GBE1 Adult Polyglucosan Body Disease

Clinical characteristics: Most individuals with classic GBE1 adult polyglucosan body disease (GBE1-APBD) present after age 40 years with unexplained progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, autonomic dysfunction (associated with orthostatic hypotension and constipation), and mild cognitive difficulties (often executive dysfunction). Some affected individuals without classic GBE1-APBD have atypical phenotypes including Alzheimer disease-like dementia and axonal neuropathy, stroke-like episodes, and diaphragmatic failure; others may have a history of infantile liver disease.

Diagnosis/testing: The diagnosis of GBE1-APBD is established in a proband with suggestive findings and biallelic GBE1 pathogenic variants identified by molecular genetic testing. Note: GBE enzyme assay (in any tissue) is not a first-line diagnostic test for GBE1-APBD.

Management: Treatment of manifestations: Optimally, symptomatic care is provided by a multidisciplinary team that includes specialists in physical medicine rehabilitation, urology, and behavioral neurology or psychology. An individualized physical therapy program can improve flexibility, reduce spasticity, maintain or improve joint mobility, and facilitate activities of daily living; antispasmodic drugs may decrease cramps and facilitate walking. Spastic bladder may be managed with anticholinergic drugs and clean intermittent catheterization or an indwelling bladder catheter to prevent urosepsis; treatment of recurrent urinary infections is essential. Treatment of cognitive decline and psychiatric manifestations is per standard practice.

Surveillance: Routine: neurologic assessments to monitor progression of upper motor neuron and lower motor neuron signs and to assess for new manifestations; urologic evaluations for complications of spastic bladder; occupational and physical therapy assessments regarding activities of daily living; and mental health assessments.

Genetic counseling: GBE1-APBD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GBE1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (carrier), and a 25% chance of being unaffected and not a carrier.

Once the GBE1 pathogenic variants have been identified in the family, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing for GBE1-APBD are possible.