Distinct features in adult polyglucosan body disease: a case series

Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV

“…We present a case with suspected GSD4 in a one-year-old boy with an inconclusive genetic test. The sequencing of GBE1 showed a known missense variant, which causes mild GBE deficiency, and a missense variant, p.Ile694Asn, of unknown clinical significance at the time of diagnosis [ 15 , 16 ]. Given the uncertainty of how the VUS influences the clinical course, we tested its disease causality and manifestation using a CRISPR/Cas9 genome-edited iPSCs in vitro system.…”

“…In addition, the GBE1 enzyme activity in the liver biopsy tissue was reduced at 4 μmol/min/gram-tissue (normal range: 85±31 μmol/min/gram-tissue). Targeted GBE1 sequencing identified two variants: a known pathogenic missense variant, c.1544G>A (p. Arg515His), [ 7 , 13 , 14 ], and a missense variant, c.2081T>A (p.Ile694Asn) previously reported as a variant of unknown significance (VUS) [ 15 , 16 ] ( Fig. 1 B).…”

Case report: Expanding the understanding of the adult polyglucosan body disease continuum: novel presentations, diagnostic pitfalls, and clinical pearls

“…Although we continue to believe that genetic testing is the gold standard, first-line option for diagnosing patients with APBD, our cases demonstrate the common limitations and pitfalls of these methods. To this regard, with the broad phenotypic, genotypic, and radiographic presentation of APBD becoming increasingly well-characterized ( Mochel et al, 2012 ; De Winter et al, 2022 ), the inclusion of GBE1 testing on relevant gene panels, including those for leukodystrophy, ataxia, and peripheral neuropathy, is critical. For those that undergo whole exome sequencing, the limitations of this method have previously been described ( Mori et al, 2017 ; Burdick et al, 2020 ) and may result in a missed diagnosis—as in cases 1–3.…”

“…Over the last decade, MRI of the brain and spinal cord has proven essential in the evaluation and eventual diagnosis of individuals with APBD. Characteristic imaging findings were first described in 2012 ( Mochel et al, 2012 ) and recently expanded on in 2022 ( De Winter et al, 2022 ). While we provided herein the radiological findings reported by the various institutions at which our cases received care, we were unable to independently evaluate primary imaging.…”