When Susan Coddon, a member of the board of directors of the Adult Polyglucosan Body Disease Research Foundation (APBDRF) e-mailed me a few weeks ago, I was intrigued. “Polyglucosan” didn’t ring any bells. Her husband learned he had the underrecognized condition in 2007, following a misdiagnosis of multiple sclerosis years earlier.
The APBDRF website describes a typical case: “In my early 50’s, I first experienced numbness in my hands, cramps, stiffness and heaviness in my legs. Also muscle twitching, soreness, foot drag and stumbling. Initially, I was incorrectly diagnosed with hereditary peripheral neuropathy. It took 13 years for a proper diagnosis.”
A recent article in the Jewish Daily Forward relates Hollywood photographer Robert Zuckerman’s multi-year diagnostic odyssey. That’s not unusual.
“Almost every patient we speak to goes on a 2 to 10 year search, in some cases even families of neurologists. We’re trying to get the word out, because APBD is very hard to distinguish from many other diseases,” Jeff Levenson, DMD, senior advisor to the APBDRF, told me.
APBD is inherited as an autosomal recessive trait, although many carriers have late-onset symptoms, making them “manifesting heterozygotes.” A genetic diagnosis may emerge from sequencing the exome, the protein-encoding part of the genome. Because APBD is actually an “atypical presentation” of a more familiar condition, tests for common neurological disorders are negative.
The particular problem of diagnosing APBD, however, may have more to do with its name than its DNA.
A COLLECTION OF COMMON SYMPTOMS
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.
Alarm bells may sound. Is it ALS? MS? Prostate cancer? Parkinson’s disease?
Evaluation begins: blood tests, electromyograms, spinal taps, brain MRIs, which might show the telltale lack of white matter myelin of a leukodystrophy. But which one? Initial genetic tests come back normal, not surprising because the symptoms do not exactly match those of the more prevalent or better-studied inherited leukodystrophies.
If a health care provider strongly suspects an atypical case of a common condition, treatment may begin. Neurontin, prednisone, anti-seizure meds. Or perhaps more than one illness is at play – benign prostatic hyperplasia might explain the urination changes, a neuropathy the distal limb numbness.
Physical or occupational therapists can help a patient with activities of daily living while the docs try to figure out why the patient isn’t fitting into any categories. And why would an internist or even a neurologist trying to diagnose a tired and shuffling 50-something with urgency issues suspect a glycogen storage disease known for fatally disrupting the heart, nerves, and muscles of babies?
For that’s what APBD is: glycogen storage disease type IV. The unfamiliar “polyglucosan” intrigued me, so I got out my old textbooks to investigate the term, which sounds more like a sushi ingredient than a polysaccharide.
A CONFUSING NAME
Polyglucosan is a form of glycogen, which is a chain of glucose molecules. Glucose is the 6-carbon sugar whose chemical bonds provide the energy that cells use to manufacture ATP, the biological energy currency.
Glycogen normally branches at every 12 to 18 glucose units, and an enzyme – glycogen branching enzyme 1 (GBE1) – makes this happen. APBD arises from specific mutations in the gene that encodes GBE1 that allow some residual enzyme activity. Long unbroken chains of glycogen grow and glom and gum up the astrocytes that keep neurons functioning. Meanwhile, at the whole-body level, fatigue sets in as glucose becomes tied up. Mutations that lead to no enzyme activity are fatal in early childhood.
The “body’ in the disease’s name refers to the clumps of abnormal glycogen, not the person. Detecting polyglucosan requires special staining of a biopsy from a leg vein, finding deficiency of the enzyme in muscle samples or skin fibroblasts, and identifying mutations in the GBE1 gene in saliva.
Neither Lehninger’s Principles of Biochemistry, Morrison and Boyd’s Organic Chemistry, nor Bloom and Fawcett’s Histology, all circa 1975, mentioned polyglucosan or even glucosan. Googling “polyglucosan” led repeatedly back to APBD. Then I found “glucosan” at drugs.com, which referred to standard medical dictionaries that say “see glucan.”
The medical literature is confusing too. A 1980 paper in the journal Brain, from Salvatore DiMauro’s group at Columbia University, offers a murky definition: “A general term – polyglucosan body – is introduced to refer to these structures in all the circumstances in which they may occur,” which includes rare inherited conditions such as Lafora’s disease, movement disorders, glycogen storage disease type IV, diabetes, and normal aging. The abstract of a 2011 paper from the group in Human Molecular Genetics defines polyglucosan as “a poorly branched form of glycogen,” which seems rather vague. Finally, the title of a 2013 Annals of Neurology report helps: “Abnormal glycogen in astrocytes is sufficient to cause adult polyglucosan body disease.”
Given the terminology and the high prevalence of the individual symptoms, it isn’t surprising that APBD has a history of misdiagnoses, including Fabry disease, ALS, liver disease, and atypical Parkinsonism.
Perhaps the rhyming of three of the four letters of APBD, plus the fact that the term “polyglucosan” is broader and much less commonly used than “glycogen,” contributes to protracted diagnostic journeys. The condition may be fairly common, but often misidentified. In one study, among 380 Ashkenazi Jews the carrier rate was 1 in 34.5 — about the same as Tay-Sachs and other “Jewish genetic diseases.” But of course DNA doesn’t know the religious affiliation of the person in which it resides. Anyone can have APBD.
JScreen.org doesn’t yet list APBD but will do so soon, and it’s among the 14 glycogen storage disorder tests that Prevention Genetics offers. I wonder how common it is in other populations, and how often it is indeed shoehorned into other diagnostic codes, and patients receiving inappropriate treatments.
EMBRACING EXOME SEQUENCING
The APBD story offers a powerful example of the evolution of classifying disease by phenotype to the precision of classifying by genotype.
The polyglucosan disorders may remain an umbrella term, but within the grouping, APBD is distinct. For example, it’s different from a condition described in a 2013 Annals of Neurology report on a polyglucosan build-up that weakens muscles and affects the heart, but due to mutation in a different gene, RBCK1. (It encodes a ubiquitin ligase, part of the cell’s garbage disposal system.)
Panels of gene tests related by function are perhaps the dying embers of the “round-up-the-usual-suspects” approach to diagnose inherited disease. In contrast, exome sequencing can illuminate mutations in genes that clinicians might not have considered – like APBD being a glycogen storage disease.
Once exome sequencing becomes routine – say 5 years from now – a health care professional evaluating an adult with distal limb weakness, profound fatigue, and urinary urgency can pop a blood sample into a device that will quickly detect, or rule out, APBD – and other inherited conditions that it masquerades as. Meanwhile, APBD researchers are trying to get the word out about this illness that is still so easily confused with others.
I think all the ice buckets were used up on ALS, so I’m hoping that people with numb feet, fatigue, and urinary issues will mention the possibility of APBD to their health care providers.