Update to: European Journal of Human Genetics (2012) 20, doi:10.1038/ejhg.2012.30; published online 29 February 2012

1. Disease characteristics

1.1 Name of the disease (synonyms):

Abetalipoproteinaemia (Bassen-Kornzweig syndrome).

1.2 OMIM# of the disease:

200100.

1.3 Name of the analysed genes or DNA/chromosome segments:

MTTP.

1.4 OMIM# of the gene(s):

157147.

1.5 Mutational spectrum:

Over 30 variants in MTTP associated with abetaliopoproteinaemia have been described, mostly missense, nonsense and splicing variants located throughout the gene's 18 exons.1, 2, 3, 4, 5, 6 The majority of variants associated with abetalipoproteinaemia are ‘private’ to specific families or ethnic communities.

1.6 Analytical methods:

DNA sequencing of genomic–exonic DNA with at least 20 bp of flanking intronic sequence. In patients where autosomal co-dominant inheritance cannot be excluded or MTTP variant(s) cannot be identified, the APOB gene should be screened as homozygous familial hypobetalipoproteinaemia can give a similar biochemical and clinical phenotype to abetalipoproteinaemia.

1.7 Analytical validation

Where a variant is identified using bi-directional DNA sequencing, the test is repeated from a fresh dilution of DNA for confirmation. When heterozygosity for two variants is found, testing of the patient's parents is recommended to confirm that the two variants are present in trans (ie, on opposite chromosomes).

1.8 Estimated frequency of the disease

(Incidence at birth (‘birth prevalence’) or population prevalence):

Estimated at <1 in 1 000 000.1

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

Not applicable.

1.10 Diagnostic setting:

Comment: Use of genetic testing is essentially limited to confirmatory diagnosis in a subject suspected to be affected, rather than other applications such as predictive testing or prenatal diagnosis.

2. Test characteristics

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present)

Approximately 100%.

2.2 Analytical specificity

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

Approximately 100%.

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present) The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

Abetalipoproteinaemia is clinically characterised by the absence of apolipoprotein (apo)B-containing lipoproteins from plasma together with systemic clinical manifestations. All reported patients have fat malabsorption, acanthocytosis, marked hypocholesterolaemia and deficiency of plasma apoB and its associated lipoproteins; chylomicrons, very low-density lipoprotein and low-density lipoprotein (LDL).1 Most cases are complicated by retinitis pigmentosa, spinocerebellar ataxia and myopathy. Should this constellation of findings be present, there are two possibilities, abetalipoproteinaemia or homozygous familial hypobetalipoproteinaemia. Family screening is useful in differentiating between these conditions as obligate heterozygote parents of homozygous familial hypobetalipoproteinaemia patients have approximately one-third plasma concentrations of LDL cholesterol and apoB, whereas obligate heterozygous parents of abetalipoproteinaemia patients have normal plasma lipid profiles.

2.4 Clinical specificity

(proportion of negative tests if the disease is not present) The clinical specificity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

Approximately 100%.

2.5 Positive clinical predictive value

(life time risk to develop the disease if the test is positive)

100%.

2.6 Negative clinical predictive value

(probability not to develop the disease if the test is negative) Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.

Index case in that family had been tested:

100%.

Index case in that family had not been tested:

Should the constellation of clinical findings be present in an index case, it is possible that they might have homozygous familial hypobetalipoproteinaemia, rather than abetalipoproteinaemia. Homozygous familial hypobetalipoproteinaemia patients receive similar treatment advice as abetalipoproteinaemia patients. Also, there are even rarer conditions called homozygous proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency and familial combined hypolipidaemia (due to homozygous variants in angiopoietin-like protein 3, ANGPTL3) that present with extremely low (but not absent) levels of apoB-containing lipoproteins, but no systemic manifestations.4 In familial combined hypolipidaemia, high-density lipoprotein (HDL) cholesterol levels are also very low. To date, there are only a handful of families in the world reported with these latter two genetic conditions.

3. Clinical utility

3.1 (Differential) diagnostics: 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

Abetalipoproteinaemia is characterised by the absence of plasma apoB-containing lipoproteins with marked hypocholesterolaemia, absence of LDL cholesterol and apoB, and low triglyceride concentrations.1,4,5 In addition, increased serum aminotransferases due to hepatic steatosis, acanthocytosis and fat-soluble vitamin deficiency are found. Abetalipoproteinaemia cannot be distinguished from homozygous familial hypobetalipoproteinaemia clinically.

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

Not applicable.

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)

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

If the test result is positive (please describe).

If the test result is negative (please describe).

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)

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

Not applicable.

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

Not applicable.

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

Not applicable.

3.4 Prenatal diagnosis

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

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

Not applicable.

4. If applicable, further consequences of testing

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)