Genetic Research/Targeted Therapies


Glycogen Branching Enzyme Mutations in the Jewish-American Population

Dr. Akman and Dr. DiMauro have submitted a proposal to determine the frequency of glycogen branching enzyme (GBE) mutations in the Jewish-American population. Their proposal has two specific aims.

Aim 1: To determine how often the typical Y329S genetic mutation occurs in samples provided by the main Jewish DNA repository in New York (DOR Yeshorim) by analyzing DNA sequences. To date 700 DNA samples have been received.

Aim 2: To find a second GBE1 mutation in patients who show typical signs and symptoms of APBD but only one proven Y329S mutation instead of the usual two, called Manifesting Heterozygote Phenomenon. Whole genome sequencing will be used (Columbia University Genome Center New York, NY).

What is Manifesting Heterozygote Phenomenon? APBD is most commonly caused by mutations in the GBE1 gene. This leads to a shortage of glycogen branching enzyme (GBE) which plays a part in storing glucose in a form called glycogen. The disease is usually inherited by receiving one mutated copy of the gene from each parent (autosomal recessive) so that both copies of the GBE1 gene in each cell have an error.

The mutations in both copies of the GBE1 gene can be identified in most APBD patients. However, using standard methods of gene sequencing, in about 40% of patients only one mutation can be identified, even though these patients have the same deficiency of glycogen branching enzyme and the same disease severity as people with mutations in both copies of the gene. A patient with this result is sometimes referred to as a ‘manifesting heterozygote’.

It is thought that the other copy of the brancher enzyme gene is also abnormal even though the abnormality cannot be detected using the common methods of gene sequencing. This mysterious abnormality of the brancher enzyme gene could be due to the complete absence of the gene, a mutation in the area that regulates the production of the gene, or more likely a mutation in the part of the gene that builds the template for making the brancher enzyme protein.

Identifying the other gene will help to more accurately diagnose APBD and open up new avenues of treatment.

Identification of APBD carrier gene frequency in Ashkenazi Jews

In August 2012, Dr. Marvin Natowicz published provocative results of an unexpectedly high frequency of APBD gene mutation in people of Ashkenazi Jewish background. His research found the mutation has a carrier frequency of 1 in 34.5 Ashkenazi Jews. Before this, APBD was considered a rare condition, with only 50 affected individuals described in the medical literature. There are now about 100 known cases. If Dr. Natowicz's results are validated, little known APBD would have a similar carrier frequency to Tay-Sachs disease.

We are interested in validating Dr. Natowicz’s research in order to continue to build awareness of the disease among physicians and researchers. This will support early correct diagnosis of APBD and speed the development of effective treatments.


Goal: $25,000.00

$627.00 raised