Adult polyglucosan body disease (APBD) is a rare, genetic disorder characterized by a deficiency of the glycogen-branching enzyme, progressive pyramidal paraparesis, and distal sensory deficit in the legs, resulting in the accumulation of polyglucosan bodies in muscle, nerves, and various other tissues of the body. It is an autosomal recessive leukodystrophy characterized by neurogenic bladder, progressive spastic gait, and peripheral neuropathy. Polyglucosan bodies are composed of large, complex, sugar-based molecules. APBD may be characterized by dysfunction of the central and peripheral nervous systems. The central nervous system (CNS) refers to the brain and spinal cord. The peripheral nerves extend from the CNS to muscles, glands, skin, sensory organs, and internal organs. Peripheral nerves include motor nerves; sensory nerves; and nerves of the autonomic nervous system, which are involved in involuntary body functions. In individuals with APBD, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; progressive urinary difficulties; occasionally mild cognitive impairment or dementia; deficiencies in the autonomic nervous system; and/or other abnormalities. APBD is caused by mutations in the glycogen branching enzyme gene (GBE1) and is inherited in an autosomal recessive pattern.
Adult polyglucosan body disease (APBD) is an orphan disease and a glycogen storage disorder that is caused by an inborn error of metabolism. Symptoms can emerge any time after the age of 30; early symptoms include trouble controlling urination, trouble walking, and lack of sensation in the legs. People eventually develop dementia. A person inherits loss-of-function mutations in the GBE1 gene from each parent, and the lack of glycogen branching enzyme (the protein encoded by GBE1) leads to a buildup of unbranched glycogen in cells, which harms neurons more than other kinds of cells.
APBD was first described in the medical literature as a clinical entity in 1980 (Robitaille Y et. al). The mutation that causes the disorder is in the same gene that causes Andersen’s disease (glycogen storage disease type IV), a severe liver disorder that affects infants. The only difference is that in Andersen’s disease, GBE is completely dysfunctional, whereas in APBD it retains some residual activity.
Causes
APBD is caused by a mutation in the GBE1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular domain, this can affect many organ systems of the body, including the brain.
APBD has traditionally been classified as an autosomal recessive disorder. Broadly, recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from both parents. However, although APBD has been classified as an autosomal recessive disorder, there have been many instances of APBD patients who carry the gene for the p.Y329S mutation in the heterozygous state (meaning they have the mutation in one copy of the GBE1 gene, but not in the other copy). These heterozygous patients should be asymptomatic carriers, yet they manifest symptoms of the disease and have been labeled as “manifesting heterozygotes”. These patients also have no other mutation in the 16 exons of the gene. Exons are specific segments of a gene that code for the protein produced by that gene. A study in 2015 (Akman et al. 2015) has discovered that in a cohort of 35 patients with APBD, 16 heterozygous patients for the p.Y329S mutation were compound heterozygotes for 2 mutations: p.Y329S as well as a mutation that affects a noncoding segment of DNA on the gene (intronic mutation). This intronic mutation resulted in a shortened (truncated) unstable protein. No patient had this intronic mutation in both copies of the GBE1 gene, possibly suggesting perinatal mortality.
The two most common mutations are p.Y329S and the deep intronic mutation.
The GBE1 gene contains instructions for producing (encoding) a protein called glycogen branching enzyme or GBE. This enzyme is required for the proper building (synthesis) of glycogen, which is a complex sugar that normally is broken down (metabolized) into a simple sugar known as glucose. Glucose is one of the main sources of energy in the body. Because of mutations in the GBE1 gene, there are insufficient levels of functional GBE. This results in improperly formed glycogen, which accumulates in various tissues of the body in a form called polyglucosan bodies. Specifically, polyglucosan bodies may accumulate in star-shaped nerve cells known as astrocytes in the brain and spinal cord (central nervous system) and in the processes (axons) that extend from nerve cells as well as in peripheral nerves and the lung, heart, liver, kidneys, and even skin cells. Tissue reduction (atrophy), tissue loss (necrosis), and/or loss of the fatty sheath surrounding nerve fibers (demyelination) may occur. The mechanism by which the polyglucosan bodies cause nerve damage in axons is suggested to be their clogging (Lossos et al. 2009), which, in a neuronal culture, leads to cell death (Kakhlon et al. 2013).
APBD is an autosomal recessive disorder that is caused when a person inherits genes from both parents containing one or more loss-of-function mutations in the gene GBE1 which encodes for glycogen branching enzyme, also called a 1,4-alpha-glucan-branching enzyme.
Diagnosis
A diagnosis is made based upon a thorough clinical evaluation, identification of characteristic findings, a detailed patient history, and a variety of specialized tests.
Clinical Testing and Workup
Direct examination of tissue by a pathologist (electron and light microscopy) can help reach a definitive diagnosis. The microscopic examination of a sample of nerve tissue (sural nerve biopsy) reveals the presence of characteristic polyglucosan bodies. These bodies may also be present in other disorders and may occur in the normal course of aging. However, in individuals with APBD, the polyglucosan bodies are mostly and almost uniquely in the fibers extending from nerve cells (axons) as opposed to the body of the cells (where they are in Lafora disease). The presence of the amorphic polyglucosan bodies in the fibers is key to the diagnosis. However, as taking a sural nerve biopsy is an uncomfortable surgical procedure, a biochemical test of GBE activity in blood cells combined with the genetic screening has replaced the biopsy as the diagnostic method of choice.
Reduced activity of the enzyme, GBE, can be measured (assayed) in cultured skin cells (fibroblasts) or white blood cells (lymphocytes) found in the peripheral blood. In addition, a specialized imaging technique known as magnetic resonance imaging (MRI) may show abnormalities in the conduction tissue (white matter) of the brain.
In some cases, molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the GBE1 gene known to cause APBD but is available only as a diagnostic service at specialized laboratories.
Treatment
To date, there is no specific therapy for individuals with APBD. Treatment is aimed at the specific symptoms present in each person. Treatment generally requires a team approach and may include neurologists, general internists, urologists, specialists in behavioral neurology, specialists in physical medicine rehabilitation, psychologists, and medical social workers. Genetic counseling is recommended for affected individuals and their families.
Antispasmodic medications may be considered for individuals with neurogenic bladder. Some individuals may require the use of an indwelling or an in-and-out catheter to drain urine from the bladder. An indwelling catheter is a tube that is inserted into the bladder and left in place to drain urine. An in-and-out catheter is used one time to drain urine and then removed.
Physical and occupational therapy is of benefit for some affected individuals. The disorder may progress so that devices that help affected people to continue their daily activities, such as braces, hand splints, limb supports, or wheelchairs, are necessary. Affected individuals who are restricted to bed may be made more comfortable with adjustable beds, water mattresses, and/or sheepskin mattress pads. In cases with cognitive impairment, behavioral modification and other cognitive aids may be considered.
There are various approaches to managing neurogenic bladder dysfunction, physical therapy, and mobility aids to help with walking, and dementia can be managed with occupational therapy, counseling, and drugs. Presently a number of promising research initiatives are underway in universities and hospitals in the United States, Canada, and Israel. These studies are in need of funding but due to the small number of known cases, both research funding and participation are small. It is estimated that there are upwards of 12,000 cases in the United States, most of which are undiagnosed.
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