Adult Polyglucosan Body Disease(APBD)

Adult polyglucosan body disease is a condition that affects the nervous system. People with this condition have problems walking due to reduced sensation in their legs (peripheral neuropathy) and progressive muscle weakness and stiffness (spasticity).

Damage to the nerves that control bladderfunction, a condition called neurogenic bladder, causes affected individuals to have progressive difficulty controlling the flow of urine. About half of people with adult polyglucosan body diseaseexperience a decline in intellectual function (dementia).

People with adult polyglucosan body disease typically first experience signs and symptoms related to the condition between ages 30 and 60.

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.

What Is Adult Polyglucosan Body Disease(APBD)?

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 GNE1) leads to buildup of unbranched glycogen in cells, which harms neurons more than other kinds of cells.

Most people first go to the doctor due to trouble with urination. The condition is diagnosed by gathering symptoms, a neurological examination, laboratory tests including genetic testing, and medical imaging. As of 2015 there was no cure or treatment, but the symptoms could be managed. People diagnosed with APBD can live a long time after diagnosis, but will probably die earlier than people without the condition.

Adult polyglucosan body disease (APBD) is a glycogen storage disease of adults characterized by progressive upper and lower motor neuron dysfunction, progressive neurogenic bladder and cognitive difficulties that can lead to dementia.

Symptoms

Symptoms and severity can vary greatly from one person to another. Typically, symptoms develop around the fifth decade of life. The initial sign may be related to neurogenic bladder, specifically an increased need to urinate that may eventually progress to cause a near complete loss of bladder control (urinary incontinence). In some cases, urinary difficulties may precede other symptoms by one or two decades.

Another common early sign of adult polyglucosan body disease is a feeling of numbness or weakness in the hands and feet (paresthesia). Affected individuals may experience an inability to lift the front part of the foot (foot drop), which results in the need to drag the front of the foot on the ground when walking.

Affected individuals may experience weakness in the arms and legs. Eventually, affected individuals may develop progressively increased muscle tone and stiffness of the legs (spasticity), causing difficulty walking. Most individuals may eventually need assistance walking (e.g., cane or walker), and ultimately the use of a wheelchair may be required.

Some affected individuals may develop mild cognitive impairment, most commonly, mild attention and memory deficits. In some cases, cognitive problems may worsen, resulting in progressive loss of memory and intellectual abilities (dementia).

Adult polyglucosan body disease is a condition that affects the nervous system. People with this condition have problems walking due to reduced sensation in their legs (peripheral neuropathy) and progressive muscle weakness and stiffness (spasticity).

Damage to the nerves that control bladder function, a condition called neurogenic bladder, causes affected individuals to have progressive difficulty controlling the flow of urine. About half of people with adult polyglucosan body disease experience a decline in intellectual function (dementia). Most people with the condition first go to the doctor due to the bladder issues.

People with adult polyglucosan body disease typically first experience signs and symptoms related to the condition between ages 30 and 60.

APBD begins, typically after age 35, with a numb foot that drags during walking. The hands too may exhibit this peripheral neuropathy, and the numbness may progress towards the body’s center. Fatigue sets in, and then urinary frequency and incontinence begin. There may be mild cognitive impairment.

The disorder is characterized bya gradual progression of involvement of both the central andperipheral nervous systems with a variable phenotype that oftenincludes pyramidal tetraparesis, sensory neuropathy in the lowerextremities, neurogenic bladder, and occasionally cognitiveimpairment. The disease progresses, relentlessly, from dif?cultywalking, impaired balance, progressive weakness, eventuallyinvolving the upper body, and can lead to early death.

Causes

Adult polyglucosan body disease 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 protein, this can affect many organ systems of the body, including the brain.

Investigators have determined that the GBE1 gene is located on the short arm of chromosome 3 (3p12.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”.

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 each parent. 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 found, however, 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 deep 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.

The GBE1 gene contains instructions for creating (encoding) a protein called glycogen branching enzyme or GBE. This enzyme is required for the proper creation (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 glycogen branching enzyme. This results in improperly formed glycogen which accumulates in various tissues of the body in the form of 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, and/or kidneys. 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 is not clear.

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 1,4-alpha-glucan-branching enzyme.

Diagnosis

Along with evaluation of the symptoms and a neurological examination, a diagnosis can be made based on genetic testing. Whether or not a person is making sufficient amounts of functional glycogen branching enzyme can be determined by taking a skin biopsy and testing for activity of the enzyme. Examination of tissue biopsied from the sural nerve under a microscope can reveal the presence of polyglucosan bodies. There will also be white matter changes visible in a magnetic resonance imaging scans.

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 adult polyglucosan body disease, the polyglucosan bodies are mostly and almost uniquely in the fibers extending from nerve cells (axons) as opposed to the body of the cells. The presence of the spheroid, polyglucosan bodies in the fibers is key to the diagnosis.

Reduced activity of the enzyme, GBE, can be measured (assayed) in cultured skin cells (fibroblasts) or certain white blood cells (lymphocytes) found in the peripheral blood. 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 adult polyglucosan body disease, but is available only as a diagnostic service at specialized laboratories.

Polyglucosan bodies.

In adult polyglucosan body disease (APBD), the polyglucosan bodies consist of acellular homogenous periodic acid-Schiff (PAS)-positive material with diastase-resistant glucose polymers and are seen in the central and peripheral nervous system.

Polyglucosans also occur in the following disorders:

• Glycogen Storage Disease Type IV (see Genetically Related Disorders)
• Double athetosis (Bielschowsky bodies)
• Normal older persons (corpora amylacea)
• Clinical distinction between these disorders is possible by neurologic history and examination.

Diagnosis is based on the presence of clinical manifestations of the disease along with the characteristic laboratory findings. Typically, MRI demonstrates cerebral white matter changes in the subcortical and periventricular areas, the posterior limb of the internal capsule and in the brainstem. Cerebral, cerebellar and spinal cord atrophy may also be seen at various stages of the disease.

Reduced GBE activity is observed in cultured skin fibroblasts and peripheral blood lymphocytes of patients with APBD and sural nerve biopsy shows the presence of polyglucosan bodies in the nerve. Genetic testing is essential for the diagnosis and makes nerve biopsy unnecessary.Antenatal diagnosis can be performed but is rarely done as the disease has an adult onset.

White matter changes on MRI.

In individuals with APBD, MRI shows increased T2 signal in the paraventricular white matter and possibly the brain stem, which may have a similar appearance to that seen in multiple sclerosis. However, the images in APBD typically do not enhance.

Treatment

There is no specific therapy for individuals with adult polyglucosan body disease. Treatment is aimed at the specific symptoms present in each person. Treatment generally requires a team approach and may include general internists, urologists, specialists in behavioral neurology, specialists in physical medicine rehabilitation, psychologists, and medical social workers. Genetic counseling may be of benefit 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 in order to drain urine from the bladder. An indwelling catheter is a tube that is inserted into the bladder and left in place in order 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 continue 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.

Investigational Therapies

Researchers are studying the use of triheptanoin, a tasteless, synthetic oil for the treatment of individuals with adult polyglucosan body disease. Triheptanoin is added to the diet of affected individuals and, in initial studies, affected individuals experienced stabilization of disease progression and limited functional improvement. However, larger clinical studies are required to determine the long-term safety and effectiveness of triheptanoin and what role, if any, it has in the treatment of individuals with adult polyglucosan body disease.

Other therapeutic approaches are being studies in cell cultures and animal models of the disease. The hope is that these will soon progress into studies in humans.

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