A diagnosis of Alpha Mannosidosis is suspected based upon identification of characteristic findings of a multi-symptomatic presentation, a thorough clinical evaluation, a detailed patient history, and results from the diagnostic tests described below:
A preliminary investigation may be run by measuring mannose-rich oligosaccharides concentrations in urine. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic.1
Diagnosis is confirmed by measuring residual alpha-mannosidase activity in leukocytes of other nucleated cells via a fluorometric assay.2This is the most reliable diagnostic method, along with genetic testing.
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.3
Light microscopy or transmission electron microscopy (TEM) demonstrates vacuoles in bone marrow smears and lymphocytes from peripheral blood in most affected individuals4E . Although detection of vacuoles by microscopy is a useful screening test, supplementary investigations are necessary when α-mannosidosis is suspected4E.
A diagnostic algorithm for alpha mannosidosis has been recently proposed by an international group of experts. Two proposals were developed for diagnostic algorithms of alpha-mannosidosis, one for patients ≤10 years of age and one for those>10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms 5A.
In patients ≤10 years of age, the presence of hearing impairment and/or speech delay is the main motivator to look for alpha-mannosidosis. The presence of hearing impairment or speech delay should then lead the clinician to look for evidence of additional symptoms. If these additional symptoms are not identified, then additional monitoring can be carried out or patients can be referred to a metabolic centre for additional testing at the discretion of the physician.
In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.
For patients >10 years of age, the presence of mental retardation and motor impairment progression and/or psychiatric manifestations (including acute psychotic events) should prompt assessment of clinical history for two of the symptoms listed the figure. If these conditions are not met then additional monitoring can be carried out, or patients can be referred to a metabolic centre for additional testing.
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