Adult polyglucosan body disease

Adult polyglucosan body disease (APBD) is a very rare adult-onset form of glycogen storage disease type IV with characteristic clinicoradiological features.

Epidemiology

Adult polyglucosan body disease is considered very rare ^1,2, but the exact incidence is not known and it may often be misdiagnosed and thus underdiagnosed ¹. It is particularly common in Ashkenazi Jews, however, has been described in other ethnicities and is likely panethnic ^1-4. There is no known sex predilection ¹. The median age of onset is approximately 50 years ¹.

Clinical presentation 

The most common clinical features in adult polyglucosan body disease reflect a neurological syndrome incorporating a dorsolateral myelopathy and a predominantly axonal sensorimotor peripheral polyneuropathy ^1-4:

• neurogenic bladder dysfunction

  • usually the first symptom to manifest and is ultimately universally (100%) present in patients

• spastic paraplegia with gait dysfunction

  • present in 90% of patients

  • often associated with spinal proprioceptive and vibration loss

  • upper limbs are involved later than lower limbs

  • weakness may also be contributed to by neuropathy

• length-dependent sensory loss and paresthesias

  • present in 90% of patients

Less common clinical features include ^1-4:

• attentional and memory deficits, often mild

• autonomic dysfunction

  • orthostatic hypotension

  • erectile dysfunction in males

• neuro-ophthalmological anomalies such as saccadic pursuit or impaired convergence

• cerebellar ataxia

• fecal incontinence

• bradykinesia and parkinsonism

• cardiomyopathy

Unlike other phenotypes of glycogen storage disease type IV, hepatic involvement is very rare in adult polyglucosan body disease ².

Pathology

Genetics

Adult polyglucosan body disease is an autosomal recessive condition caused by mutation in the GBE1 gene on chromosome 3p12.2 ^1-4. The most implicated mutation is the missense mutation p.Y329S, which is particularly common within the Ashkenazi Jewish population ^1-4.

GBE1 normally encodes for the glycogen branching enzyme (GBE), also known as 1,4-alpha-glucan-branching enzyme ^1,2. Mutation to GBE1 results in a reduction in GBE activity, usually to <25% of normal ^1,2. This causes an accumulation of polyglucosan inclusions in various bodily tissues, including, and most importantly, within the central and peripheral nervous systems, leading to the clinical phenotype ^1,2.

Markers

GBE activity can be measured in peripheral leukocytes or skin fibroblasts ¹.

Radiographic features

MRI

Brain

MRI brain is always abnormal ^1,4. In nearly all patients, there is evidence of leukoencephalopathy with confluent and/or multifocal, symmetrical periventricular white matter abnormalities with an occipital predominance ^1,3. Additionally, nearly all patients have signal abnormalities affecting the medial lemniscus and corticospinal tracts through the brainstem, and most patients have signal abnormalities of the posterior limb of the internal capsule (often sparing the anterior limb) and the external capsule ^1,3. These regions are ¹:

• T1: isointense or hypointense

• T2/FLAIR: hyperintense

In addition to signal abnormalities, cavitation may occur ⁸. If seen, this is most common in the posterior limb of the internal capsule ⁸. Atrophy is also a common feature ¹. In particular, the medulla oblongata is nearly always atrophied, but there may also be atrophy of the cerebellar vermis, corpus callosum, and less commonly of other supratentorial structures ¹.

Spinal cord

The most common anomaly is spinal cord atrophy, affecting the entire length of the spinal cord ^1,3-5. Within the spinal cord, signal change has rarely been reported, but there may be increased T2 signal within the dorsal columns ⁵.

Treatment and prognosis

There is no disease modifying therapy available ^2,6, and thus, management consists of symptomatic treatment (e.g. indwelling catheter for urinary retention, gait aids for mobility, etc.) and genetic counseling ². However, due to frequent misdiagnosis, many patients are initiated on treatments for other conditions (e.g. pharmacotherapy for benign prostatic hyperplasia or immunosuppressive therapy for multiple sclerosis) ⁴.

Prognosis and quality of life is variable depending on the severity of the clinical syndrome and the supports available, but the median survival is reduced at approximately 70 years ^1,2.

History and etymology

Adult polyglucosan body disease was first described in a 1980 seminal case series ⁷.

Differential diagnosis

• hereditary spastic paraplegia

• adrenomyeloneuropathy

• adult-onset Alexander disease

• causes of cerebral small vessel disease (e.g. CADASIL)

• multiple sclerosis

• amyotrophic lateral sclerosis

• other causes of leukoencephalopathy or adult leukodystrophy