Clinical characteristics of alpha-mannosidosis1

The onset and type of symptoms will depend on the severity of the disease. The salient features of alpha-mannosidosis are detailed below.

Main features of alpha-mannosidosis2

Facial features

Several facial traits are characteristic of alpha mannosidosis. Facial traits may be subtle, to the degree that they can even be overlooked by an inexperienced observer5B. However, independent of race and background genetics, all patients will have some degree of coarse Hurler-like features. Classically, the head is large with a prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth and prognathism. The neck of patients is usually short6C. Depending on the severity, some patients will develop hydrocephalus in the first year of life7C.

Description

Classically a large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth and prognathism2B

The neck is usually short


Notes

Facial traits may be subtle and difficult to distinguish2B

Skeletal abnormalities

Bone disease ranges from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis8B. Clinical or radiographic signs of mild-to-moderate dysostosis multiplex are present in 90% of patients. Conventional x-rays may reveal thickened calvaria; ovoid configuration, flattening and hook-shaped deformity of the vertebral bodies; hypoplasia of the inferior portions of the ilia; and mild expansion of the short tubular bones of the hands. The most frequent abnormalities are scoliosis and deformation of the sternum, which are present at birth9B. Genu valgus (knock-knee) is also common and contributes to gait disturbance. Similar to the same complication in Gaucher disease, genu valgus may be treated with epiphyseal arthrodesis at a young age before the epiphyseal lineation of the knee is closed10B.

Over time, in long-term survivors of the disease, from the second till the fourth decade of life patients may develop destructive polyarthropathy, especially coxarthrosis and gonarthrosis8B. Many of the skeletal abnormalities are so severe that orthopaedic corrections are needed.

Description

Most frequent abnormalities are scoliosis and deformation of the sternum2C


Notes

Clinical or radiographic signs of mild-to-moderate dysostosis multiplex are present in 90% of the patients2C

From the second to fourth decade of life patients may develop destructive polyarthropathy, especially coxarthrosis, but also gonarthrosis3C

Hearing impairment

Most individuals will have early-childhood-onset8B. Indeed, moderate or severe sensorineural hearing loss seems inevitable. In many, if not most individuals, hearing loss is partly conductive and partly sensorineural9B. Hearing deficit is regularly worsened by otitis or accumulation of fluid in the middle ear, thereby adding a mechanical component to hearing impairment. If untreated in early childhood, reduced hearing will contribute to disturbances in both speech and mental function10B.

Description

Moderate or severe sensorineural hearing loss inevitable2D


Notes

Regularly worsened by otitis or accumulation of fluid in the middle ear, adding a mechanical component to the hearing deficit2D

Ocular changes

Hyperopia, myopia, or slight strabismus are considered to be common14B. Lenticular changes, superficial corneal opacities, and blurred discs appear to be rare, but have been reported14B. Most of these ophthalmologic findings can be corrected.

Description

Slight strabismus is common2E


Notes

Hyperopia more frequently than myopia2E

Mental disorders

Mental retardation

Early psychomotor development may appear normal, but intellectual disability is present in all individuals15B. Persons with adult-onset disease are usually mildly or moderately intellectually disabled with an IQ of 60-80. In many patients, the first symptom is often delayed development of speech or motor or mental functions with a declining tendency over later decades16B. The measurement of total mental performance is complex, and it has been reported that patients tend to score better in nonverbal tests16B. Individuals are late in initiating speech (sometimes as late as the second decade of life)16X, their vocabularies are restricted and their pronunciation is difficult to understand, which may be a consequence of congenital and/or later-onset hearing loss.

Description

Almost all patients show some degree of mental retardation4F

Delayed development of language2F


Notes

First symptom may be delayed development of speech or motor or mental functions4F

All the patients generally mildly-moderately mentally retarded with a declining tendency over later decades2F

Considerable variation in clinical progression3F


Psychiatric symptoms

Psychiatric symptoms distinct from the intellectual disability may affect 25% or more of individuals with alpha mannosidosis17B. Onset is typically from late puberty to early adolescence. 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, hallucinations18B. Periods of psychosis usually last 3 to 12 weeks, and are followed by a long period of hypersomnia and may be accompanied by loss of abilities, such as difficulty speaking or inability to read19B. The organic causes of psychiatric symptoms are unclear19B.

Description

Psychiatric symptoms present in >25% of patients, typically presenting in in adolescence or early adulthood2H


Notes

Form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs2H

Can present with acute and recurrent attacks of confusion, sometimes with anxiety, depressions or, hallucinations2H

Periods of psychosis usually last 3 to 12 weeks, followed by a long period of hypersomnia and sometimes loss of abilities2H


Motor function disturbances

Ataxia is the most characteristic and specific motor disturbance20B. The development of motor functions in affected patients is generally slow, and children appear clumsy21B. This is caused by a combination of factors including muscular weakness, joint abnormalities and ataxia due to cerebral atrophy and cerebral demyelination. As such, affected children learn to walk somewhat later than normal22B.

In addition to joint abnormalities and metabolic myopathy, the disease affects areas of the brain that are responsible for fine motor function and muscular coordination23B. Muscular hypotonia is common. Spastic paraplegia has also been described, but in general, spasticity, rigidity and dyskinesia are not seen. The impairment motor function is progressive by nature, with gradual worsening in the second and third decade of life24B. However, there may be considerable variation in clinical progression.

Description

Development of motor function is generally slow2G


Notes

Clumsiness caused by muscular weakness, joint abnormalities and ataxia due to cerebral atrophy and cerebral demyelination2G

Impairment is progressive, with gradual worsening in the second and third decades2G

Immunodeficiency and autoimmunity

Patients with alpha mannosidosis suffer from recurrent infection, especially during the first decade of life25B. Analysis of humoral and cellular immunological functioning has demonstrated that post-immunisation levels of antibody are lower in patients with alpha mannosidosis, thus showing a decreased ability to produce specific antibodies after antigen presentation. Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in serum or because of the lack of specific antibodies26B. In addition, leukocytes have a decreased capacity for intracellular killing, which may contribute to the frequently serious outcomes of bacterial infections26B.

In alpha mannosidosis, increased levels of oligosaccharides in plasma are found27B. Oligomannosides with five and six mannose residues bind to interleukin-2 (IL-2) receptors and alter IL-2-dependent responses. Since IL-2 activates T-, B- and NK cells, it can be hypothesised that blockage of this receptor is responsible for the immune deficiency present in alpha mannosidosis.

Description

Patients suffer from recurrent infection, especially in the first decade of life2I


Notes

Blockage of IL-2 receptor may be involved2I

Renal and cardiac complications

Cardiac and renal complications are rarely encountered28B. End-stage kidney failure has been reported in only one case, which was managed by kidney transplant29. In some case descriptions, a murmur of the heart has been noted, but manifest heart disease has not been documented28B.

  1. Beck M Olsen KJ, Wraith JE et al. Natural history of alpha-mannosidosis: a longitudinal study. Orphanet J Rare Dis 2013;8:88
  2. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  3. Malm D, et al. The natural course and complications of alpha-mannosidosis—a retrospective and descriptive study. J Inherit Metab Dis. 2014 Jan;37(1):79-82.
  4. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/
  5. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/
  6. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  7. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  8. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  9. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/
  10. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  11. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  12. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  13. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  14. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/
  15. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  16. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  17. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  18. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  19. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  20. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  21. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  22. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  23. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  24. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  25. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  26. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/.
  27. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21
  28. Malm D, Nilssen O. Alpha-Mannosidosis. NCBI. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1396/
  29. Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21

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