Alpha-mannosidosis (AM) is a lysosomal storage disease, which may also be referred to as lysosomal acid hydrolase alpha-mannosidase or LAHAM. It is caused by mutations of the MAN2B1 gene, which lead to alpha-mannosidase deficiency. AM is associated with facial dysmorphism, skeletal abnormalities, motor and mental disabilities, hearing impairment, and immune deficiency. The disease follows a progressive course, but its severity varies largely. It may be fatal in infancy, but milder forms of AM may allow for prolonged survival.
The clinical presentation of AM varies largely. Mental retardation, dysmorphic features, skeletal abnormalities, motor deficits, hearing impairment, and immune deficiency are the clinical hallmarks of AM, but the severity of the disease and the speed of progression differ between individual patients. Indeed, the distinction of severe and mild AM, also referred to as type 1 and type 2 disease, has been proposed, but intermediate phenotypes have repeatedly been reported . In a large study comprising 130 cases, 13 cases have been classified as severe, 11 as mild, and 106 as intermediate , but even the distinction of three subtypes doesn't do justice to the continuum of symptoms and severity .
Coarse facial features and skeletal abnormalities such as scoliosis, kyphosis, pectus carinatum, genu valgum, and pes equinus may be noted at birth. Even though facial dysmorphism may be subtle and mild to moderate AM may not be immediately recognized, virtually all patients eventually develop Hurler-like facies with a prominent forehead, rounded eyebrows, a flattened nasal bridge, prognathism, widely spaced teeth, and macroglossia. Mental and motor development is delayed, but in this context, the progressive course of AM has to be considered: Affected children often appear clumsy, and milestones in speech and language development are achieved late. Overt mental retardation in infancy is not an exclusion criterion, however, and long-term studies rather suggest a gradual decline of intellectual and motor skills. It should be noted that those suffering from severe AM may not live to develop sensorineural hearing loss, learning difficulties and other cognitive deficits, psychiatric disorders, ataxia, and polyarthropathy, which are often diagnosed during childhood . In particularly mild forms of the disease, these conditions may not be noted until the late first decade of life or teenage years .
Immune deficiency is a life-threatening feature of AM. The molecular mechanisms behind the impairment of the immune systems are poorly understood, but recurrent infections mainly occur in the first decade of life. In severe AM, repeated ear, respiratory, and gastrointestinal infections may be the presenting and dominating symptoms. Hepatomegaly is commonly diagnosed. Unfortunately, severely affected children usually succumb to infections during their first years of life .
Clinical findings may raise suspicion as to a lysosomal storage disease but are hardly diagnostic of AM. Laboratory analyses of blood and urine samples may yield further hints at a specific disorder. In detail, AM is characterized by an increased excretion of mannose-containing oligosaccharides, and peripheral blood smears often reveal the presence of vacuoles in lymphocytes . In order to confirm a tentative diagnosis of AM, the activity of alpha-mannosidase should be assessed in leukocytes or fibroblasts. The identification of the underlying MAN2B1 mutation isn't mandatory if the results of enzyme activity measurements are in agreement with a diagnosis of AM, but knowledge regarding the genotype of a determined patient may largely facilitate the workup of related cases, including, but not limited to, prenatal diagnosis.
To date, there is no curative treatment. Decades ago, the supplementation of zinc had been postulated to augment the residual activity of alpha-mannosidase. This hypothesis was based on observations made in vitro but couldn't be reproduced in vivo . Because enzyme replacement therapy and hematopoietic stem cell transplantation have successfully been used to treat other lysosomal storage disorders, they have also been considered in AM patients. In animal models, both have yielded promising results  , and although few patients have been treated with these methods, important advances have been made in men:
Beyond that, affected individuals should be provided symptomatic treatment and supportive care :
AM follows a progressive course. Available data - which have been gathered before the approval of velmanase alfa for AM therapy - show that mortality is high for severe AM, where children die from infections or central nervous system disorders. Hydrocephalus, cerebral atrophy, and demyelination have all been related to the disease. Mild to moderate AM is associated with significant morbidity, with the progressive loss of cognitive and motor functions. The majority of patients becomes wheelchair-dependent and requires assistance in their everyday life. Little is known about the life expectancy of these individuals, but several patients have been reported that lived beyond the age of 50 .
Whether velmanase alfa treatment is associated with long-term improvements, increased quality of life and prolonged survival times could not yet be proven, but experts are confident that enzyme replacement therapy may change the outcome for the better .
AM is inherited in an autosomal recessive manner. The disease is caused by mutations of the MAN2B1 gene, which is located at 19p13.13 and encodes for alpha-mannosidase. Alpha-mannosidase is a lysosomal enzyme catalyzing the hydrolysis of alpha-linked mannose residues from N-linked oligosaccharides. To this day, >100 pathogenic mutations of MAN2B1 have been described. Insertions, deletions, duplications, missense, nonsense, and splicing mutations have been reported, with most of them being private . However, missense mutation c.2248C>T (p.R750W) has been identified in several kindreds from different countries. In agreement with the haplotype background of carriers of this mutation, it has been speculated to originate from two founder events. It accounts for about a quarter of all cases known to date .
The establishment of genotype-phenotype correlations has initially been hindered by the 4spectrum of mutations. Still, Kuokkanen and colleagues have made valuable contributions to this field and have identified a number of mutations that prevent the enzyme's transport to the lysosome, thereby inducing a complete deficiency of alpha-mannosidase. These mutations affect arginine, proline, and cysteine residues, and they include the aforementioned mutation c.2248C>T . However, most individuals who are homozygous for c.2248C>T show an intermediate phenotype, which is suggestive of the influence of additional genetic or environmental factors . Additional research is required to identify these factors, to evaluate how they may modulate the phenotype associated with a given genotype.
AM is a rare, but pan-ethnic disease. The incidence of AM has been estimated to be 1 in 500,000 life births .
MAN2B1 mutations may result in a dysfunctional active site of alpha-mannosidase or may interfere with the post-translational processing of the enzyme, either causing it to be retained in the endoplasmatic reticulum or remain dysfunctional despite locating to the lysosomes. Mutations leading to retention in the endoplasmatic reticulum are associated with a complete lack of enzyme activity and have thus been postulated to induce severe AM . This hypothesis, however, is not unequivocally supported by clinical findings: Retention in the endoplasmatic reticulum is observed in individuals carrying mutation c.2248C>T, but most of these patients develop moderate AM only  . On the other hand, residual enzyme activities between 5 and 15% are measured in AM patients with mild, moderate, or severe disease, so there is no apparent correlation between test results and disease severity. Possibly, these results don't reflect true alpha-mannosidase activity but rather the activity of related enzymes able to cleave the substrate .
In any case, deficiency of alpha-mannosidase results in the progressive accumulation of partially degraded mannose-containing oligosaccharides in the lysosomes . Subsequent lysosomal swelling interferes with a myriad of cellular functions but doesn't seem to be the only trigger of clinical disease . Further research is required to shed more light on the pathogenetic mechanisms underlying AM.
Affected families may benefit from genetic counseling. Prenatal diagnosis is largely facilitated if the genotypes of the parents-to-be are known, but a more general approach is also feasible. Newborn screenings for lysosomal storage diseases have been proposed in distinct countries and may be based on urinary oligosaccharide profiles .
AM is a rare lysosomal storage disease. Due to alpha-mannosidase deficiency, mannose-containing oligosaccharides cannot be adequately degraded and accumulate within the lysosomes of cells in all tissues. Notwithstanding differences in the enzymes' substrates, the pathophysiological events causing clinical disease in AM patients largely resemble those observed in other lysosomal storage diseases. Thus, there are considerable overlaps between the clinical presentations of AM, mucopolysaccharidosis, mucolipidosis, and other entities belonging to this group of disorders. They are characterized by Hurler-like facial features, skeletal abnormalities, and intellectual disability, and should therefore be included in the differential diagnosis. Analyses of blood and urine samples, enzyme activity measurements, and molecular biological studies should be carried out to distinguish these conditions and to confirm a tentative diagnosis of AM. While the disease remains incurable, enzyme replacement therapy has recently been approved for the treatment of determined forms of the disease.
Alpha-mannosidosis (AM) is a hereditary lysosomal storage disease. Affected individuals harbor mutations of the MAN2B1 gene, which lead to alpha-mannosidase deficiency. Alpha-mannosidase is an enzyme required for the breakdown of determined macromolecules in the lysosomes of cells in all tissues, and in the absence of functional alpha-mannosidase, these macromolecules accumulate and interfere with a myriad of cell functions. Accordingly, AM is a multisystem disorder. Patients show coarse facial features and skeletal abnormalities comprising, but not limited to, abnormal curvature of the spine and knock-knees. Most are mentally retarded. Delays in the acquisition of language and speech may be due to intellectual disability, but are often associated with hearing impairment. Furthermore, AM patients suffer from immunodeficiency and are prone to infections. In sum, the clinical spectrum is broad and ranges from severe disease, often fatal in infancy, to intermediate phenotypes and mild AM, which is associated with prolonged survival.
The diagnosis of AM is based on laboratory analyses of blood and urine samples, measurements of the activity of alpha-mannosidase, and genetic studies. Curative treatment is not available, and, to date, affected individuals have mainly been provided with symptomatic therapy and supportive care. In this context, physical and occupational therapy, surgical interventions, hearing aids, and educational support, among others, have been offered according to the needs of the individual patient. Beyond that, in 2018, human recombinant alpha-mannosidase has been approved to treat non-neurological symptoms of mild to moderate AM. This drug, whose name is velmanase alfa, essentially compensates for the deficiency of alpha-mannosidase and aids by degrading the abovementioned macromolecules. Experts are confident that velmanasa alfa may improve the prognosis of patients suffering from this progressive disease.