Deep IntronicGBE1Mutation inManifesting Heterozygous PatientsWith Adult Polyglucosan Body Disease

Abstract

A dult polyglucosan body disease (APBD) is character-ized after 50 years of age by the onset of progressivepyramidal paraparesis, distal sensory deficits, neu-rogenic bladder, ambulation loss, and premature death owing to complications of myelopathy and peripheral neuropathy.1,2 The disease, which is often included in the differential diagnoses of multiple sclerosis and amyotrophic lateral sclerosis, is distinct from multiple sclerosis by late-onset progressive symmetric course and peripheral neu-ropathy; from amyotrophic lateral sclerosis by sensory defi-cits, incontinence, and florid subcortical and spinal cord changes on magnetic resonance imaging; and from both by autosomal recessive inheritance.2-6 The neuropathological hallmarks of APBD are polyglucosan bodies (PBs), which are accumulations of aggregated, poorly branched, and insoluble glycogen both in the central nervous system and in the peripheral nervous system. In neurons, PBs are prin-cipally in axons, often appearing to clog the axonal flow. Other features include central nervous system demyelin-ation and gliosis and loss of peripheral nervous system myelinated fibers.6-12 Adult polyglucosan body disease is allelic to glycogeno-sis IV (glycogen storage disease IV [GSD-IV]; OMIM 232500). Patients with classic GSD-IV have profound glycogen branching enzyme (GBE) deficiency and die in childhood of liver failure with massive hepatic and extrahepatic polyglu-IMPORTANCE We describe a deep intronic mutation in adult polyglucosan body disease. Similar mechanisms can also explain manifesting heterozygous cases in other inborn metabolic diseases. OBJECTIVE To explain the genetic change consistently associated with manifesting heterozygous patients with adult polyglucosan body disease