1.1 Name of the disease (synonyms)

α-Mannosidosis, lysosomal α-D-mannosidase deficiency, and α-mannosidase B deficiency.

1.2 OMIM# of the disease

OMIM# 248500.

1.3 Name of the analysed genes or DNA/chromosome segments

MAN2B1, LAMAN, and 19p13.2.

1.4 OMIM# of the gene(s)


1.5 Mutational spectrum

More than 40 different disease-causing mutations have been reported. The vast majority of patients studied originate from Europe. The genetic aberrations 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, the missense mutation c.2248C>T, resulting in the replacement of arginine with tryptophan at amino acid position 750 (p.Arg750Trp) appears to be frequent among α-mannosidosis patients, as it has been reported from most European populations studied, accounting for more than 30% of all disease alleles detected (reviewed in 1 and 2).

1.6 Analytical methods:

Oligosaccharides in urine: elevated urinary excretion of mannose-rich oligosaccharides can be demonstrated by thin-layer chromatography or high-performance liquid chromatography. This finding is suggestive of α-mannosidosis, but not diagnostic.

Acid α-mannosidase activity: the most efficient and reliable method of establishing the diagnosis of α-mannosidosis is the assay of acidic α-mannosidase activity in leucocytes or in 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 leucocytes is 5–15% of normal activity. Residual enzyme activity might represent α-mannosidase activity from other organelles or compartments (eg, golgi apparatus or cytosol), as they show 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. Such testing is not performed routinely. In carriers, acid α-mannosidase enzyme activity might occasionally overlap with that of normal controls and is therefore unreliable for carrier detection.

Genetic testing: identification of disease-causing mutations is carried out on DNA from peripheral blood cells by PCR amplification of all 24 MAN2B1 exons followed by DNA sequencing. If the mutation(s) is/are known, genetic testing might be carried out by allele-specific DNA sequencing. For prenatal testing, carrier analysis of parents (mutation identification) must be carried out before pregnancy.

1.7 Analytical validation

DNA analysis is carried out by bidirectional DNA sequencing. The homozygous or compound heterozygous state of the index person is confirmed by carrier testing of the parents.

1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence)

Estimated frequencies of α-mannosidosis range from 1:750 000 (Norway) to 1:500 000 (Australia).

1.9 If applicable, prevalence in the ethnic group of investigated person

Prevalence has been estimated only in Norway and Australia.

1.10 Diagnostic setting

Comment: α-Mannosidosis is a congenital disorder; hence, predictive testing is never carried out in non-affected individuals.

2. Test characteristics

2.1 Analytical sensitivity (proportion of positive tests if the genotype is present)

Sensitivity is 98% in patients who are negative for MAN2B1 activity.

2.2 Analytical specificity (proportion of negative tests if the genotype is not present)

Biochemical test (MAN2B1 activity measurements) is always carried out before genetic testing. This test is conducted by the referring laboratories or clinical centres. Thus, as genetic testing is only carried out on patient samples that have been assayed and found negative for MAN2B1 activity, analytical specificity cannot be calculated as the genotype is always present.

2.3 Clinical sensitivity (proportion of positive tests if the disease is present)

By DNA sequencing, we detect 98% of all disease alleles present in patients who have been subjected to biochemical pre-screening.

2.4 Clinical specificity (proportion of negative tests if the disease is not present)

Not applicable to index patients as genetic testing depends on MAN2B1 deficiency determined by biochemical testing. For prenatal genetic testing, the clinical specificity is 100% if the parental genotypes are known.

2.5 Positive clinical predictive value (life-time risk to develop the disease if the test is positive)

α-Mannosidosis is a congenital disorder and new index cases already have the disorder (100%). In prenatal cases, the predictive value is 100%, given that parental genotypes are known.

2.6 Negative clinical predictive value (probability not to develop the disease if the test is negative)

Index case in that family had been tested: 100%.

Index case in that family had not been tested: 100%. MAN2B1 is the only gene in which mutations are known to be associated with α-mannosidsosis.


3.1 (Differential) diagnosis: the tested person is clinically affected

(To be answered if in 1.10 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

None, as biochemical testing might be carried out using a blood sample.

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Biochemical testing might be more cost effective as compared with genetic testing, but is less reliable when it comes to carrier diagnosis (see 1.6).

3.1.4 Will disease management be influenced by the result of a genetic test?

3.2 Predictive setting: the tested person is clinically unaffected but carries an increased risk based on family history

(To be answered if in 1.10 ‘B’ was marked)

Not applicable.

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe):

Not applicable.

If the test result is negative (please describe):

Not applicable.

3.2.2 Which options in view of lifestyle and prevention does a person at risk have if no genetic test has been done (please describe)?

Not applicable.

3.3 Genetic risk assessment in family members of a diseased person

(To be answered if in 1.10 ‘C’ was marked)

Not applicable (see 4).

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

Not applicable (see 4).

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Not applicable (see 4).

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

Not applicable (see 4).

3.4 Prenatal diagnosis

(To be answered if in 1.10 ‘D’ was marked)

Prenatal testing is available for pregnancies of carrier parents. Prenatal testing might be performed either by analysis of acid α-mannosidase enzyme activity in foetal cells, obtained by chorionic villus sampling at 10–12 weeks of gestation, or preferably by mutation analysis (genotyping). DNA from the same sources can be used for mutation analysis. Mutation analysis must be carried out in the parents in advance of pregnancy. Genotype does not allow prediction of severity of disease.

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnostic?



Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (please describe).

The results from a genetic test facilitate analysis of other family members, as this will allow allele-specific analysis rather than complete gene sequencing. In particular, this is important with regard to prenatal diagnosis.