dult polyglucosan body disease (APBD) is characterized after 50 years of age by the onset of progressive pyramidal paraparesis, distal sensory deficits, neurogenic 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 lateonset progressive symmetric course and peripheral neuropathy; from amyotrophic lateral sclerosis by sensory deficits, 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 principally in axons, often appearing to clog the axonal flow. Other features include central nervous system demyelination and gliosis and loss of peripheral nervous system myelinated fibers. 6-12 Adult polyglucosan body disease is allelic to glycogenosis 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. DESIGN, SETTING, AND PARTICIPANTS This retrospective study took place from November 8, 2012, to November 7, 2014. We studied 35 typical patients with adult polyglucosan body disease, of whom 16 were heterozygous for the well-known c.986A>C mutation in the glycogen branching enzyme gene (GBE1) but harbored no other known mutation in 16 exons. MAIN OUTCOMES AND MEASURES All 16 manifesting heterozygous patients had lower glycogen branching activity compared with homozygous patients, which showed inactivation of the apparently normal allele. We studied the messenger ribonucleic acid (mRNA) structure and the genetic change due to the elusive second mutation. RESULTS When we reverse transcribed and sequenced the mRNA of GBE1, we found that all manifesting heterozygous patients had the c.986A>C mutant mRNA and complete lack of mRNA encoded by the second allele. We identified a deep intronic mutation in this allele, GBE1-IVS15 + 5289_5297delGTGTGGTGGinsTGTTTTTTACATGACAGGT, which acts as a gene trap, creating an ectopic last exon. The mRNA transcript from this allele missed the exon 16 and 3′UTR and encoded abnormal GBE causing further decrease of enzyme activity from 18% to 8%. CONCLUSIONS AND RELEVANCE We identified the deep intronic mutation, which acts as a gene trap. This second-most commo...

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Epidemiological studies show that stimulating activities reduce the risk of dementia. In animal models of Alzheimer disease, there have been conflicting results of the effects of environmental enrichment (EE) on disease-related amyloid pathology. Here, we tested the direct effect of EE, independently of amyloid pathology, on brain neurofibrillary tangles (NFTs), which best correlate with dementia. We exposed transgenic mice (E257K/P301S-Tau-Tg driven by the natural tau promoter) to moderate nonstrained EE or regular environment. Concomitant with neurogenesis, we detected a decrease in NFT burden and a decrease in the activation of microglia in EE versus regular-environment mice. There was also a trend toward improvement in cognitive tasks in the EE mice. Increased immunoreactivity of brain-derived neurotrophic factor, which is involved in the regulation of tau phosphorylation, was detected in the EE mice, suggesting its possible involvement in the beneficial effects on NFTs and other parameters in the EE mice. These results suggest that NFTs may be directly responsive to environmental stimulating activities and that even nonstrained activities may mitigate tauopathies independent of the involvement of amyloid.

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