Adult Polyglucosan Body Disease.

Diagnosis by Sural Nerve and Skin Biopsy

Adult polyglucosan body disease is a chronically progressive neurological disease first described in 1980.[1] The disease is rare; a recent review listed only 25 cases.[2] The disease is characterized by adult onset, sensorimotor or pure motor peripheral neuropathy, upper motor neuron symptoms, neurogenic bladder, and dementia. Familial clustering is observed in 30% of cases. The disorder derives its name from the widespread accumulation of polyglucosan bodies throughout the nervous system. These inclusions, which are basophilic in hematoxylin-eosin, periodic acid-Schiff positive, and diastase resistant, measure up to 70 [micro]m in diameter. Chemically, they consist of abnormally branched glycogen with small amounts of protein, sulfate, and phosphate groups.[3] The diagnosis can be made by light microscopic evaluation of a sural nerve biopsy. It has been suggested, however, that the diagnosis can be established by a less invasive skin biopsy revealing similar inclusions in myoepithelial cells of apocrine glands.[4]

REPORT OF A CASE

A 61-year-old white man with no family history of neurological disease presented for evaluation of peripheral neuropathy with bowel and a bladder dysfunction. Constipation, bladder dysfunction, and impotence began 20 years before the present evaluation. Foot numbness and tingling, leg weakness, and imbalance followed 10 years later, after a myelographic procedure. By 16 years after onset, the patient required a cane to walk, and he subsequently became wheelchair dependent. He began self-catheterization 2 years before the current assessment. Medications included nortriptyline hydrochloride and acetazolamide.

Physical examination revealed a blood pressure of 112/72 mm Hg and a regular pulse of 80 beats per minute. He was alert, oriented, and cognitively intact. Cranial nerve examination was normal. He could move his upper extremities with full strength, except for minimal weakness in the hypothenar muscles. He was able to move his lower extremities proximally against gravity only, and distally when gravity was eliminated. Tendon reflexes were normal, except for absent ankle reflexes. Tone was decreased in the lower extremities and a Babinsky sign was present bilaterally. Sensation to pinprick and vibration was absent in the toes and decreased in the ankles and, to a lesser degree, in the knees and hands. Coordination was normal in the upper extremities.

Nerve conduction studies and electromyography showed a pattern consistent with an axonal peripheral neuropathy, severe in the lower extremities and minimal in the upper extremities. The neuropathy manifested by absent sural nerve and posterior tibial and peroneal motor responses and by evidence of chronic denervation with reinnervation changes predominantly in the legs. Autonomic testing was normal. Urodynamic studies showed an atonic bladder. Magnetic resonance imaging of the brain and spine and chest radiography were normal. The patient's erythrocyte sedimentation rate was 40 mm/h (reference range, 0-22 mm/h), and his vitamin [B.sub.12] level was 49.22 pmol/L (reference range, 1.48-47.97 pmol/L). Serum protein electrophoresis and immunofixation electrophoresis were normal, except for mildly elevated immunoglobulin (Ig) A (4.12 g/L, normal, [is less than or equal to] 4 g/L). Thyroid function tests were normal. Anti-DS-DNA (IgG), antinuclear antibody, rapid plasma reagin, and Lyme titers were negative. Cerebrospinal fluid examination showed normal cell count and glucose values, elevated protein (90 mg/dL, reference range, 15-45 mg/dL), and no evidence of oligoclonal bands.

MATERIALS AND METHODS

A 2.4-cm, excised segment of left sural nerve, pinned to cork, was fixed in 2.5% glutaraldehyde. A few weeks later, a 6-mm punch biopsy of left axillary skin was obtained and divided, with portions fixed in 10% neutral buffered formalin or 2.5% glutaraldehyde, respectively.

Segments of nerve and skin were embedded in paraffin, and 4-[micro]m sections were stained with hematoxylin-eosin and periodic acid-Schiff, with and without diastase predigestion. Additional nerve sections were stained with Mallory trichrome and Congo red. Portions of nerve and glutaraldehyde-fixed skin were embedded in resin. One-micrometer-thick sections, stained with toluidine blue and with methylene blue-azure II/basic fuchsin, were scanned to select appropriate areas for ultrathin sections. Thin sections were mounted on copper grids, stained with uranyl acetate and lead citrate, and examined with a Philips CM-10 transmission electron microscope.

PATHOLOGIC FINDINGS

Light microscopic study of paraffin- and resin-embedded nerve disclosed a slight to moderate decrease in both small- and large-diameter myelinated fibers. Surviving axons showed rare scattered examples of axonal degeneration, atrophy, secondary remyelination, and regeneration clusters. Intra-axonal basophilic inclusions ranging from 5 to 70 [micro]m in diameter were seen in several nerve fascicles (Figure 1, A). These inclusions appeared round in transverse and ovoid in longitudinal sections. As many as 3 inclusions were detectable in a single fascicular cross section. In longitudinal section, some axons contained more than 1 inclusion (Figure 1, B), and some inclusions had a darker staining center (Figure 1, C). The inclusions stained strongly with periodic acid-Schiff, even after diastase predigestion. There was no evidence of vasculitis, amyloid, inflammation, or onion-bulb formation.

[Figure 1 ILLUSTRATION OMITTED]

Light microscopy of the skin biopsy disclosed 1 complete apocrine unit or coil, with a portion of a second. Apocrine coils were composed of several apposed tubular cross sections, with a mean of 16 tubular profiles in each histologic section. Round or ovoid basophilic inclusions identical to those in the nerve biopsy were seen in myoepithelial cells of the apocrine coils, often indenting the nucleus in a characteristic fashion (Figure 2, A). The inclusions ranged in diameter from 10 to 18 [micro]m. Occasionally, inclusion bodies were seen on each side of one nucleus forming a bow tie configuration (Figure 2, B). As many as 3 inclusions could be found in a single myoepithelial cell (Figure 2, C). Inclusions were also noted in 2 vascular endothelial cells in the papillary dermis. In 4 step sections of skin examined, 32 separate inclusions were seen distributed over the portions of 2 apocrine coils represented in each section, yielding a mean of 4 inclusions per apocrine coil. No inclusions were noted in apocrine duct epithelial cells.

[Figure 2 ILLUSTRATION OMITTED]

Ultrastructural study confirmed dropout of large- and small-diameter myelinated fibers and disclosed inclusions located mainly in myelinated fibers (Figure 3, A). The inclusions were intra-axoplasmic, non-membrane bound, and composed of compact masses of branched fine filaments measuring 6 to 8 nm in thickness (Figure 3, B).

[Figure 3 ILLUSTRATION OMITTED]

COMMENT

Adult polyglucosan body disease is a clinicopathologic entity typically presenting in the fifth to seventh decades with peripheral neuropathy, upper motor neuron signs, neurogenic bladder, and dementia. Many patients, however, lack 1 or more of these features. Less common manifestations include cerebellar dysfunction, isolated dementia of the frontal lobe type, extrapyramidal signs, seizures, an amyotrophic lateral sclerosis-like disorder, and entrapment neuropathy.[2,3,5]

Polyglucosan bodies are the pathologic hallmark of this disease. However, identical or similar inclusions can be seen in other disorders thoroughly reviewed recently, such as type IV glycogenosis and Lafora disease.[6] In a nerve biopsy, more than 1 polyglucosan body per fascicular cross section, polyglucosan bodies outside an axon, unusually large polyglucosan bodies (larger than 30 [micro]m), or polyglucosan bodies in a young patient (younger than 20 years) should lead to consideration of these diseases.[3] Polyglucosan bodies have also been described in inflammatory demyelinating polyneuropathy and diabetic neuropathy. One or two polyglucosan bodies in a single nerve biopsy specimen are considered a nonspecific finding.[3] The sural nerve biopsy of the present patient revealed intra-axonal basophilic inclusions ranging from 5 to 70 [micro]m in diameter with as many as 3 inclusions in a single fascicular cross section and more than 1 inclusion in some axons in longitudinal sections.

Busard and coworkers[4] investigated the value of an axillary skin biopsy for the diagnosis of adult polyglucosan body disease in a 65-year-old woman in whom the diagnosis had been established by sural nerve biopsy. They observed a mean of 3 polyglucosan body inclusions, measuring up to 17 [micro]m, per apocrine-coil cross section. The inclusions were present in myoepithelial cells of apocrine, and rarely eccrine, glands. As many as 4 inclusions were found in 1 cell. In biopsies from 130 neurologically intact control subjects, polyglucosan bodies were found in 26 individuals, ranging in age from the third

to ninth decades. In these controls, total inclusions in the entire biopsy numbered 5 or less, and they all measured less than 10 [micro]m in diameter. Our findings, which comprise a mean of 4 inclusions per apocrine coil, each measuring up to 18 [micro]m and located in apocrine myoepithelial cells, confirm the observation of Busard et al. Polyglucosan bodies in endothelial cells of the papillary dermis were not seen in the case reported by Busard and colleagues, but they have been described around endoneurial blood vessels and in perivascular macrophages in sural nerve biopsies.[7] In contrast to adult polyglucosan body disease, in which inclusions are most prominent in myoepithelial cells of the apocrine secretory coil, Lafora disease shows inclusions in apocrine and eccrine duct cells.[8]

The pathogenesis of the adult polyglucosan body disease appears to be heterogeneous. In an Ashkenazi Jewish subgroup, a missense mutation in the glycogen-branching enzyme gene on chromosome 3, resulting in a deficiency of this enzyme, has been shown to be the molecular basis of the disease.[5] More recently, 2 novel missense mutations, Arg515His and Arg524Gln, in the glycogen-branching enzyme gene were identified in a non-Ashkenazi patient with adult polyglucosan body disease. The authors postulate that adult polyglucosan body disease is one manifestation of glycogen storage disease type IV, the other clinical presentations being hepatic and neuromuscular forms.[9]

In summary, adult polyglucosan body disease should be suspected in patients with a late-onset progressive disorder of the peripheral and central nervous system, especially when upper motor neuron signs, dementia, or bladder impairment is present. Although sural nerve biopsy is an established diagnostic procedure, skin biopsy appears to be a simple, reliable, and less invasive diagnostic tool.

References

[1.] Robitaille Y, Carpenter S, Karpati G, DiMauro S. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora's disease and normal aging. Brain. 1980;103:315-336.

[2.] Robertson NP, Wharton S, Anderson J, Scolding NJ. Adult polyglucosan body disease associated with an extrapyramidal syndrome. J Neurol Neurosurg Psychiatry. 1998;65:788-790.

[3.] Midroni G, Bilbao JM, eds. Biopsy Diagnosis of Peripheral Neuropathy. Boston, Mass: Butterworth-Heinemann; 1995;65:455-456.

[4.] Busard HLSM, Gabreels-Festen AAWM, Renier WO, et al. Adult polyglucosan body disease: the diagnostic value of axilla skin biopsy. Ann Neurol. 1991; 29:448-451.

[5.] Lossos A, Meiner Z, Barash V, et al. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the [Tyr.sup.329]Ser mutation in the glycogen-branching enzyme gene. Ann Neurol. 1998;44:867-872.

[6.] Cavanagh JB. Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev. 1999;29:265-295.

[7.] Vos AJM, Joosten EMG, Gabreels-Festen AAWM. Adult polyglucosan body disease: clinical and nerve biopsy findings in two cases. Ann Neurol. 1983;13: 440-444.

[8.] Busard BLSM, Renier WO, Gabreels FJM, Jaspar HHJ, van Haelst UJG, Slooff JL. Lafora's disease: comparison of inclusion bodies in skin and in brain. Arch Neurol. 1986;43:296-299.

[9.] Ziemssen F, Sindern E, Schroder JM, et al. Novel missense mutations in the glycogen branching enzyme gene in adult polyglucosan body disease. Ann Neurol. 2000;47:536-540.

Accepted for publication September 6, 2000.

From the Department of Dermatopathology, Armed Forces Institute of Pathology, Washington, DC (Dr Milde); Pathology and Laboratory Medicine Service, Department of Veterans Affairs Medical Center, Washington, DC (Dr Guccion); and the Departments of Neurology (Drs Kelly and Locatelli) and Pathology (Dr Jones), The George Washington University Medical Center, Washington, DC. Dr Locatelli is now at the Department of Neurology, Cleveland Clinic Florida, Fort Lauderdale, Fla.

Presented at the 20th Annual Colloquium, The International Society of Dermatopathology, Prague, Czech Republic, September 25, 1999, and at the American Society of Dermatopathology 36th Annual Meeting, La Jolla, Calif, November 4-7, 1999.

Reprints not available from the authors.