A pseudodeficiency allele or pseudodeficiency mutation is a mutation that alters the protein product or changes the gene's expression, but without causing disease. For example, in the lysosomal storage diseases, patients with a pseudodeficiency allele show greatly reduced enzyme activity, yet they remain clinically healthy.

In medical genetics, a false positive result occurs in an enzyme assay

Enzyme assay

Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.-Enzyme units:...

 test when test results are positive, but disease or morbidity is not present. One possible cause of false positive results is a pseudodeficiency allele. Disease may also be present, but at a subclinical level.

Examples

• Tay-Sachs disease
  Tay-Sachs disease
  Tay–Sachs disease is an autosomal recessive genetic disorder...
  
  . Enzyme assay testing was especially effective among Ashkenazi Jews because fewer pseudodeficiency alleles are found in this population, as compared with the general population. Carrier screening has not been as reliable in the general population.

• Metachromatic leukodystrophy
  Metachromatic leukodystrophy
  Metachromatic leukodystrophy is a lysosomal storage disease which is commonly listed in the family of leukodystrophies. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous...
  
  . Low arylsulphatase A
  Arylsulfatase A
  Arylsulfatase A is an enzyme that breaks down cerebroside 3-sulfate into cerebroside and sulfate. In humans, arylsulfatase A is encoded by the ARSA gene.-External links:* *...
  
   activity can occur in healthy individuals. This poses a challenge in genetic testing, making it difficult to distinguish between patients who are at risk of developing the disease and those who are healthy carriers of a pseudodeficiency mutation. Metachromatic leukodystrophy is a classic example of the difficulties caused by pseudodeficiency in carrier screening, because very high pseudodeficiency carrier frequencies have been detected in some populations.

Implications

A pseudodeficiency allele may indicate a deficiency of the enzyme assay method, or it may reflect incomplete understanding of the enzyme's activity.

• The enzyme assay may be invalid because of differences between the natural substrate and an artificial substrate used in testing.
• The gene may be expressed differently in different tissues, causing a positive result in the tissue that is tested even though no disease is present. Blood serum is often used for enzyme assay testing because it can be sampled inexpensively. Testing with other tissue types may produce more reliable results.
• The enzyme assay may be valid, but understanding of the disease and the metabolic pathway
  Metabolic pathway
  In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
  
   in which it occurs may be incorrect or incomplete.

Because of pseudodeficiency alleles, the results of enzyme assay testing in one population cannot be generalized to other populations. For example, while Tay-Sachs screening was able to nearly eliminate Tay-Sachs disease among Ashkenazi Jews

Ashkenazi Jews

Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim , are the Jews descended from the medieval Jewish communities along the Rhine in Germany from Alsace in the south to the Rhineland in the north. Ashkenaz is the medieval Hebrew name for this region and thus for Germany...

, similar screening in the general population has proven less effective.

For some genetic diseases, especially those that have low penetrance

Penetrance

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...

 or are easily treatable, carrier screening

Genetic testing

Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...

may be of questionable value when pseudodeficiency alleles are present at high frequency.