Early references have described that early psychomotor development appears normal, and that pathophysiology develops over time 419. However, some children are born with ankle equinus or develop hydrocephalus in the first year of life 1720.

In α-mannosidosis guinea pigs, long before the onset of obvious neurologic abnormalities at 2 months, cerebral pathophysiology like neuronal lysosomal vacuolation, and reduced myelination of white matter was observed. Thus, complex neuropathologic changes in α-mannosidosis guinea pigs are already present at birth, long before clinical changes are evident, and similar events are likely to occur in humans with this disorder 21.

Facial traits may be subtle, but independent of race and background genetics, all patients have some degree of coarse Hurler-like features. This is classically a large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. The neck is usually short (Fig 1).

According to Chester (1982), clinical or radiographic signs of mild-to-moderate dysostosis multiplex are present in 90% of the patients 14. The most frequent abnormalities are scoliosis and deformation of the sternum 22 (Fig 2). These changes are present at birth. Genu valgus (knucle knee) is common and, like the same complication in Gaucher disease, may be treated with epiphyseal arthrodesis at a young age before the epiphyseal lineation of the knee is closed 23. Over time, from the second till the fourth decade of life the patients may develop destructive polyarthropathy, especially coxarthrosis (Fig 3), but also gonarthrosis 2425. These are often so serious that orthopedic corrections are needed 26. Patellar bilateral dislocation and severe synovial hypertrophy have also been described along with Charcot elbow and bilateral hip and elbow avascular necrosis in one patient 27.

Moderate or severe sensorineural hearing loss seems inevitable 12222829. It is regularly worsened by otitis or accumulation of fluid in the middle ear, adding a mechanical component to the hearing deficit 17.

Slight strabismus is common and also hyperopia more frequently than myopia 1430. Blurred discs 31, superficial corneal opacities, and lenticular changes seem to be rare but have been reported 4.

As soon as the age of the patients makes intelligence quotient (IQ) measurements feasible, almost all patients show some degree of mental retardation. In a clinical study that included eight patients the age at onset of symptoms varied from 6 months to 3 years 10. The first symptom was usually delayed development of speech or motor or mental functions. All the patients were mildly or moderately mentally retarded with an IQ of 60–80, with a declining tendency over later decades. With their poor ability to speak combined with sensorineural hearing loss, patients score generally better in nonverbal tests 10. Although some have suggested the disease stabilises in puberty 32, most follow-up observations suggest gradual impairment of mental and motor functions and speech with age. Longitudinal assessments of three brothers have been done by testing of general intelligence, language, visual spatial skills, and overall adaptive abilities over two years. During the follow-up, the cognitive findings showed that the patients manifested mild cognitive deficits. Cognitive deficits were generally uniform with no signs of progressive deterioration, except receptive language abilities 33. Other patients are described as having profound retardation even at young age 1934. Again, there can be remarkable differences in mental functioning among siblings 283536.

Patients learn to speak late, sometimes in the second decade of life. This impaired development of language with limited vocabularies and poor pronunciation might be explained by their congenital and/or later-onset hearing loss. Many patients learn to read, but have difficulties in understanding abstracts (Malm D: personal observation).

The development of motor functions in affected patients is generally slow, and the children appear clumsy. This is caused by a combination of factors like muscular weakness, joint abnormalities and ataxia due to cerebral atrophy and cerebral demyelination 37.

The impairment is by nature progressive, with gradual worsening in the second and third decade of life 10. However, as for mental retardation, there is a considerable variation in the clinical progression and in a long term observation of two patients, no progression of neurological function has been noted 28, whereas some investigators have suggested that the disease progression is halted after puberty 32. Additional studies on the natural course of the disease are needed.

In intellectually disabled patients, psychiatric symptoms may be overlooked. However, a systematic survey found psychiatric symptoms in more than 25% of adult patients with mannosidosis 38. It typically presented in adolescence or early adulthood. In mentally retarded patients, psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. It can present with acute and recurrent attacks of confusion, sometimes with anxiety, depressions or, hallucinations. These might be associated with loss of function, like decreased appetite with severe weights loss or incontinence for urine and feces. The periods of psychosis usually last 3 to 12 weeks, followed by a long period of hypersomnia and sometimes loss of abilities, like difficulty speaking or inability to read. Search for organic causes has been negative 38. As specific treatments should be more effective at the initial stage before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms in patients with inborn errors of metabolism 39.

Mannosidosis patients suffer from recurrent infection, especially in the first decade of life. In one single patient, impaired leukocyte chemotaxis and reduced phagocytosis were found 9. Malm and co-workers compared the humoral and cellular immunological functioning in six patients to that of six age- and sex-matched healthy controls 40. They found that post-immunization levels of antibody were lower in patients, proving a decreased ability to produce specific antibodies after antigen presentation. More interestingly, there was a serum factor in patient plasma, inhibiting phagocytosis 40. In mannosidosis, there are increased levels of oligosaccharides in plasma 41. Oligomannosides with five and six mannose residues bind to interleukin-2 (IL-2) receptors disturbing the IL-2-dependent responses 42. IL-2 activates T-, B-, and NK cells. It can therefore be speculated that blockage of this receptor is the mechanism causing the immune deficiency seen in mannosidosis.

The same mechanism could contribute to the increased prevalence of autoimmune disorders among mannosidosis patients (13 and Malm D: personal observations). Interestingly, in a mice model, alpha-mannosidase II deficiency reduces complex-type N-glycan branching and induces an autoimmune disease similar to human systemic lupus erythematosus (SLE) with induction of antinuclear antibodies with reactivity towards histone, Sm antigen, and DNA 43.

End-stage kidney failure has been reported only once, where an Italian patient successfully received a kidney transplant 44. In a study in mannosidosis mice, deposits of storage material in myocardium were reduced after enzyme replacement 45. In some case descriptions, a murmur of the heart is mentioned, but so far, reports on manifest heart disease have not been reported.

A total of 40 different disease-causing mutations have been reported over the last 10 years. Except for two unrelated patients from Japan and one patient of Arabian origin 135455, the patients studied originate from Europe 1115545657585960. The genetic aberrations reported are scattered all over the MAN2B1 gene and include missense, nonsense, small and large deletions, small insertions and splice site mutations. Most mutations are private as they occur in single or in a few families only. However, missense mutation c.2248C>T resulting in the replacement of arginine with tryptophane at amino acid position 750 (p.R750W) appears to be frequent among mannosidosis patients, as it has been reported from most European populations studied, accounting for more than 30% of all disease alleles detected by Berg et al. (1999) 15. Haplotyping based on 5 internal single nucleotide polymorphisms (SNP) markers showed that a common haplotype was shared by Finnish, Polish and Italian homozygotes, whereas a second haplotype, deviating at one marker, was observed in a Turkish patient 15. These findings indicate that the frequency and wide geographical distribution of the "p.750W" allele may result both from founder effects and from recurrent mutational events. However, further analysis including patients of other origins must be carried out in order to explore this fully.

Altogether 12 missense mutations have been functionally characterized by expression analysis in mammalian cell lines followed by enzyme activity measurements and modeling into the MAN2B1 3-dimensional structure. Missense mutations affect residues located in the active site, in the dimer interphase as well as in the interior of the protein 5585961. Based on pulse chase experiments and immune fluorescence microscopy, Hansen et al. (2004) monitored the intracellular transport of mutant enzymes. They concluded that mutant enzymes (missense) could be divided into two groups: Group 1 that was correctly sorted to the lysosomes and group 2 that was retained (transport arrested) in the endoplasmic reticulum (ER) 61.

There is no apparent correlation between MAN2B1 genotype and clinical phenotype in α-mannosidosis 15. Clinical variation within sib ships has been observed 17283536, and patients characterized as less severely or moderately affected were shown to be homozygous for null mutations 15. However, attempts to predict genotype/phenotype relationships often suffer from lack of data. Case reports on clinical findings are few and often include few patients and variability of methods used. Likewise, mutation reports often lack sufficient clinical data.

Enzyme activity measurements from patient leukocytes or fibroblast cells provide no clue either to a MAN2B1 genotype/phenotype correlation as these values range from 5% to 15% of normal levels. Using a refined method Berg et al. (1999) demonstrated that the level of cross-reacting α-mannosidase activity was less than 1.3% of that in controls, with no consistent variation among affected individuals. However, one cannot rule out the existence of MAN2B1 genotypes ("mild" mutations) that cause sub-clinical symptoms associated with residual enzyme activity. Such cases would likely escape detection as they will not be severe enough to arouse the suspicion of α-mannosidosis.

Environmental factors and other genetic factors may contribute to the clinical heterogeneity seen in α-mannosidosis. Environmental factors might be exposure to pathogens causing recurrent infections and thereby worsening of the disease symptoms. Other genetic factors might be those that encode other mannosidases like cytosolic α-mannosidase that potentially might contribute to the intra cellular clearance of undigested oligosaccharides 1441626364. However, no such salvage pathway has yet been proven to contribute to the clinical variability.

A thorough clinical and molecular investigation of many patients is warranted in order to explore the clinical variability of α-mannosidosis. Indeed, a study on the natural history of mannosidosis was recently initiated by HUE-MAN – a multinational research project supported by the sixth framework program of the European Union 8.

Light microscopy or transmission electron microscopy (TEM) demonstrates vacuoles in bone marrow smears and lymphocytes from peripheral blood in most affected individuals (Fig 4) (reviewed in 14). Although detection of vacuoles by microscopy is a useful screening test, supplementary investigations are necessary when α-mannosidosis is suspected.

Elevated urinary excretion of mannose-rich oligosaccharides can be demonstrated by thin-layer chromatography 41 or high performance liquid chromatography (HPLC) 65. This finding is suggestive of α-mannosidosis, but not diagnostic.

The most efficient and reliable method of establishing the diagnosis of α-mannosidosis is the assay of acidic α-mannosidase activity in leukocytes or other nucleated cells. This fluorometric assay is performed at low pH (usually at pH 4) with the substrate 4-methylumbelliferyl α-D-mannopyranoside. In affected individuals, acid α-mannosidase enzyme activity in peripheral blood leukocytes is 5%–15% of normal activity. Residual enzyme activity could possibly represent α-mannosidase activity from other organelles or compartments (e.g., Golgi apparatus; MAN2A1, cytosol; MAN2C1 or ER; MAN1B1), showing some activity also at low pH. Following immunoprecipitation with anti-acid α-mannosidase polyclonal antibodies, acid α-mannosidase enzyme activity ranges from 0.1% to 1.3% of normal 15. Such testing is not performed routinely. In carriers, acid α-mannosidase enzyme activity is usually 40%–60% of normal, and is therefore unreliable for carrier detection because of the overlap between carriers and non-carriers.

Identification of disease causing mutations is carried out on DNA from peripheral blood cells, by polymerase chain reaction (PCR) amplification of all 24 MAN2B1 exons followed by DNA sequencing.

The main symptoms of mannosidosis, like dysmorphic traits, dysostosis, and mental retardation, are shared with the symptoms in many lysosomal storage diseases like mucopolysaccharidosis.

In general, the approach to the patients should be pro-active, searching for emerging complications. After a full physical examination, focusing on the known complications of mannosidosis like hydrocephalus, otitis media, hearing loss, dental state, joint status, kyphoscoliosis, and mental state, a plan should be made to limit the health consequences for the patient.

This would also include examination by an ophthalmologist, an otolaryngologist, audiometry and neuropsychological assessment, blood tests, and skeletal evaluation with radiographs, especially of the head, spine, knees or other skeletal sites displaying symptoms.