APBD (Adult Polyglucosan Body Disease) is an elusive genetic disorder. One study estimates that one in 34.5 Jews of Ashkenazi descent carry the Y329S genetic mutation that causes APBD.
APBD has many similarities to other disorders and is often mis-diagnosed. Symptoms in both men and woman begin as early as age 35 and are shared with other illnesses such as Prostate Cancer, ALS, Alzheimer’s, Multiple Sclerosis, Peripheral Neuropathy, Benign Prostatic Hyperplasia (BPH), and Spinal Stenosis.
Progress made in the understanding of APBD is not only helping uncover its mysteries but is providing information about a range of other disorders, including:
· Lafora Disease/ Ubiquitin ligase deficiency
· AMPK deficiency
· All 16 known glycogen storage diseases, especially ones caused by excessive accumulation of glycogen such as Pompe Disease (GSD type II), Forbes-Cori Disease (GSD type III), Anderson’s Disease (GSD type IV fatal infantile form of APBD) , and MacArdle Disease (GSD type V)
· Other neurodegenerative diseases with involvement of polyglucosan such as Alzheimer's & Parkinson’s Disease
· Muscular Dystrophy and other manifesting heterozygous disorders.
Below is a brief discussion of how APBD research may be of value to other diseases:
Lafora Disease/ Ubiquitin ligase deficiency: Lafora Disease affects young people from ages 5 to 25. It is caused by an over-production of glycogen. Although the patient has a normal amount of glycogen branching enzyme, there is not enough enzyme to support the excessive glycogen production. Malin, a ubiquitin ligase - one of more than three hundred ubiquitin ligases - is associated with Lafora Disease. Another ubiquitin ligase called RBCK1 has been found to cause polyglucosan accumulation, but unlike Lafora Disease it causes immune deficiency, cardiomyopathy, and muscle weakness. As a result, polyglucosan bodies are created as in APBD, and damage otherwise healthy cells. Significant progress has been made in APBD research towards reducing glycogen production (glycogen synthase). These results are also expected to apply to Lafora Disease and other ubiquitin ligase deficiencies.
Diabetes: Insulin resistance is at the center of Type 2 diabetes. At the heart of insulin resistance is faulty glycogen metabolism. Our understanding of the details of glycogen metabolism is crucial to understanding insulin resistance and overcoming it. Current APBD research reveals a major new entryway into understanding and treating insulin resistant states.
Pompe Disease: (GSD type II) Pompe Disease, one of the 16 glycogen storage diseases, causes a destructive buildup of normal glycogen in the cells. A recessive genetic disorder, it comes in several varieties. One of these varieties affects children under the age of one. Other varieties can affect children at an older age, or even as young adults. Late-onset Pompe disease can have some of the same neuro-muscular effects as APBD. In addition, it can sometimes lead to respiratory arrest and death. Reducing glycogen could also significantly help Pompe Disease as well as many of the other glycogen storage diseases.
Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's Disease: In both ALS and Alzheimer's Disease recent research points to deleterious involvement of an enzyme called “Glycogen Synthase Kinase 3” or GSK-3 in regulating Glycogens Synthase. (Evidence points to GSK-3 being involved in other diseases as well including cancer, Type 2 diabetes, and bipolar disorder.) It is quite possible that APBD research on reducing Glycogen Synthase may provide clues about these other diseases.
Muscular Dystrophy (MD) and other manifesting heterozygous disorders: With MD, like APBD, there are a percentage of patients characterized as manifesting heterozygotes. This is a strange phenomenon as both diseases are typically recessive genetic disorders. In other words, in the normal presentation of recessive disorders, including APBD and MD, both parts of a gene pair (father and mother’s side) must carry the genetic defect for the patient to have the disease. However, in some cases a patient may present with a “full blown” case of APBD or MD, despite having a defect on only one side of the gene pair. These manifesting heterozygote patients are sometimes called “manifesting carriers.” Results of a several year, multi country, collaborative research endeavor led by Columbia University is illuminating other manifesting heterozygous disorders in addition to APBD and MD. During the course of mining for mutations that cause APBD, our researchers developed a new molecular approach to identify mutations that will solve the genetic dilemma from which other patients with manifesting heterozygous disorders suffer. Dr. Akman and colleagues will soon publish an article which will change the definition of the manifesting heterozygote patient. They will also suggest some unique treatment possibilities. Dr. Akman and collaborators have already identified two such mutations affecting carriers of APBD mutations. This methodology and genetic information will soon be available for general public and it is believed that our soon to be published results will benefit MD and other diseases.
The above list of related disorders is by no means complete. One should remember that glycogen production and consumption are fundamental processes to human metabolism. APBD is one of many ways the glycogen process can be broken. As we solve more pieces of the APBD puzzle, we look forward to seeing our research results applied to other disorders.