometimes severe asthma, a restrictive component and sleep apnoeas, both obstructive and central; laryngotracheal lesions (malacia, stenosis, compression) may be poorly symptomatic at rest in adults, and the adult chest radiograph is examined for ground-glass opacities [9].

Kidney. End-stage chronic renal failure has been described once, in an Italian patient who underwent kidney transplantation [3].

Blood. Lymphocytes are vacuolated in all types, polymorphonuclear cells may be vacuolated, and marrow contains foamy macrophages [21].

3.5 Natural history cohorts and quality of life

The European longitudinal HUE-MAN study (NCT00498420; Mainz, Tromsø, Manchester and Prague) screened 45 non-transplanted patients with mild disease (31 males and 14 females, 1.4–42.1 years, mean 19.8; 22 minors and 23 adults), of whom 43 completed two years [29]. Distance in the 6-minute walk test (6MWT) was 341.1 ± 104.9 m in minors and 324.7 ± 118.1 m in adults, corresponding to 50–60% and 40–45% of predicted; the 3-minute stair climb test (3MSCT) yielded 141 ± 30 steps in minors and 100 ± 58 in adults [29]. FVC in minors fell from 71% to 61% of predicted over two years, without statistical significance [29]. Urinary oligosaccharides correlated with the 6MWT (r=0.616; p=0.0014) and 3MSCT (r=0.568; p=0.0072), and functional ability questionnaires showed high dependence on others and more pain in adults [29].

A Norwegian retrospective study initiated in 1991 through ISMRD obtained questionnaires for 125 patients (64% of those contacted), 45 aged 15 years or older, and described the course of facial dysmorphism, spinal cord disease, arthritis, myopathy, hearing loss, intellectual impairment, psychosis, bone disease and motor function [44]. In a UK survey of nine patients aged 7 to 37 years, five walked unaided, one with assistance, one was wheelchair-dependent and two were severely immobile; quality of life was worse in those with less mobility, and caregivers had high levels of stress and anxiety [45]. In an international survey (51 responses from 18 countries, patients aged 10 years or older), self-reported mobility change over five years, on a scale where positive values indicate worsening, was +1.8 ± 2.0 in untreated patients, +0.7 ± 1.2 during ERT and +0.1 ± 1.9 after HSCT, and self-care worsened in untreated patients (+0.6 ± 0.9) and improved in treated patients [46].

3.6 Mortality and causes of death

Hennermann and colleagues surveyed 78 clinicians from 70 centres in 21 countries and 34 patient organisations in 31 countries between April and May 2021 about deaths in patients never treated with HSCT or ERT [32]. They obtained 15 deaths with age and cause (Germany 6, Norway 2, USA 2, France/Réunion, Italy, the Netherlands, New Zealand and the United Kingdom one each), with median age at death of 45 years and mean age of 40.3 ± 13.2 years (18–56); 14 of the 15 died aged 20 years or older, four in the fifth decade and four aged 50 years or older [32]. GeneReviews presents both values as if both were means; in the article, 45 years is the median and 40.3 years the mean [1, 32]. Pneumonia caused 7/15 deaths (46.7%; median 49 years) and cancer 3/15 (20%: colon carcinoma, breast cancer and leukaemia; median 39 years); the remaining causes were sepsis after intestinal perforation with acute renal failure at 27 years, anaemia of unknown cause, renal failure with SLE, aortic insufficiency with heart failure, and dehydration due to catatonia [32]. Four additional deaths from HSCT complications were excluded from this analysis [32]. The sample is small and subject to reporting bias, and does not allow estimation of life expectancy in the patient population [32].

3.7 Treated disease

During ERT, serum oligosaccharides fall, IgG rises and infections decrease, and functional gains are greater in children; ERT does not cross the blood–brain barrier and does not alter cognitive impairment or established skeletal deformities [12, 33, 47]. After HSCT, no patient in the series of 17 achieved age-typical development, but all progressed and retained acquired skills, and expressive speech and hearing impairment remained the most relevant problems [1, 23]. The long-term prognosis of patients treated early is not yet known; efficacy data are presented in section 7 [1].

4. Clinical Recognition and Warning Signs

4.1 Diagnostic delay

Diagnosis is frequently delayed because early signs (hearing loss, otitis, respiratory infections, speech delay) are common in the paediatric population and facial features may be subtle [1, 48]. In a series of 25 patients diagnosed at 16 years or older, at 11 centres in 7 countries, mean delay between the first sign and diagnosis was 26.8 years (10–46) in mild disease and 19.7 years (14–30) in moderate-to-severe disease; the first sign was hearing loss in mild cases and learning or communication difficulty in moderate-to-severe cases, and the latter was the sign most often leading to diagnosis [10]. In an Iraqi series of nine children from five consanguineous families, symptoms began at 1.1 ± 0.5 years and diagnosis occurred at 10.7 ± 7.6 years [37]. In the United Arab Emirates, mean age at diagnosis was 14 years in adults and 2 years in paediatric patients [36]. Hennermann and colleagues report delays exceeding 10 years in some patients [32]. A review on this topic proposes registries, validated algorithms, screening tools, professional education and collaboration with patient organisations, and emphasises that ERT effects are greater in children [48].

4.2 When to suspect the disease: age-based algorithm

The 2019 international working group algorithm separates two age groups [11]. Up to 10 years, hearing loss and/or speech delay are the cardinal signs that should prompt a search for additional signs, such as recurrent infections, coarse facial features, macrocephaly, skeletal abnormalities, hypotonia or ataxia [1, 11]. After 10 years, the signs that should lead to diagnosis are intellectual disability, progression of motor impairment and/or psychiatric manifestations [11]. Lehalle and colleagues described seven French patients from four families, diagnosed between 3 and 23 years, all referred for syndromic hearing loss with moderate learning difficulties; five were diagnosed by exome sequencing, and the authors consider alpha-mannosidosis probably underdiagnosed as a cause of syndromic hearing loss [49].

The 2024 French PNDS (National Diagnosis and Care Protocol) converts these signs into criteria for referral by the attending physician to paediatric neurology, neurology, metabolic diseases or genetics: in the infant or child, hearing loss associated with at least one of the following: recurrent infections, IgG deficiency, macrocephaly or dysmorphism, balance and coordination disturbances or school difficulties; in the adolescent or adult, mild to moderate cognitive impairment associated with hearing loss, psychiatric disturbances, osteoarticular problems or dysmorphism, even if subtle [9]. Confirmation and disclosure of the diagnosis are the responsibility of a paediatric neurologist, neurologist, metabolic disease specialist or geneticist familiar with the disease [9].

GeneReviews lists macrocephaly with progressive coarse facial features, sensorineural or mixed hearing loss, frequent infections, developmental delay or intellectual disability, and ataxia as suggestive, together with dysostosis multiplex, lytic or sclerotic bone lesions, osteonecrosis or osteopenia on radiographs, mannose-rich urinary oligosaccharides, vacuolated peripheral blood lymphocytes, and a family history compatible with autosomal recessive inheritance; absence of vacuolated lymphocytes or family history does not exclude the diagnosis [1].

4.3 Clinical settings that should lead to diagnosis

Saudubray's adult tables distinguish the classic childhood presentation (intellectual disability, deafness, upper respiratory infections, dysmorphic features) from adult-onset forms with episodes of psychosis, confusion, cerebellar ataxia and posterior leukoencephalopathy [41]. When investigating cataract, association with coarse facial features and macroglossia should suggest alpha-mannosidosis [20]. Sensorineural deafness in alpha-mannosidosis is detectable in infancy and early childhood, whereas that of beta-mannosidosis appears from late childhood to adolescence [19]. Coarse facial features begin in infancy or early childhood and are not present at birth, unlike galactosialidosis, I-cell disease, GM1 gangliosidosis, sialidosis type 2 and MPS VII [19].

4.4 Warning signs and urgent situations

4.5 Newborn screening

No newborn screening programme included alpha-mannosidosis in the sources consulted [1, 14]. Most affected individuals are clinically normal at birth, and availability of ERT and HSCT, whose outcomes are better when treatment starts early, led GeneReviews to emphasise the need for neonatal identification before irreversible pathology develops [1]. A preprint published on medRxiv on 22 September 2026, not yet peer-reviewed, described quantification of Man2GlcNAc (equivalent to GlcNAc(Man)2) in dried blood spots by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS): 420 controls had 0.1–0.8 µmol/L and 27 untreated patients 3.2–11.3 µmol/L, without overlap, and stored newborn screening samples from five subsequently confirmed patients had 7.7–11.3 µmol/L [14]. These data indicate a candidate biomarker, not a validated programme; positive predictive value and specificity at population scale were not studied [14].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

The diagnosis is established in a proband with suggestive findings by demonstration of deficient lysosomal acid alpha-mannosidase activity in leucocytes or other nucleated cells and/or by identification of biallelic pathogenic or likely pathogenic variants in MAN2B1 [1]. The criterion is disjunctive: documented enzyme deficiency is sufficient for the diagnosis, and negative sequencing in the presence of deficient enzyme should prompt a search for deletions and duplications rather than abandonment of the diagnosis [1, 2]. Isolated clinical findings are not enough, because of the overlap with other storage diseases [1]. The Delphi consensus recommends genetic testing for confirmation in all patients (statement G1, 100% agreement), while recognising that the diagnosis can be made without it [4]. Pathogenic and likely pathogenic variants have the same clinical value, according to the classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); two variants of uncertain significance (VUS), or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [1]. The 2024 French PNDS (National Diagnosis and Care Protocol) bases confirmation on deficient leucocyte alpha-mannosidase activity (or in fibroblasts or chorionic or amniotic cells) accompanied by abnormal urinary excretion of mannose-rich oligosaccharides, and uses MAN2B1 sequencing to identify the variants in the biallelic state; when the diagnosis arises from next-generation sequencing, it must be confirmed by measurement of enzyme activity, and molecular study of the parents is considered indispensable to establish allele segregation and confirm the genotype [9]. This requirement for functional confirmation differs from the disjunctive criterion of GeneReviews, in which biallelic pathogenic or likely pathogenic variants are sufficient [1, 9].

5.2 Testing algorithm

The 2019 international algorithm proposes as initial screening the testing of oligosaccharides in urine (historically) or serum, accepts enzyme activity as first choice in some centres and reserves molecular testing for final confirmation [11]. GeneReviews describes two pathways [1]. When the phenotype suggests the diagnosis, alpha-mannosidase activity should be measured before single-gene testing; MAN2B1 sequencing is the first molecular step, and if only one variant or none is found, targeted deletion and duplication analysis follows; a multigene LSD panel including MAN2B1 is an alternative, with the risk of VUS and of findings that do not explain the phenotype; if only VUS are found, enzyme activity is measured in leucocytes [1]. When the phenotype is atypical and the diagnosis has not been considered, the usual pathway is exome or genome sequencing [1]. In the French pathway, urinary oligosaccharides may guide testing before the enzyme assay, activity can be measured in leucocytes, dried blood spots or cultured fibroblasts, biochemical tests are performed in a reference medical biology laboratory, and sequencing is usually performed with next-generation sequencing panels dedicated to lysosomal diseases or to other indications (hearing loss, intellectual disability), more rarely by exome or genome [9].

5.3 Enzyme activity

Acid alpha-mannosidase activity is measured by a fluorimetric assay at a pH close to 4 using the substrate 4-methylumbelliferyl-alpha-D-mannopyranoside, in leucocytes or nucleated cells [3]. In affected individuals it is 5–10% of normal according to GeneReviews and 5–15% according to Malm and Nilssen, and low but non-zero activity is the expected finding and does not exclude the diagnosis [1–3]. Leucocytes tend to yield lower values than fibroblasts, but either tissue allows diagnosis; plasma measurement was used in the past and is unreliable [21]. In clinical trials, activity in enrolled patients was below 10–11% of normal, ranging from 8 to 29 µmol/h/mg [13]. Carrier activity is around 40–60% of normal and overlaps with that of non-carriers, so enzyme measurement is unsuitable for carrier detection [1, 3].

5.4 Oligosaccharides

Thin-layer chromatography (TLC) with orcinol staining gives a diagnostic pattern in fucosidosis, mannosidosis, sialidosis and aspartylglucosaminuria [50]. In alpha-mannosidosis, several mannosyl oligosaccharides appear, predominantly the trisaccharide Man-alpha(1,3)Man-beta(1,4)GlcNAc [21]. TLC is not always available and may miss cases: in the mildly affected patient described in the Atlas, bands were visible only with twenty-fold concentrated urine [18, 21]. Tandem mass spectrometry improves sensitivity [18].

In 2026, a quantitative UPLC-MS/MS method without derivatisation was published for GlcNAc(Man)2, GlcNAc(Man)3 and GlcNAc(Man)4 in spot urine, validated in 208 controls, 20 patients and 26 patients with other LSDs [51]. Separation was complete: controls had 0.0–9.0 and patients 39.4–99.3 µmol GlcNAc(Man)2 per mmol creatinine, and values distinguished untreated patients from those receiving ERT or after HSCT [51]. In serum, oligosaccharides measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) serve mainly for monitoring; the normal GlcNAc(Man)2 range is not well established, but clinical experience suggests values below 1 µmol/L, and trial patients had baseline values of 6–8 µmol/L [13, 31, 47]. The natural history cohort, using another method, recorded serum values of 7.16–82.45 nmol/mL [29]. Values depend on the laboratory and method and are not interchangeable.

5.5 Molecular testing and its limitations

A negative molecular result does not exclude the disease when the enzyme is deficient, and a result with VUS requires enzyme assay [1, 2]. If a variant is found in only one parent, with confirmed parentage, a de novo variant in the proband, post-zygotic mosaicism in a parent and uniparental isodisomy should be considered [1]. In the series of patients diagnosed in adulthood, genetic confirmation was obtained in 90% [10]. The French PNDS counts more than 180 pathogenic variants in MAN2B1, about one hundred of them point variants [9].

The molecular report should identify the gene, reference transcript with version (NM_000528.4), HGVS nomenclature at complementary DNA and protein levels, zygosity, ACMG/AMP classification of each variant and, when investigated, trans phase demonstrated through the parents [1, 6]. Reports using the previous transcript NM_000528.3 should be reconverted before comparison with databases [6].

5.6 Additional characterisation investigations

Radiographs of the skull, spine (lateral), knees (anteroposterior) and symptomatic sites document dysostosis multiplex and lytic lesions, and densitometry (DXA) assesses osteopenia [1]. Brain MRI documents white matter abnormalities, cerebellar atrophy and hydrocephalus; the consensus leaves the choice between MRI and CT to the clinical situation, age and availability [1, 4]. Pure-tone audiometry, or brainstem auditory evoked potentials (BAEPs) when the child cannot cooperate, characterises hearing loss [3]. Serum immunoglobulins, antinuclear and anti-double-stranded DNA antibodies complete the immunological assessment [1].

5.7 Prenatal and preimplantation diagnosis

When both familial variants are known, prenatal diagnosis is performed by molecular testing of chorionic villi (10–12 weeks) or amniocytes (15–18 weeks), and preimplantation genetic testing (PGT) is possible [1, 3]. When the variants are not known, enzyme activity is measured in fetal cells; normal activity in villi may be considerably lower than in amniocytes, and interpretation must take into account the residual activity of other mannosidases [1, 21]. It is therefore preferable to identify the parental variants before pregnancy [3]. Severity cannot be predicted from fetal molecular or biochemical results [1]. The French PNDS places chorionic villus sampling at 11–13 weeks of gestation and amniocentesis at 15–17 weeks of gestation, with testing for the parental variants in fetal DNA (villi or fresh or cultured amniocytes), possibly supplemented by enzyme activity [9]; the 10–12 and 15–18 week windows of the other sources do not state the dating convention and in practice essentially coincide [1, 3].

6. Differential Diagnosis

6.1 Principles

The main features of alpha-mannosidosis (intellectual disability, ataxia, coarse facial features, dysostosis multiplex) overlap with other LSDs, particularly MPS I and II, and differentiation relies on each disease's specific features, biochemical tests and natural history [1]. Dysostosis multiplex is a radiological pattern common to MPS, oligosaccharidoses and glycoproteinoses: it indicates defective degradation of complex carbohydrates but does not identify the disease, and grading as severe, moderate or mild provides guidance without replacing clinical, laboratory and molecular diagnosis [42]. Its major findings include macrocephaly, a J-shaped sella and thickened calvarium; paddle-shaped ribs, broad clavicles and thick scapulae; ovoid and hooked vertebral bodies; excessive constriction of iliac bodies with flared wings, femoral epiphyseal dysplasia and coxa valga; irregular diaphyseal modelling and submetaphyseal constriction of long bones; proximal tapering of metacarpals 2 to 5; and osteoporosis with coarse trabeculation [42]. In alpha-mannosidosis, dysostosis is usually mild to moderate [1]. In a normal-consistency or soft liver with splenomegaly, association with coarse facial features, skeletal abnormalities, joint stiffness, ocular symptoms, vacuolated lymphocytes and neurological deterioration suggests an oligosaccharidosis or MPS [19].

6.2 Comparative table

In the table, AR denotes autosomal recessive and AD autosomal dominant inheritance.

6.3 Main differential diagnoses

Beta-mannosidosis. This is the deficiency of beta-mannosidase, encoded by MANBA (OMIM 248510; ORPHA:118, prevalence unknown), much less frequent than alpha-mannosidosis [2, 18]. It was first described in goats with severe neurodegeneration; in humans severity is variable and may be mild [21]. Published examples include a 44-year-old man with intellectual disability and genital angiokeratomas, consanguineous Turkish siblings with deafness and speech delay, an 18-year-old with bilateral hearing loss, mild cognitive impairment and symptoms of Tourette syndrome, progressive spinocerebellar ataxia, and neonatal seizures with communicating hydrocephalus [21]. Severe intellectual disability, challenging behaviour, deafness and frequent infections are relatively common [18]. Angiokeratomas and demyelinating peripheral neuropathy point to beta-mannosidosis rather than alpha-mannosidosis [19, 41]. MANBA variants are frequently null, and the stored disaccharide is among the smallest in the LSDs [21]. The Oxford skeletal dysplasia table groups the two diseases under “mannosidosis” with the MANBA and MAN2B1 genes, which makes it necessary to specify the enzyme in the laboratory request [30]. HSCT in beta-mannosidosis has been described in fewer than five cases, with a poor result in the only symptomatic patient [18]. The French PNDS (National Diagnosis and Care Protocol) counts fewer than 20 published patients, describes isolated language delay or intellectual disability, hearing loss, dysmorphism and respiratory and skin infections, with more marked neurological signs in the severe infantile forms (early psychomotor delay, spastic tetraparesis, epilepsy), urinary excretion of mannosyl(1-4)N-acetylglucosamine and markedly reduced beta-mannosidase activity, states that prenatal diagnosis is possible and accepts discussing HSCT in the attenuated forms; this position differs from the unfavourable experience reported by Saudubray, which rests on very few cases [9, 18].

Mucopolysaccharidoses. Coarse facial features and dysostosis multiplex make alpha-mannosidosis resemble MPS I (Hurler), with which Öckerman compared the first patient [1, 21]. Short stature and contractures predominate in MPS, and urinary glycosaminoglycans are increased; in alpha-mannosidosis, glycosaminoglycans are normal and urinary excess consists of oligosaccharides [1, 39].

Mucolipidoses and related glycoproteinoses. Fucosidosis lacks the typical facial dysmorphism and has variable neurodegeneration with seizures, mild dysostosis and extensive angiokeratomas [18]. Aspartylglucosaminuria is distinguished by joint laxity and multiple sulfatase deficiency by ichthyosis [19]. Mucolipidosis II, galactosialidosis, GM1 gangliosidosis, sialidosis type 2 and MPS VII may have coarse facial features from birth, unlike alpha-mannosidosis [19].

Adult with a neuropsychiatric presentation. In an adult with mild intellectual disability, cerebellar ataxia, leukoencephalopathy, psychotic episodes and deafness, alpha-mannosidosis is part of the differential diagnosis of inborn errors of metabolism with neurological and psychiatric presentations, and urinary oligosaccharide testing and leucocyte enzyme activity allow differentiation [1, 41].

Syndromic hearing loss. In a child with hearing loss, speech delay and learning difficulties, particularly with recurrent otitis, subtly coarse facies or hypotonia, alpha-mannosidosis should be considered before attributing the hearing loss to non-syndromic causes [11, 49]. The French PNDS places intellectual disabilities with hearing loss at the head of the differential diagnosis, followed, when there are signs of storage, by the MPS, the mucolipidoses, beta-mannosidosis and the other glycoproteinoses (fucosidosis, sialidosis, aspartylglucosaminuria) [9].

7. Treatments and Risk Management Strategies

7.1 General principles

There is no cure for alpha-mannosidosis [1]. Management rests on three components: defect-directed therapy (ERT with velmanase alfa or HSCT), supportive treatment for each manifestation, and coordination by a long-term multidisciplinary team at a specialist centre, with access to otorhinolaryngological, orthopaedic and neurosurgical procedures and palliative care when required [4, 18]. The 2024 Delphi consensus obtained 100% agreement on the need for a long-term multidisciplinary team (IC1), 95% for involvement of other specialists in acute care (IC2), and 90% for access to a multidisciplinary clinic and social worker (IC3) [4]. ERT does not cross the blood–brain barrier and does not correct irreversible complications (skeletal deformities, dysostosis multiplex, neurological manifestations and cognitive impairment); HSCT is the only option directed at CNS manifestations, and its outcomes depend on age at transplantation [1, 12].

The French PNDS (National Diagnosis and Care Protocol) sets three objectives: to improve or slow the multisystem course, to improve quality of life and social, educational or occupational integration, and to inform the patient and family about the disease, its complications and treatment [9]. Initial assessment and follow-up are coordinated by a hospital physician at a reference or competence centre for inherited metabolic diseases, lysosomal diseases or constitutional bone diseases; the paediatrician coordinates in children and, in adults, the internist, rheumatologist, neurologist or physical and rehabilitation medicine specialist, with about twenty specialties depending on the manifestations and with hearing-aid specialists, occupational therapists, physiotherapists, neuropsychologists, speech and language therapists, orthotists and prosthetists, psychologists, psychomotor therapists and social workers [9].

7.2 Initial assessment after diagnosis

GeneReviews recommends, based on the consensus, baseline assessment by system, and the Delphi panel listed 15 baseline assessments in children and adults (BL1 and BL2), to be individualised according to severity (BL3, 100%) [1, 4].

7.3 Enzyme replacement therapy: velmanase alfa

Identification and mechanism. Velmanase alfa (Lamzede®; velmanase alfa-tycv in the USA) is a recombinant human alpha-mannosidase produced in Chinese hamster ovary (CHO) cells, approximately 130 kDa, with a sequence identical to the human enzyme [13]. It is taken up by cells through mannose receptors and degrades oligosaccharides accumulated in peripheral tissues [12]. Its Anatomical Therapeutic Chemical (ATC) classification code is A16AB15 [12].

Presentation. A single-dose vial containing 10 mg lyophilised powder, reconstituted with 5 mL water for injections to give 2 mg/mL; excipients are disodium phosphate, glycine, mannitol and monosodium phosphate [13]. The number of vials is rounded upwards, the vial is neither shaken nor inverted, and proteinaceous filaments are retained by a low-protein-binding in-line filter (0.2 µm in the US label; 0.22 µm in the EU label) [12, 13]. The reconstituted solution may be stored for up to 24 hours at 2–8 °C, including infusion time, and must be infused within 10 hours of removal from the refrigerator; at completion, the line is flushed with 10 mL 0.9% sodium chloride [13].

Dose and posology. The dose is 1 mg/kg of actual body weight, once weekly, by intravenous infusion at a controlled rate, using a pump [12, 13, 52]. This dose resulted from rounding the 25 U/kg (0.8 mg/kg) studied in phases I and II [28]. There is no adjustment for renal or hepatic impairment or for paediatric age, and there are no data in the elderly; the European summary of product characteristics (SmPC) notes that no patient older than 41 years had been identified in Europe at the time of assessment [12]. A missed dose is given as soon as possible if 3 or more days remain until the next one; if fewer than 3 days remain, only the next scheduled dose is given [13]. The European SmPC recommends periodically assessing the effect and considering discontinuation if there is no clear benefit [12]. Neither label defines a maximum dose [12, 13]. The highest dose used in clinical studies was a single administration of 100 U/kg (about 3.2 mg/kg), with mild fever lasting 5 hours in one patient, and there is no experience of overdose [12].

Infusion rate and duration. In the USA, infusion lasts at least 60 minutes in patients weighing up to 49 kg, and from 50 kg the maximum rate is 25 mL/h to control the protein load [13]. In the EU, the maximum rate is 25 mL/h and minimum duration 50 minutes, with a slower rate initially and after reactions; the patient remains under observation for at least 1 hour after infusion [12]. The European SmPC table gives examples: 10 kg, 5 mL at 6 mL/h over 50 minutes; 20 kg, 10 mL at 12 mL/h over 50 minutes; 42 kg, 21 mL at 25 mL/h over 50 minutes; 50 kg, 25 mL at 25 mL/h over 60 minutes; 70 kg, 35 mL over 84 minutes; 99 kg, 49.5 mL over 119 minutes [12]. In children weighing less than 18 kg (volume below 9 mL), the rate is adjusted so that infusion lasts at least 50 minutes [12]. GeneReviews reproduces the rule of 60 minutes below 49 kg and 25 mL/h above 50 kg without mentioning the interval between 49 and 50 kg; the US label uses the same wording [1, 13].

Home infusion. It may be considered in the EU in patients who tolerate infusions well, after medical assessment and training, with the same dose and rate as in hospital [12]. In France, ERT is initiated at a reference or competence centre; the first infusions are given in hospital, via a peripheral vein or an implantable port, and since June 2024 velmanase alfa has also been dispensed by community pharmacies (rétrocession), which allows home infusions by nurses supported by a service provider [9]. The PNDS accepts home infusion only after 3 to 6 months of hospital administration, without IARs in the previous 2 to 8 weeks and without major pulmonary or obstructive involvement (vital capacity below 40%), under a strict protocol; the European SmPC does not set these time frames [9, 12].

Position of the French PNDS on efficacy and discontinuation. The PNDS maintains the SmPC dose of 1 mg/kg weekly, with no maximum dose defined, considers that ERT is more effective the earlier it starts, before 18 years and especially before 6, and lists as effects the fall in serum oligosaccharides and improvement in immunity, functional and physical capacity and, sometimes, hearing, neurodevelopment, social skills and quality of life, with no direct effect on the CNS [9]. It accepts discussing discontinuation in the event of severe neurological progression, less benefit than expected or excessive infusion risk, for example IARs poorly controlled with antihistamines and corticosteroids, with a collegial decision by the CETMPS-GP [9].

Premedication and reaction management. The US label recommends considering premedication with antihistamines, antipyretics and/or corticosteroids [13]. The European SmPC states that most trial patients did not receive routine premedication and that pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions [12]. For a mild or moderate reaction, infusion is suspended for 15–30 minutes, the rate reduced to 25–50%, and treatment given; if the reaction persists, infusion is stopped and, if it continues, discontinued, with consideration of restarting 7 to 14 days later at 25–50% of the rate with premedication; if it resolves, infusion resumes at 25–50% and increases in 25% increments to the recommended rate [13]. For a severe reaction, infusion stops immediately, resuscitation equipment must be available, and desensitisation may be considered [13]. Anaphylaxis should be suspected with angioedema, upper airway obstruction or hypotension, and anti-velmanase antibodies should be tested for in severe reactions or loss of effect [12].

The French PNDS adds that the risk of IAR is greatest between the 6th and 15th infusions, although it may arise after months or years, and that it increases with intercurrent infection, particularly respiratory, and with a history of allergy, so it advises against infusing in the presence of fever; premedication with paracetamol, an antihistamine and/or a corticosteroid should be discussed for infusions following an IAR [9]. Annex 3 of the PNDS grades the management: in mild reactions (peripheral tingling, warmth, lacrimation, nasal congestion, sneezing, mild nausea, slight urticaria or pruritus) the rate is reduced by 50% and, when symptoms subside, the previous rate is resumed, increasing it by 50% for 15–30 minutes before continuing the escalation schedule; in moderate reactions (urticaria, local oedema, generalised pruritus, severe nausea or vomiting, tachycardia of 125–140/min, hypertension, chills, anxiety, mild dyspnoea, cough or asthma) the rate is reduced by 50%, an antihistamine is given and at least 30 minutes are allowed before deciding whether to stop the infusion that day; in severe reactions (bronchospasm, angioedema, tachycardia above 140/min, arrhythmia, hypotension, severe dyspnoea, collapse) the infusion is stopped immediately and intramuscular adrenaline is given, with an inhaled beta-2 agonist, intravenous corticosteroid, oxygen, fluid and electrolyte management and resuscitation if necessary [9]. The diagnosis of anaphylaxis follows the Sampson criteria of the 2016 French emergency medicine recommendations, which the PNDS reproduces [9].

Doses in the French PNDS for the treatment and prevention of IARs (names and brand names in France):

The PNDS gives an explicit maximum only for intramuscular adrenaline (0.5 mg per dose), paediatric hydroxyzine (50 mg), prednisolone (50 mg) and paediatric hydrocortisone (1.5 mg/kg); for the weight-based doses of dexchlorpheniramine, methylprednisolone, paracetamol and ibuprofen it gives no maximum or daily limit, which follow the SmPC of each medicine in the respective jurisdiction [9].

The PNDS table designates the first regimen as standard premedication for all patients, whereas the text of the PNDS itself calls for premedication to be discussed after an IAR, the European SmPC states that most trial patients did not receive routine premedication and the US label only asks for it to be considered [9, 12, 13]. The rechallenge schedule after a reaction also differs: the PNDS reduces the rate by 50% and increases it again in 50% steps, and the US label reduces it to 25–50% and increases it in 25% increments [9, 13]. Ibuprofen is among the French premedication options; the only case of acute kidney injury on velmanase occurred with high-dose, prolonged ibuprofen (600 mg/day), an exposure different from a single dose before infusion [13, 33].

Adverse effects. The US label carries a boxed warning on severe hypersensitivity reactions, including anaphylaxis [13]. Among the 38 patients treated in trials, hypersensitivity reactions occurred in 19 (50%; 5 adults and 14 children), anaphylaxis in 2 (5%; one adult and one child), and severe hypersensitivity requiring treatment in another 3 children (8%); four of the five patients with anaphylaxis or severe hypersensitivity had antidrug antibodies (ADA) [13]. Infusion-associated reactions (IARs) occurred in 19/38 patients (50%; 3 adults and 16 children), 5 required premedication and 1 discontinued because of recurrent IARs; the most frequent symptoms were fever, chills, erythema, vomiting, cough, urticaria, rash and conjunctivitis [13]. Overall hypersensitivity affected 36% of adults and 58% of children, and IARs occurred in 80% of patients with ADA and 20% without ADA [13]. The European SmPC, using a different definition, records IARs in 13% (5/38), weight gain in 15%, diarrhoea in 10%, and headache and arthralgia in 7% [12]. Frequency differences between the two labels reflect different case definitions, not different populations [12, 13].

Among serious adverse reactions, one patient developed moderate acute renal failure after approximately 12 months while taking prolonged high-dose ibuprofen (600 mg/day), with a 4-week interruption and resolution in approximately 3 months, subsequently resuming treatment; another had loss of consciousness for 2–3 minutes 8 days after an infusion, with a later diagnosis of epilepsy; another had chills and hyperthermia [12, 13, 33]. There was also one case of IgA vasculitis (Henoch–Schönlein purpura) with high ADA, and one patient with seizures without a previous history, in whom a drug relationship was not excluded [13]. Postmarketing reporting outside the USA included aortic valve insufficiency, palpitations, tachycardia, deafness, endocarditis, staphylococcal infections, ataxia, somnolence, psychotic disorder, agitation, angioedema, pharyngeal oedema and hypotension, without established causality [13]. The maximum dose studied was a single dose of 100 U/kg (approximately 3.2 mg/kg), causing mild fever for 5 hours in one patient [12].

Immunogenicity. In the European SmPC, 8/33 patients (24%) in the phase I to III studies had anti-velmanase IgG, and in children under 6 years 4/5 (80%), with a more sensitive and non-comparable method; no clear correlation was found between titres and efficacy or anaphylaxis [12]. In the integrated analysis of 33 patients, 10 (30.3%) had ADA at some point: five were already positive before treatment, with low titres and possible cross-reactivity, one only on placebo and four developed ADA on treatment [38]. Two patients with high titres (1012 and 440 U/mL) had controlled mild to moderate IARs; patients with low titres did not [33, 38]. The fall in serum oligosaccharides was 45.8% in patients with ADA and 70.1% in those without ADA (p=0.05), a difference that disappeared when any one of three influential patients was removed; IgG, 3MSCT and 6MWT were similar [38]. The US label states that ADA were associated with lower plasma concentrations and that two children with high titres had a smaller reduction in oligosaccharides [13]. GeneReviews summarises that, with up to 48 months of treatment, 4/33 patients (12%) developed treatment-related ADA, with similar functional outcomes regardless of genotype or ADA status [1]. The French PNDS considers that ADA titres are not accompanied by a significant loss of biological efficacy or by functional deterioration and that the effect of neutralising antibodies has not been studied [9].

Pharmacokinetics. In adults at steady state, maximum concentration is approximately 8 µg/mL after 1.8 hours, distribution volume 0.27 L/kg, clearance 5.7–6.7 mL/h/kg and terminal half-life approximately 30–34 hours, with linear kinetics between 0.8 and 3.2 mg/kg; exposure in children aged 3 to 17 years is lower (area under the curve 75.9–109.8 µg·h/mL, versus 159.8 in adults) [12, 13].

7.4 Regulatory status

Health technology assessment agencies differ on access. The National Institute for Health and Care Excellence (NICE; England, HST29, 13-12-2023) recommends velmanase alfa for non-neurological manifestations of the mild to moderate form only if treatment starts before 18 years of age, with the possibility of continuing beyond that age, subject to a commercial arrangement; the decision is based on benefits in walking, stair climbing, lung capacity and quality of life, of very uncertain magnitude [53]. In France, the Commission de la Transparence of the Haute Autorité de Santé (HAS) issued on 11-12-2024 a favourable opinion on reimbursement in outpatient care and on continued hospital listing, with an important actual clinical benefit and a minor improvement in actual clinical benefit (ASMR IV) [54]. The December 2024 PNDS confirms that velmanase alfa is authorised and reimbursed in France, dispensed by hospital pharmacies and, since June 2024, also through rétrocession in community pharmacies [9]. In Spain, according to a 2026 case report, velmanase alfa has recently become funded by the public health system [39]. The sources consulted do not include data on assessment or access in Portugal (INFARMED) or Brazil (ANVISA and CONITEC).

7.5 Velmanase alfa clinical trials

The development programme included phase I rhLAMAN-02 (NCT01268358), phase II rhLAMAN-03/-04 (NCT01285700/NCT01681940), phase III rhLAMAN-05 (NCT01681953), open-label follow-up rhLAMAN-07 (NCT01908712) and rhLAMAN-09 (NCT01908725), the integrated analysis rhLAMAN-10 (NCT02478840), and the paediatric study rhLAMAN-08 (NCT02998879) [28, 47]. Development was initiated by Zymenex with funding from the European ALPHA-MAN project and continued by Chiesi [28].

In the phase III trial, mean serum oligosaccharide reduction at 52 weeks was 77.6% with velmanase and 24.1% with placebo; baseline values were 6.8 and 6.6 µmol/L [13, 28]. The 3MSCT effect did not reach statistical significance; the prespecified efficacy definition required a significant oligosaccharide reduction (p<0.025) with a trend towards improvement in the 3MSCT and one secondary outcome [28]. The placebo arm had better baseline performance: 40.0% of placebo patients and 13.3% of treated patients climbed 65 or more steps per minute and walked 500 m or more [28]. By age, treated patients under 18 years improved the 3MSCT by 3.5 steps/min (placebo −2.3), 6MWT by 12.3 m (placebo +3.6), and FVC by 14.2 points (placebo +8.0), while adults stabilised; age was the only identified predictor of response [12, 28]. In the responder analysis using a minimal clinically important difference, 87.9% of long-term patients responded in at least two domains [12].

In the integrated analysis, paediatric patients with 48 months of treatment improved the 3MSCT by 17.1 steps/min (n=9; +39.1%), with similar gains below 12 years and between 12 and 17 years, not explained by growth alone; FVC increased by 0.6 L (+28.4%), the BOT-2 scale by 13%, and four of five children and three of five adults using walking aids became independent of them [33]. CSF biomarkers did not change significantly [33]. In follow-up up to 12 years, hearing remained mostly stable, IgG normalised in three previously untreated children (+84.3% at 2.25 years), and oligosaccharides rose again in three patients, two after interruptions exceeding one year during the pandemic and one with ADA [47]. Long-term safety recorded 697 adverse events in 20 of 21 patients, 32 treatment-related in 8 patients, and 23 serious events in 8 patients (three related: diarrhoea, hypokalaemia and vomiting, resolved within 1 day or less), with no deaths or discontinuations due to adverse events; one child with multiple IARs withdrew consent after more than 5 years [47]. In the study in children under 6 years, one child had severe IARs (chills and hyperthermia, with overnight admission) approximately 10 months after ADA detection, and another had recurrent urticaria controlled with cetirizine; both began corticosteroid and antihistamine prophylaxis, and neither stopped treatment [31].

Evidence limitations. The only controlled trial included 25 European patients with mild-to-moderate disease, without a formal sample-size calculation, and failed the functional coprimary outcome, with baseline imbalance between arms [28]. Long-term data come from open-label extensions without a natural history control group, with confounding by growth and ageing; the HUE-MAN cohort showed stable FVC in adults and a fall of up to 10% in children over two years, a value without clinical significance, limiting attribution of observed improvements to treatment [29, 47]. Relative percentage results (article) and absolute differences (labels) are not directly comparable, and trials should not be compared with one another or extrapolated to severe disease, patients over 35 years or CNS manifestations [12, 28]. The planned post-authorisation 24-week randomised trial was withdrawn without enrolling patients [57]. A 2026 systematic review (12 studies; 75 patients on ERT and 28 with HSCT) concluded that ERT had favourable safety and improved respiratory function and quality of life, with limited efficacy for neurocognitive decline, and used narrative synthesis because of study heterogeneity [58].

7.6 Haematopoietic stem cell transplantation

Rationale and indication. HSCT at least partially corrects the biochemical defect, with some evidence of neurodevelopmental benefit, particularly when performed early, and its primary indication is preservation of neurocognitive function and prevention of early death [1, 18]. GeneReviews offers it in severe alpha-mannosidosis and recommends that it be performed as early as possible, preferably in the first decade, before irreversible damage accumulates; benefits are greater in younger patients and risks increase with age [1, 3]. The Saudubray indications table records 20 to 30 published cases and indicates HSCT in young patients with neuronopathic disease and a good donor [18]. Even late transplantation may resolve some systemic manifestations and stabilise brain function [1]. The French PNDS reserves HSCT mainly for severe paediatric forms, asks that it be raised in particular before 6 years of age and that the indication, especially with early or neonatal diagnosis, be discussed case by case at the CETMPS-GP and at a national multidisciplinary meeting dedicated to transplantation; it considers umbilical cord blood the currently recommended technique, without this eliminating morbidity and mortality [9]. According to the same text, HSCT reduces tissue storage and oligosacchariduria, but in most cases manifestations continue to progress with a slower slope, particularly in the skeleton, the ENT sphere and the nervous system, and may stabilise hearing and cognition; it advises cardiac assessment with Holter monitoring before myeloablative conditioning, to detect rhythm disturbances, and accepts ERT from diagnosis until satisfactory enzyme activity is recovered, for at least three months after transplantation, by decision of the CETMPS-GP, to improve cardiorespiratory, infectious and immunological status during the transplant period [9]. The 6-year limit is more restrictive than the first decade of GeneReviews [1, 9].

In transplanted patients, MRI showed fewer white matter abnormalities, less demyelination and gliosis than in untreated patients, and normalisation of spectroscopy [1]. Expressive speech and hearing impairment remain the most relevant problems after transplantation [1]. Morbidity and mortality are comparable to those of HSCT for other non-malignant diseases [1]. In Hennermann's series, four of 25 deaths reported by clinicians were due to HSCT complications [32]. The 2025 series was read only in abstract form, and the conditioning regimens and the content of the two published corrections are not included in the sources consulted [61]. Two trials are registered: NCT02254863 (Duke; umbilical cord blood HSCT with intrathecal DUOC-01 cells, phase 1, recruitment planned until 10/2027) and NCT02171104 (Minnesota; busulfan and fludarabine conditioning; active, not recruiting, completion expected in 07/2029) [57, 63].

Choice between ERT and HSCT. The sources do not compare the two strategies in a trial. HSCT is the only option with the potential to modify neurological progression and should be discussed early in young children, particularly those with neuronopathic disease and a suitable donor; ERT treats peripheral manifestations, may serve as a bridge to engraftment, and is the option for patients with an attenuated form, adults and those in whom HSCT is not feasible [1, 12, 18, 62]. An international survey suggests better self-reported mobility and self-care trajectories in treated than untreated patients, based on retrospective data without adjustment for severity [46].

7.7 Supportive treatment by manifestation

Development and education. GeneReviews describes the US model: early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and language and feeding therapy, special education), developmental preschool with an individualised education plan from 3 to 5 years, developmental paediatric follow-up at all ages, and a transition plan during adolescence [1]. In each country, the equivalent comprises early intervention services and inclusive education measures. Oromotor dysfunction should be assessed at every visit, and swallowing studies are requested for choking, faltering growth, frequent respiratory infections or food refusal [1]. The Bruininks–Oseretsky scale is used to measure motor proficiency in children and young adults receiving ERT [1].

Psychotropic medication. Behaviours within the attention deficit hyperactivity disorder spectrum are managed by developmental paediatrics, and confusion, delusions, hallucinations, anxiety and depression by child and adolescent psychiatry or adult psychiatry [1]. The number of patients with psychiatric symptoms is too small to draw conclusions about drugs; olanzapine, 5–15 mg at bedtime, has been used in several adult patients with some success according to a personal observation by one of the former GeneReviews authors, representing off-label use supported by anecdotal evidence [1]. Psychotic episodes should prompt exclusion of an organic cause, which was not undertaken in four of nine patients studied [1].

Immune-mediated myopathy. Worsening of myopathy through an immune-mediated mechanism has also been described after HSCT, and in one patient strength improved after a single plasma exchange; this is an isolated observation [1].

7.8 Agents and procedures to avoid or use with caution

The sources consulted do not include a formal list of drugs contraindicated in alpha-mannosidosis. Ventriculoperitoneal shunting should be avoided in favour of ventriculocaval shunting [1, 3]. The case of acute renal failure during velmanase treatment occurred in a patient taking high-dose ibuprofen over a prolonged period, and both labels record this circumstance [13, 33]. Patients receiving velmanase alfa who have previously experienced severe reactions should receive premedication and infusions at a reduced rate, and the Delphi consensus statement on premedication and rate reduction in patients at high risk of IARs achieved 90% agreement (E4) [4, 13].

7.9 Pregnancy, contraception and breastfeeding

There are no data on the use of velmanase alfa in pregnant women [12, 13]. The US label describes malformations in rats exposed to about 7 times the exposure of the human dose (cleft palate, bent pelvic girdle, duplicated sternebrae) and in rabbits at all doses, up to about 2.5 times (incomplete interventricular septum, reduced lung lobes, unilateral renal agenesis, diaphragmatic hernia, hydrocephalus, vertebral and rib malformations); it therefore requires a pregnancy test before starting treatment and effective contraception during treatment and for 14 days after the last dose, and leaves the decision to continue in pregnancy to the weighing of maternal need, fetal risk and the risk of untreated disease [13]. The European SmPC states that animal studies do not indicate direct or indirect harmful effects and does not recommend use in pregnancy unless the woman's clinical condition requires treatment [12]. In breastfeeding, the US label has no data and asks for benefits to be weighed, and the European SmPC permits use because absorption by the infant is considered minimal [12, 13]. The articles consulted do not describe pregnancies in women with alpha-mannosidosis, and pregnancy was an exclusion criterion in the extension trials [47]; the French PNDS states, without identifying the cases, that women with a moderate form carried pregnancies to term without complications [9]. The PNDS considers that ERT does not contraindicate pregnancy, a more permissive position than that of the European SmPC (not recommended unless clinically necessary) and the US label (pregnancy test before starting and contraception) [9, 12, 13]. It recommends choosing the maternity unit according to symptoms, the risk of prematurity and obstetric experience with storage diseases, favouring caesarean section when orthopaedic deformities hinder delivery and arranging the anaesthetic consultation early, with assessment of intubation difficulty; combined oral contraception or an intrauterine device are discussed case by case [9]. Before HSCT, myeloablative chemotherapy exposes the patient to premature loss of fertility, and the PNDS advises cryopreservation of oocytes or sperm before transplantation, with a view to later medically assisted reproduction [9]. Human fertility has not been studied, and animal studies showed no impairment [12].

7.10 Anaesthesia and surgery

Before any surgery under general anaesthesia, cardiopulmonary assessment and careful airway assessment are recommended because of macroglossia, adenotonsillar hypertrophy, craniofacial abnormalities and skeletal dysplasia, although difficulties are generally less pronounced than in MPS [1, 18]. The same precautions apply to ventilation tube placement, orthopaedic and cardiac surgery, and gastrostomy [1]. Hypoplasia of the odontoid process with a tendency towards atlantoaxial subluxation has been described in an infant and warrants attention to the cervical spine [35]. The sources consulted do not describe perioperative adjustments to velmanase alfa.

The French PNDS requires any planned anaesthesia to be performed at a specialised centre, with an anaesthetist and ENT surgeon experienced with these patients; intubation may require endoscopic guidance and extubation may also be difficult, so the patient stays in intensive care afterwards, because of the risk of upper airway obstruction and of pulmonary, laryngeal or lingual oedema, even some time after extubation [9]. It recommends explaining these risks to the family in advance, grouping several procedures under a single anaesthetic (with the opinion of the CETMPS-GP), preferring locoregional anaesthesia when possible, for example in carpal tunnel syndrome, and keeping the duration of the procedure as short as possible [9]. The preoperative work-up for general anaesthesia includes an ENT consultation with experience of lysosomal diseases, tracheobronchial CT, recent pulmonary function tests, possibly polysomnography, and echocardiography; if a follow-up MRI requires general anaesthesia, the benefit is weighed against the risk [9].

7.11 Transition to adulthood

The Delphi consensus recommends formal cognitive assessments at school transitions in children (C4, 100%) and continuity of the multidisciplinary team throughout life [4]. GeneReviews recommends a transition plan during adolescence [1]. The NICE recommendation makes funding conditional on starting treatment before 18 years of age, reinforcing the importance of diagnosis and treatment decisions during childhood in England [53]. Psychiatric episodes usually begin during this period and should be anticipated with the family [1].

The French PNDS calls for an early and organised transition, guided by clinical status and not only by legal age, with a first joint consultation by the paediatrician and the adult physician, a summary document and definition of the arrangements for follow-up and continuation of ERT (day hospital, hospital at home or home nursing) [9]. At this stage it recommends a comprehensive adult assessment with screening for laryngotracheal lesions (malacia, stenosis, compression), often poorly symptomatic at rest, by cervicothoracic CT with a dedicated study of the trachea and pulmonary function tests with inspiratory measures (maximal inspiratory pressure and sniff test), and the communication to the patient and carers of information on anaesthetic risks [9]. The G2M filière provides transition booklets, and the therapeutic education programme “Enzy-Moi”, intended for patients older than 12 years and for parents or carers of children with lysosomal disease, whether or not treated with ERT, offers ten workshops, mostly remote, after a shared educational diagnosis [9]. Information for the patient includes planning, weeks or months ahead, of holidays and stays abroad to adapt ERT, treatment adherence, vaccines, particular follow-up in pregnancy, the genetics clinic for the extended family and the existence of disease registries [9].

7.12 Guidelines, consensus and differences

GeneReviews (June 2024 update) and the ACMG therapeutic bulletin (January 2024) stated that no published management guidelines existed [1, 63]. The Delphi consensus published in August 2024 is the first document on monitoring and care coordination: three rounds between October 2022 and October 2023, 20 voting panellists from 13 countries (including Brazil), with a mean of 16 years' experience and approximately 225 patients, consensus defined as at least 75% agreement, and 60 final statements, 49 of which achieved 90–100% agreement [4]. The study was funded by Chiesi, did not include patient associations and was not endorsed by scientific societies, and the authors acknowledge that a different panel might reach a different consensus [4]. The full text of the 60 statements appears in tables that were not accessible in the sources consulted; the statements and intervals described in the article text are reproduced here.

The HAS PNDS of December 2024, developed by the reference centre for lysosomal diseases and the CETMPS-GP with the G2M filière according to the 2012 HAS method, is the first national protocol dedicated to the disease; it was reviewed by reviewers including the patient association, with no industry involvement in drafting or review, although most authors declare relationships with industry [9]. It does not grade its recommendations, cites the Delphi consensus as a recent international recommendation and proposes its own schedules of consultations and investigations (section 11.3) [9]. The main divergences from the other sources are summarised in the following table.

7.13 Developments in the last 12 months (October 2025 to October 2026)

Outside this window, but relevant to therapeutic developments, are the 2025 preclinical studies with AAV1 in the cisterna magna of cats, in which treatment at 12 weeks achieved less correction than at earlier ages, and with AAV6 targeting the choroid plexus in mice, which restored brain enzyme activity to levels equal to or greater than those in heterozygotes and was proposed as a candidate for studies supporting investigational authorisation [68, 69]. No human gene therapy trials were registered on ClinicalTrials.gov on 10 October 2026 [57]. No new authorisation, indication extension or drug withdrawal was found within the window; this negative search does not exclude unindexed decisions [12, 13]. The prospective international SPARKLE registry, sponsored by Chiesi, collects data on the safety and effectiveness of velmanase alfa in clinical practice, including untreated patients [70].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

Alpha-mannosidosis is inherited in an autosomal recessive manner, and all families should be referred for genetic counselling, carrier testing and information on prenatal and preimplantation diagnosis [1, 18].

Heterozygotes are asymptomatic and are not at risk of developing the disease [1]. Genotype does not predict severity, given intrafamilial variability and the absence of a genotype–phenotype correlation applicable to the individual [1, 3].

8.2 Carrier detection and cascade testing

Carrier detection is by molecular testing and requires prior identification of the familial variants [1]. Carrier enzyme activity (40–60% of normal) overlaps with that of non-carriers and is not reliable for this purpose [3, 21]. All at-risk siblings, of any age, should be tested to allow early diagnosis and treatment: by molecular testing when the familial variants are known and by leucocyte activity assay when they are not [1]. Population database data indicate an overall carrier frequency of 0.23%, highest in Finns (0.49%), followed by East Asians (0.30%); these estimates depend on variant curation and are not equivalent to an observed frequency [71]. The sources consulted do not address carrier screening in the general population. In France, the law requires relatives to be informed of the risk of being a carrier; testing for the familial variant is offered to relatives who wish it, and counselling about offspring is reassuring when the partner is unrelated, given the rarity of the disease, with partner testing reserved for consanguineous unions; the French PNDS (National Diagnosis and Care Protocol) sets out these provisions [9].

8.3 Prenatal diagnosis and preimplantation genetic testing

With both familial variants identified, prenatal diagnosis can be performed on chorionic villi at 10–12 weeks or on amniocytes at 15–18 weeks, and PGT is possible [1, 3]. The ideal time to determine risk and discuss these options is before pregnancy, and counselling should be offered to young adults who are affected, carriers or at risk [1]. When the proband does not have a confirmed molecular diagnosis, DNA banking is recommended [1]. The French PNDS points out that preimplantation diagnosis requires in vitro fertilisation, may be lengthy and has a success rate of the order of 30%, and that, in the case of an affected fetus, the couple may opt for termination of pregnancy for medical reasons [9].

Two reports illustrate practice. In a Spanish family, exome sequencing of the affected daughter was expedited because the mother was pregnant; amniocentesis showed a fetus homozygous for c.2248C>T and the pregnancy was terminated [39]. In a Saudi family of first cousins, following diagnosis of the eldest son, homozygous for c.437-1G>A, the next brother was diagnosed prenatally by molecular analysis of chorionic villi and amniocytes, confirmed in the fifth week of life, started ERT at 5 months, and had normal development at 11 months and normal IgG after one year [35]. Severity cannot be predicted from fetal results, and views on the use of prenatal diagnosis vary among professionals and families; most centres consider the decision personal [1].

8.4 Patients of reproductive age

The labels contain no data on pregnancy or human fertility, and the French PNDS mentions only, in generic terms, term pregnancies without complications in women with a moderate form and advises preserving fertility before HSCT (section 7.9) [9, 12, 13]. Counselling of patients on velmanase alfa should include the divergence between the US label, which requires contraception during treatment and for 14 days after the last dose, and the European SmPC, which does not recommend use in pregnancy unless clinically necessary (section 7.9) [12, 13]. Intellectual disability requires attention to capacity to consent and to the involvement of carers in reproductive decisions, in accordance with the legislation of each country.

8.5 Minors

Testing at-risk minor siblings has direct clinical benefit because it allows diagnosis before symptoms and early discussion of HSCT or ERT, and is recommended at any age [1]. Carrier testing in healthy minors has no immediate clinical benefit, and decisions about its timing should follow the country's standards for genetic counselling of minors; disease-specific sources do not address this point.

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency estimates and what they measure

Frequency estimates for alpha-mannosidosis range from 1/300,000 to 1/1,000,000, and many are cited second-hand from a small number of original studies [1, 28, 33, 47]. The disease affects people of all ancestries, with patients described worldwide [1].

Birth prevalence and point prevalence are not interchangeable because early mortality in the severe form reduces the latter; underdiagnosis of mild forms affects both [5, 10]. Incidences calculated from genomic databases depend on variant classification and are not observed frequencies [71]. The diagnostic delay of decades described in adults suggests that estimates based on clinical diagnosis underestimate the true frequency [10, 49].

9.2 Founder populations and consanguinity

The c.2248C>T p.(Arg750Trp) variant accounts for approximately one-quarter of alleles in European patients and originates from a small number of ancestral haplotypes shared by Finnish, Polish and Italian patients [3, 25]. The highest carrier frequency was estimated in Finns [71]. In the Middle East, published series come from consanguineous families with homozygous variants: in the United Arab Emirates, six families with nine patients aged 23 months to 42 years, with nonsense and splice variants recurring in Emirati families, all with childhood onset, macrocephaly, autoimmune disease in three and psychiatric disease in two adults, treated with ERT (two) or HSCT (two) [36]; in Iraq, nine children from five consanguineous families, all with psychomotor delay, sensorineural hearing loss and coarse facial features, and with dysostosis multiplex in four [37]; in Saudi Arabia, a first-cousin family with two brothers homozygous for c.437-1G>A [35]. Patients studied up to 2008 were predominantly European, with two Japanese patients and one of Arab origin [3].

9.3 Data from the USA, Europe, Portugal and Brazil

European frequency data come from Norway, Sweden, the Netherlands, the Czech Republic and Portugal [1, 5]. The phase III trial included exclusively white European patients, and HSCT series include centres in the USA and Europe [13, 23, 61]. In the mortality series, two of the 15 reported deaths occurred in the USA [32]. In Portugal, in addition to the Orphanet figure, a group from Porto described a case with thalamic and dentate nucleus hyperintensity [40]. The sources consulted do not include frequency estimates for Brazil or the USA; Brazil participated in the Delphi consensus panel [4]. The absence of data in these sources does not mean that no publications exist.

9.4 Special populations

Adults and older people. The European SmPC states that no patient older than 41 years had been identified in Europe at the time of assessment, but the mortality series includes untreated patients who lived to 56 years, and the 2008 review mentions patients older than 50 years [3, 12, 32]. Adults have more valvular heart disease, arthropathy and psychiatric episodes, and the functional benefit of ERT is smaller than in children [1, 28, 47].

Young children. Children have more hypersensitivity reactions during ERT than adults (58% versus 36%), four of five children younger than 6 years developed ADAs, and data below 3 years of age are being collected in an observational study [13, 31, 57].

People with intellectual disability. Therapeutic and reproductive decisions involve families and caregivers, and caregiver burden is high [45].

9.5 Reference networks, registries and patient associations

MetabERN (European Reference Network for Hereditary Metabolic Disorders) includes alpha-mannosidosis in its lysosomal disease subnetwork [15]. ISMRD (International Advocates for Glycoprotein Storage Diseases) supports families affected by glycoproteinoses and collaborated in natural history and mortality studies [16, 32, 44]. The UK MPS Society also supports families affected by alpha-mannosidosis, and GeneReviews additionally lists Metabolic Support UK and the US National MPS Society [1, 17]. Orphanet maintains the ORPHA:61 entry with information and resources by country [5]. The SPARKLE (international, prospective) and Étoile Alpha (France) registries collect data on treated and untreated patients [56, 70]. The amamutdb.no variant database was not responding on 10 October 2026 [26].

In France, rare disease centres have been accredited since 2004; the Centre de Référence des Maladies Lysosomales (coordinating centre at Hôpital Armand Trousseau, Paris, with constituent and competence centres) and the inherited metabolic disease centres belong to the Comité d'Évaluation du Traitement des maladies Lysosomales (CETL), whose CETMPS-GP subgroup, dedicated to the mucopolysaccharidoses and glycoproteinoses, can be consulted by any physician about a suspected or confirmed patient [9]. Multidisciplinary lysosomal disease clinics bring together specialists and investigations over half a day to two days, once or twice a year, and multidisciplinary consultation meetings take place on an online platform [9]. Biochemical and molecular tests are performed in reference laboratories in Lyon, Paris (Necker), Rouen, Toulouse, Grenoble, Nancy and Lille, and the G2M filière provides an emergency and care card, issued and completed by the centre following the patient [9]. The disease confers exemption from patient co-payments as a long-term condition (ALD 17), with 100% coverage of disease-related costs, reimbursement of transport to centres more than 150 km away subject to prior request, and family and disability benefits: parental presence leave and allowance for up to 310 days over a 3-year period, with a maximum of 22 days per month; carer's leave of up to 3 months; education allowance for a disabled child and allowance for disabled adults, and disability compensation benefit; mobility card with a disability rate of at least 80%; recognition of disabled worker status [9]. Schooling may require adaptations in mainstream settings (personalised plan, support assistant, extra time), support from early medico-social action centres before 6 years or referral to medico-social facilities, and in adulthood work may take place in mainstream settings, in an adapted company or in a sheltered work establishment, with legal protection (guardianship or curatorship) when necessary [9]. The patient association Vaincre les Maladies Lysosomales (VML), recognised as being of public utility, welcomes all people with lysosomal disease, and the PNDS also refers to ISMRD and the MPS Society [9].

10. Illustrative Clinical Case

10.1 Presentation

Bonilla Fornes and colleagues described a Spanish girl in 2026, the seventh case diagnosed in Spain, born to first cousins, with a healthy 2-year-old brother [39]. She was born by spontaneous vaginal delivery at 40 weeks, weighing 3280 g, with normal anthropometric measurements, and had an umbilical hernia from birth [39]. She rolled over at 5 months, walked at 17 months, had severe language delay and remained incontinent at 3 years [39]. At 15 months, she developed repetitive limb movements, classified as a non-epileptic paroxysmal disorder, with a normal electroencephalogram; at 24 months, physiotherapy documented pes valgus and pes cavus; she was assessed by ENT for hypertrophic tonsils and bilateral otitis media with effusion; and at 2 years and 11 months she was admitted with pain and inflammation of the left knee, treated with arthrocentesis and antibiotics [39].

10.2 Examination and investigations

At 3.5 years she weighed 14.5 kg (P44), measured 94 cm (P25) and had a head circumference of 47.5 cm (P7) [39]. She had trigonocephaly, horizontal palpebral fissures, exophthalmos, hypertelorism, a broad, flat and depressed nasal root, everted lips, macroglossia, a hoarse voice and fractured incisors, with a palpable spleen and a liver 1 cm below the costal margin [39]. Skeletal radiographs showed a thick calvarium with pronounced digital impressions (a “copper-beaten” skull), thick ribs, failure of fusion of the posterior arch of L5, and short, thick long bones with mild metaphyseal widening (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13435371/figure/ccr373276-fig-0001/) [39]. Cranial MRI revealed metopic and coronal synostosis and corpus callosum dysgenesis (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC13435371/figure/ccr373276-fig-0002/), and the trigonocephaly and anterior brachycephaly were corrected surgically [39]. Cardiac assessment was normal, and ophthalmological examination showed neither corneal deposits nor lens opacities [39].

Urinary oligosaccharide excretion was increased, with normal glycosaminoglycans, and the enzyme study was described as showing complete absence of alpha-mannosidase activity [39]. Array comparative genomic hybridisation was normal, and phenotype-directed exome sequencing (LSDs and skeletal dysplasias) showed homozygosity for NM_000528.3:c.2248C>T p.(Arg750Trp), in exon 18 of 24, described using the transcript preceding MANE; in ClinVar, NM_000528.4:c.2248C>T p.(Arg750Trp) is classified as pathogenic/likely pathogenic [34, 39]. The parents and brother were heterozygotes [39]. Exome sequencing was requested in parallel with biochemical testing because the mother was pregnant; amniocentesis revealed a homozygous fetus and the pregnancy was terminated [39].

10.3 Treatment and course

In April 2022, in the presence of mucoid otitis media with effusion, adenoid hypertrophy and obstructive sleep apnoea, she underwent adenotonsillectomy and bilateral myringotomy with drainage tubes [39]. She started velmanase alfa 1 mg/kg/week by hospital infusion in June 2022, without reactions or complications [39]. After 12 months, language and behaviour had improved, with speech and language therapy support, hearing remained stable, with normal auditory evoked potentials at baseline and 12 months, and coordination had improved: the 6MWT increased from 343.2 to 396 m and the 3MSCT from 240 to 254 steps [39]. At 6.5 years, after 18 months of ERT, she formed simple two- to three-word sentences and understood instructions given in context [39].

10.4 Critical appraisal

The case brings together several typical features of the disease: consanguinity, umbilical hernia, language delay, otitis media with effusion and adenotonsillar hypertrophy, coarse facial features with macroglossia, mild hepatosplenomegaly, dysostosis and knee arthritis [1, 39]. Metopic and coronal craniosynostosis is unusual; the authors count three published cases and propose including it in the spectrum [39]. Management (expedited molecular diagnosis to enable prenatal diagnosis, ENT surgery with ventilation tubes, and weekly ERT at the SmPC dose) follows GeneReviews and European SmPC recommendations [1, 12]. In a child younger than 5 years with severe language impairment, HSCT would be an option to discuss according to the same sources, and the report does not mention such a discussion [1, 18].

The article contains inconsistencies that should be interpreted with caution: the age of 3.5 years at presentation is incompatible with an age of 6.5 years after 18 months of treatment started in June 2022, and the functional test table labels the baseline value as “6 years and 9 months”; the “complete absence” of enzyme activity contrasts with the residual activity of 5–10% usually measured in patients' leucocytes; and the article places the gene at 19p13.2-q12, whereas its current location is 19p13.13 [1, 39]. A 3MSCT of 240 steps in 3 minutes is far higher than the mean values in children in the natural history cohort (141 ± 30) and the trials, suggesting differences in method or unit [29, 39]. Improvement over 12 months cannot be attributed solely to treatment because it coincided with ENT surgery, speech and language therapy, and expected age-related development.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis without treatment

In the severe form, older series describe death between 3 and 10 years of age, often from pneumonia, and the seven published deaths reviewed by Hennermann occurred at a median age of 4.3 years [21, 32]. In the attenuated forms, progression is slow, over decades, with increasing dependence: most adults eventually become wheelchair-dependent, none of the Norwegian patients was fully independent and many live beyond 50 years [3]. In the 15 deaths of untreated patients reported by clinicians and associations, the median age at death was 45 years (mean 40.3 ± 13.2; 18–56), and the main causes were pneumonia (46.7%) and cancer (20%) [32]. The sample is small and does not allow life expectancy to be estimated [32]. Degeneration over time appears to be the rule in all phenotypes [21]. The French PNDS (National Diagnosis and Care Protocol) observes that, with advances in care, death now occurs more often in adulthood than in childhood, and recommends early involvement of a supportive and palliative care team, distinct from end-of-life care, with decisions guided by quality of life [9].

11.2 Prognosis with treatment

During velmanase alfa treatment, data up to 12 years show a sustained decrease in serum oligosaccharides (approximately 63–68%), normalisation of IgG, fewer infections and functional gains in children, whereas adults tend to stabilise or decline more slowly, without a control group [33, 47]. ERT does not alter cognitive impairment or established deformities [12]. After HSCT, survival was 88% in the 2012 series and 100% in the 2025 series, with developmental progress without normalisation and persistent impairment in 85% of assessed patients [23, 61]. The long-term prognosis of patients treated early, particularly those diagnosed in the neonatal period, is not yet known [1].

11.3 Surveillance

The table combines GeneReviews surveillance with Delphi consensus statements; where intervals differ, both are given [1, 4].

It is not known how many complications improve or resolve with ERT or HSCT, warranting continued surveillance of all systems in treated patients [1].

The French PNDS (National Diagnosis and Care Protocol) sets the frequency of consultations: without complications or targeted treatment, every 6 months while the patient is followed in paediatrics, until the end of growth, and annually in adults; with targeted treatment, every 3 months in the first year and then every 6–12 months; at each consultation, quality of life and pain are assessed with dedicated scales, and it is checked that the record contains the enzyme activity, oligosaccharides and genetic result of the diagnosis [9]. Its tables distinguish paediatric age, until the end of puberty, from adulthood, and investigations are brought forward in the presence of complaints or before surgery [9].

12. Summary and Final Considerations

Alpha-mannosidosis is an autosomal recessive glycoproteinosis caused by biallelic variants in MAN2B1 (19p13.13), which encodes lysosomal alpha-mannosidase; deficiency leads to accumulation of mannose-rich oligosaccharides and a multisystem disorder with a continuous spectrum between a severe childhood-onset form, fatal within the first decade in older series, and attenuated forms that reach adulthood with progressive dependence [1, 3, 32]. The c.2248C>T p.(Arg750Trp) variant accounts for approximately one-quarter of European alleles, but most variants are private, and genotype–phenotype correlation exists only at group level, through the subcellular localisation of the mutant protein [8, 25].

The signs that should prompt diagnosis change with age: up to 10 years, mixed hearing loss, speech delay and recurrent infections with subtly coarse facial features; after 10 years, intellectual disability, motor decline with ataxia and psychiatric episodes [11]. Diagnostic delay, which may extend to decades, deprives patients of the window in which treatment offers the greatest benefit [10, 48]. Diagnosis rests on leucocyte alpha-mannosidase activity of 5–10% of normal and/or biallelic variants, with urinary or serum oligosaccharides used for screening and as a response marker; enzyme assay is unsuitable for carrier detection [1, 3].

Velmanase alfa, 1 mg/kg weekly, reduces serum oligosaccharides, increases IgG and improves motor and respiratory function, particularly in children, but the controlled trial was small, missed the functional co-primary endpoint and the drug does not act on the CNS; indications differ between the EU (mild to moderate forms) and the USA (no severity restriction), and the labels diverge on pregnancy and breastfeeding [12, 13, 28]. HSCT, performed in the first decade and preferably before symptoms, is the CNS-directed option, with high survival in recent series and improvement in hearing, infections and organomegaly, without normalisation of development [23, 61]. The 2024 Delphi consensus provides multidisciplinary surveillance intervals, to be combined with GeneReviews [1, 4]. Gene therapy is at the preclinical stage, and a dried blood spot biomarker opens the possibility of newborn screening, so far described only in a preprint [14, 67]. The 2024 French PNDS (National Diagnosis and Care Protocol) adds a national decision pathway (CETMPS-GP), criteria for home infusion, premedication and IAR treatment regimens and age-based surveillance schedules, and diverges from the other sources in requiring enzymatic confirmation, in the preferred age for HSCT, in the intervals of several investigations and on pregnancy on ERT [9].

13. References

1. Ficicioglu C, Stepien KM. Alpha-Mannosidosis. 2001 Oct 11 [Updated 2024 Jun 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1396/ PMID: 20301570.
2. GeneGuidance. MAN2B1 / Alpha-mannosidosis (OMIM 248500). Accessed 2026-09-26.
3. Malm D, Nilssen Ø. Alpha-mannosidosis. Orphanet J Rare Dis. 2008;3:21. doi:10.1186/1750-1172-3-21. PMID: 18651971. PMC2515294.
4. Guffon N, Burton BK, Ficicioglu C, Magner M, Gil-Campos M, Lopez-Rodriguez MA, et al. Monitoring and integrated care coordination of patients with alpha-mannosidosis: A global Delphi consensus study. Mol Genet Metab. 2024;142(4):108519. doi:10.1016/j.ymgme.2024.108519. PMID: 39024860.
5. Orphanet. Alpha-mannosidosis (ORPHA:61). Available from: https://www.orpha.net/en/disease/detail/61
6. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166. Tool: https://variantvalidator.org/
7. Nilssen O, Berg T, Riise HM, Ramachandran U, Evjen G, Hansen GM, et al. alpha-Mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet. 1997;6(5):717-726. doi:10.1093/hmg/6.5.717. PMID: 9158146.
8. Borgwardt L, Stensland HM, Olsen KJ, Wibrand F, Klenow HB, Beck M, et al. Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. Orphanet J Rare Dis. 2015;10:70. doi:10.1186/s13023-015-0286-x. PMID: 26048034. PMC4465300.
9. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Alpha-mannosidose. Centre de Référence des Maladies Lysosomales, CETMPS-GP et filière G2M; texte de décembre 2024. Saint-Denis La Plaine: HAS; 2024 Nov 21. Available from: https://www.has-sante.fr/jcms/p_3557763
10. Nurse JH, Hennermann JB, Curiati MA, Vashakmadze N, Lampe C, Magalhães M, et al. Delayed diagnosis and clinical course of alpha-mannosidosis: A retrospective study of 25 patients with varying severity. Genet Med Open. 2025;3:103465. doi:10.1016/j.gimo.2025.103465. PMID: 41334501. PMC12666804.
11. Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, et al. Recognition of alpha-mannosidosis in paediatric and adult patients: Presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126(4):470-474. doi:10.1016/j.ymgme.2019.01.024. PMID: 30792122.
12. European Medicines Agency. Lamzede (velmanase alfa): EPAR – Product information [Summary of Product Characteristics]. EMEA/H/C/003922. Chiesi Farmaceutici S.p.A.; first authorisation 23 March 2018, latest renewal 13 January 2023; page last updated 2 March 2026. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/lamzede
13. Chiesi USA, Inc. LAMZEDE (velmanase alfa-tycv) for injection, for intravenous use. Prescribing information. BLA 761278. Initial U.S. approval: 2023 [revised 02/2023]. Silver Spring (MD): U.S. Food and Drug Administration; 2023. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761278 ; DailyMed setid 36d50a08-60bd-40eb-807c-778d69bf2d2e.
14. Badekow D, Jeschik M, Dreyer B, Hoff K, Köhn AF, Lindschau M, et al. Alpha-Mannosidosis: Quantitative Oligosaccharide Biomarker Analysis in Dried Blood Spots for Diagnosis, Newborn Screening, and Treatment Monitoring [preprint]. medRxiv. 2026 Sep 22. doi:10.64898/2026.09.16.26362975.
15. MetabERN – European Reference Network for Hereditary Metabolic Disorders. Available from: https://metab.ern-net.eu/
16. ISMRD – The International Advocates for Glycoprotein Storage Diseases. Available from: https://www.ismrd.org/
17. Society for Mucopolysaccharide Diseases (UK MPS Society). Available from: https://mpssociety.org.uk/
18. Jones S, Wijburg FA. Glycosaminoglycans and Oligosaccharides Disorders: Glycosaminoglycans Synthesis Defects, Mucopolysaccharidoses, Oligosaccharidoses and Sialic Acid Disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 41, sections 41.2 (Table 41.3) e 41.3.1–41.3.5.
19. Saudubray JM, García-Cazorla Á. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, sections 1.5.2, 1.6.5, 1.6.7, 1.6.11 (Tables 1.1, 1.16, 1.19, 1.21, 1.41, 1.42).
20. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 88–91 (Cataract).
21. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. α-Mannosidosis (β-Mannosidosis). In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 726–32.
22. Grewal SS, Shapiro EG, Krivit W, Charnas L, Lockman LA, Delaney KA, et al. Effective treatment of alpha-mannosidosis by allogeneic hematopoietic stem cell transplantation. J Pediatr. 2004;144(5):569-573. doi:10.1016/j.jpeds.2004.01.025. PMID: 15126988.
23. Mynarek M, Tolar J, Albert MH, Escolar ML, Boelens JJ, Cowan MJ, et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant. 2012;47(3):352-359. doi:10.1038/bmt.2011.99. PMID: 21552297.
24. Berg T, Riise HM, Hansen GM, Malm D, Tranebjaerg L, Tollersrud OK, et al. Spectrum of mutations in alpha-mannosidosis. Am J Hum Genet. 1999;64(1):77-88. doi:10.1086/302183. PMID: 9915946. PMC1377705.
25. Riise Stensland HM, Klenow HB, Van Nguyen L, Hansen GM, Malm D, Nilssen Ø. Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. Hum Mutat. 2012;33(3):511-520. doi:10.1002/humu.22005. PMID: 22161967.
26. Riise Stensland HM, Frantzen G, Kuokkanen E, Buvang EK, Klenow HB, Heikinheimo P, et al. amamutdb.no: A relational database for MAN2B1 allelic variants that compiles genotypes, clinical phenotypes, and biochemical and structural data of mutant MAN2B1 in α-mannosidosis. Hum Mutat. 2015;36(6):581-586. doi:10.1002/humu.22787. PMID: 25762455.
27. Borgwardt L, Dali CI, Fogh J, Månsson JE, Olsen KJ, Beck HC, et al. Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study. J Inherit Metab Dis. 2013;36(6):1015-1024. doi:10.1007/s10545-013-9595-1. PMID: 23494656.
28. Borgwardt L, Guffon N, Amraoui Y, Dali CI, De Meirleir L, Gil-Campos M, et al. Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018;41(6):1215-1223. doi:10.1007/s10545-018-0185-0. PMID: 29846843. PMC6326984.
29. Beck M, Olsen KJ, Wraith JE, Zeman J, Michalski JC, Saftig P, et al. Natural history of alpha mannosidosis a longitudinal study. Orphanet J Rare Dis. 2013;8:88. doi:10.1186/1750-1172-8-88. PMID: 23786919. PMC3691585.
30. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 853–5 (Skeletal dysplasia charts).
31. Guffon N, Konstantopoulou V, Hennermann JB, Muschol N, Bruno I, Tummolo A, et al. Long-term safety and efficacy of velmanase alfa treatment in children under 6 years of age with alpha-mannosidosis: A phase 2, open label, multicenter study. J Inherit Metab Dis. 2023;46(4):705-719. doi:10.1002/jimd.12602. PMID: 36849760.
32. Hennermann JB, Raebel EM, Donà F, Jacquemont ML, Cefalo G, Ballabeni A, et al. Mortality in patients with alpha-mannosidosis: a review of patients' data and the literature. Orphanet J Rare Dis. 2022;17(1):287. doi:10.1186/s13023-022-02422-6. PMID: 35871018. PMC9308362.
33. Lund AM, Borgwardt L, Cattaneo F, Ardigò D, Geraci S, Gil-Campos M, et al. Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis. J Inherit Metab Dis. 2018;41(6):1225-1233. doi:10.1007/s10545-018-0175-2. PMID: 29725868. PMC6326957.
34. National Center for Biotechnology Information. ClinVar [Internet]. Variation IDs 1687 (NM_000528.4:c.2248C>T), 21207 (c.1830+1G>C), 21210 (c.2426T>C). Available from: https://www.ncbi.nlm.nih.gov/clinvar/
35. AlAnzi T, Mohamed S, AlHashem A, AlRukban H. Prenatal Diagnosis of c.437-1G>A Mutation in the MAN2B1 Gene in a Family With Alpha-Mannosidosis: Unraveling Clinical Presentation and Treatment Outcomes in a Novel Prenatal Case. Cureus. 2024;16(4):e58922. doi:10.7759/cureus.58922. PMID: 38800253. PMC11121650.
36. Saad AK, Al-Hammadi T, Al-Ameri S, Al-Shamsi A, Al-Dhaheri N, Al Tenaiji A, et al. Retrospective Study of Clinical and Genetic Profiles of Alpha-Mannosidosis Patients From the UAE. JIMD Rep. 2025;66(2):e70001. doi:10.1002/jmd2.70001. PMID: 39926434. PMC11802633.
37. Al Tai MR, Saadi NW, Alothman MS, Ahmed IA, Arif HS, Abdulwahhab SB. Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant. Mol Genet Metab Rep. 2026;46:101282. doi:10.1016/j.ymgmr.2025.101282. PMID: 41567994. PMC12818985.
38. Borgwardt LG, Ceravolo F, Zardi G, Ballabeni A, Lund AM. Relationship between MAN2B1 genotype/subcellular localization subgroups, antidrug antibody detection, and long-term velmanase alfa treatment outcomes in patients with alpha-mannosidosis. JIMD Rep. 2023;64(2):187-198. doi:10.1002/jmd2.12349. PMID: 36873087. PMC9981422.
39. Bonilla Fornes S, Mendez Perez MP, Torres Diaz M, Sanchez Gutierrez ME, Galán Gómez E. Alpha-Mannosidosis in a 3.5-Year-Old Girl: A Case Report. Clin Case Rep. 2026;14(8):e73276. doi:10.1002/ccr3.73276. PMID: 42553539. PMC13435371.
40. Malaquias MJ, Pinto E, Oliveira J, Freixo JP, Caseiro C, Magalhães M. Alpha-Mannosidosis: A Novel Cause of Bilateral Thalami and Dentate Nuclei Hyperintensity. Can J Neurol Sci. 2022;49(5):704-705. doi:10.1017/cjn.2021.208. PMID: 34486965.
41. Mochel F, Sedel F. Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 2, Tables 2.1, 2.7, 2.9, 2.11, 2.13.
42. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Dysostosis multiplex. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 109–16.
43. Gerards AH, Winia WP, Westerga J, Dijkmans BA, van Soesbergen RM. Destructive joint disease in alpha-mannosidosis. A case report and review of the literature. Clin Rheumatol. 2004;23(1):40-42. doi:10.1007/s10067-003-0770-x. PMID: 14749981.
44. Malm D, Riise Stensland HM, Edvardsen Ø, Nilssen Ø. The natural course and complications of alpha-mannosidosis--a retrospective and descriptive study. J Inherit Metab Dis. 2014;37(1):79-82. doi:10.1007/s10545-013-9622-2. PMID: 23739775.
45. Adam J, Malone R, Lloyd S, Lee J, Hendriksz CJ, Ramaswami U. Disease progression of alpha-mannosidosis and impact on patients and carers - A UK natural history survey. Mol Genet Metab Rep. 2019;20:100480. doi:10.1016/j.ymgmr.2019.100480. PMID: 31198684. PMC6557729.
46. Stepien KM, Thomas S, Hennermann JB, Lampe C, Muschol NM, Ballesta-Martínez MJ, et al. Evolution of mobility, pain/discomfort, self-care, and mental health in patients with alpha-mannosidosis: an international caregiver and patient survey. Orphanet J Rare Dis. 2025;20(1):217. doi:10.1186/s13023-025-03694-4. PMID: 40336024. PMC12057280.
47. Guffon N, Borgwardt L, Tylki-Szymańska A, Ballabeni A, Donà F, Joseph A, et al. Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis. J Inherit Metab Dis. 2025;48(1):e12799. doi:10.1002/jimd.12799. PMID: 39381850. PMC11667663.
48. Santoro L, Cefalo G, Canalini F, Rossi S, Scarpa M. Diagnosis of alpha-Mannosidosis: Practical approaches to reducing diagnostic delays in this ultra-rare disease. Mol Genet Metab. 2024;142(1):108444. doi:10.1016/j.ymgme.2024.108444. PMID: 38555683.
49. Lehalle D, Colombo R, O'Grady M, Héron B, Houcinat N, Kuentz P, et al. Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: Report of seven new cases. Am J Med Genet A. 2019;179(9):1756-1763. doi:10.1002/ajmg.a.61273. PMID: 31241255.
50. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Fucosidosis. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 721–5.
51. Dörfel D, Dreyer B, Lindschau M, Barbato A, Altavilla N, la Marca G, et al. Quantification of Specific Urinary Oligosaccharide Biomarkers for Diagnosis and Treatment Monitoring of Alpha-Mannosidosis. J Inherit Metab Dis. 2026;49(3):e70208. doi:10.1002/jimd.70208. PMID: 42175676.
52. Morris AAM, Jones S. Medications Used in the Treatment of Inborn Errors of Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 45.
53. National Institute for Health and Care Excellence. Velmanase alfa for treating alpha-mannosidosis. Highly specialised technologies guidance HST29. London: NICE; 13 December 2023. Available from: https://www.nice.org.uk/guidance/hst29
54. Haute Autorité de Santé, Commission de la Transparence. LAMZEDE (velmanase alfa) – Alpha-mannosidosis. Avis du 11 décembre 2024 (publié le 10 janvier 2025). Saint-Denis: HAS; 2025. Available from: https://www.has-sante.fr/jcms/p_3577018/en/lamzede-velmanase-alfa-alpha-mannosidosis
55. Harmatz P, Cattaneo F, Ardigò D, Geraci S, Hennermann JB, Guffon N, et al. Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab. 2018;124(2):152-160. doi:10.1016/j.ymgme.2018.04.003. PMID: 29716835.
56. Guffon N, Mention-Mulliez K, Gaches F, Garavaglia D, Salomone F, Héron B. Changes in motor function, quality of life, and clinical manifestations in patients with Alpha-mannosidosis treated with Velmanase Alfa: Data from the French Étoile Alpha registry. Mol Genet Metab Rep. 2026;48:101351. doi:10.1016/j.ymgmr.2026.101351. PMID: 42733529. PMC13571468.
57. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine. Pesquisa «alpha-mannosidosis» incl. NCT06184503, NCT04031066, NCT04959240, NCT02254863, NCT02171104, NCT01681953, NCT02998879, NCT01908712, NCT01908725, NCT02478840. Available from: https://clinicaltrials.gov/
58. Azzi A, Shlhoob RB, Al-Shehri H. Clinical outcomes in alpha-mannosidosis: a systematic review of therapeutic approaches. Orphanet J Rare Dis. 2026;21(1):255. doi:10.1186/s13023-026-04394-3. PMID: 42482083. PMC13390369.
59. Broomfield AA, Chakrapani A, Wraith JE. The effects of early and late bone marrow transplantation in siblings with alpha-mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option?. J Inherit Metab Dis. 2010;33 Suppl 3:S123-7. doi:10.1007/s10545-009-9035-4. PMID: 20165920.
60. Yesilipek AM, Akcan M, Karasu G, Uygun V, Kupesiz A, Hazar V. Successful unrelated bone marrow transplantation in two siblings with alpha-mannosidosis. Pediatr Transplant. 2012;16(7):779-782. doi:10.1111/j.1399-3046.2012.01763.x. PMID: 22775975.
61. Šáhó R, Formánková R, Eisengart JB, Lund AM, Videbaek C, Gürbüz BB, et al. Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis. J Inherit Metab Dis. 2025;48(4):e70047. doi:10.1002/jimd.70047. PMID: 40551549.
62. Santoro L, Monachesi C, Zampini L, Padella L, Galeazzi T, Santori E, et al. First experience of combined enzyme replacement therapy and hematopoietic stem cell transplantation in alpha-mannosidosis. Am J Med Genet A. 2023;191(7):1948-1952. doi:10.1002/ajmg.a.63210. PMID: 37045799.
63. Lander JM, Penon-Portmann M, Sutton VR, Chang I, ACMG Therapeutics Committee. Velmanase alfa approved for treatment of non-central nervous system manifestations of alpha-mannosidosis: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). Genet Med Open. 2024;2:101832. doi:10.1016/j.gimo.2024.101832. PMID: 39669629. PMC11613763.
64. Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, et al. Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. J Paediatr Child Health. 2018;54(3):223-233. doi:10.1111/jpc.13768. PMID: 29504223.
65. European Medicines Agency. Aclasta (zoledronic acid): EPAR — product information. Available from: https://www.ema.europa.eu/en/documents/product-information/aclasta-epar-product-information_en.pdf
66. Laboratórios Pfizer, Lda. Pamidran 3 mg/ml e 9 mg/ml concentrado para solução para perfusão — Resumo das Características do Medicamento. INFARMED/Infomed, med_id 33494. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=33494&tipo_doc=rcm
67. Hunter JE, Molony CM, Clarke DL, Panek W, Vite CH, Chawla S, et al. Clinical response to systemic AAV gene therapy in a large animal model of late-stage lysosomal storage disease. Gene Ther. 2026;33(4):495-503. doi:10.1038/s41434-026-00618-0. PMID: 42082637. PMC13472877.
68. Hunter JE, Molony CM, Panek WK, Vite CH, Chawla S, Poptani H, et al. Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease. Mol Ther Methods Clin Dev. 2025;33(3):101552. doi:10.1016/j.omtm.2025.101552. PMID: 40893159. PMC12397823.
69. Choi EY, Wolfe JH, Kaler SG. Choroid plexus-targeted viral gene therapy for alpha-mannosidosis, a prototypical neurometabolic lysosomal storage disease. Hum Mol Genet. 2025;34(7):577-585. doi:10.1093/hmg/ddae201. PMID: 39815619. PMC11924188.
70. Hennermann JB, Guffon N, Cattaneo F, Ceravolo F, Borgwardt L, Lund AM, et al. The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis. Orphanet J Rare Dis. 2020;15(1):271. doi:10.1186/s13023-020-01549-8. PMID: 32993743. PMC7525940.
71. Park JE, Lee T, Ha K, Cho EH, Ki CS. Carrier frequency and incidence of alpha-mannosidosis: population database-based study-focus on the East Asian and Korean population. Front Genet. 2023;14:1297543. doi:10.3389/fgene.2023.1297543. PMID: 38107468. PMC10725197.
72. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-254. doi:10.1001/jama.281.3.249. PMID: 9918480.
73. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004;12(2):87-92. doi:10.1038/sj.ejhg.5201044. PMID: 14685153.