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Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by glycogen branching enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

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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...

SummaryAlthough Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State.Genotyping for the CETP −2708 G/A, −971 A/G, −629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors.In men, there was little evidence for an association between single SNPs and MI risk, but in women the age-and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (−2708 G, −971 G, −629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (−2708 G, −971 A, −629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4-14.8] and haplotype B (−2708 G, −971 G, −629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18;]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes.Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations.