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. 2022 Jan 12;10(1):160.
doi: 10.3390/biomedicines10010160.

Phenotypic Heterogeneity among GBA p.R202X Carriers in Lewy Body Spectrum Disorders

Valerio Napolioni  1 , Carolyn A Fredericks  1 , Yongha Kim  1 , Divya Channappa  2 , Raiyan R Khan  1 , Lily H Kim  1 , Faria Zafar  2 , Julien Couthouis  3 , Guido A Davidzon  4 , Elizabeth C Mormino  1 , Aaron D Gitler  3 , Thomas J Montine  2 , Birgitt Schüle  2 , Michael D Greicius  1
Affiliations

Phenotypic Heterogeneity among GBA p.R202X Carriers in Lewy Body Spectrum Disorders

Valerio Napolioni et al. Biomedicines. .

Abstract

We describe the clinical and neuropathologic features of patients with Lewy body spectrum disorder (LBSD) carrying a nonsense variant, c.604C>T; p.R202X, in the glucocerebrosidase 1 (GBA) gene. While this GBA variant is causative for Gaucher's disease, the pathogenic role of this mutation in LBSD is unclear. Detailed neuropathologic evaluation was performed for one index case and a structured literature review of other GBA p.R202X carriers was conducted. Through the systematic literature search, we identified three additional reported subjects carrying the same GBA mutation, including one Parkinson's disease (PD) patient with early disease onset, one case with neuropathologically-verified LBSD, and one unaffected relative of a Gaucher's disease patient. Among the affected subjects carrying the GBA p.R202X, all males were diagnosed with Lewy body dementia, while the two females presented as PD. The clinical penetrance of GBA p.R202X in LBSD patients and families argues strongly for a pathogenic role for this variant, although presenting with a striking phenotypic heterogeneity of clinical and pathological features.

Keywords: Gaucher’s disease; Lewy body dementia; Parkinson’s disease; genetics; glucocerebrosidase; mutation; neuropathology; sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Neuropathologic examination of the index case from Family 1 showing diffuse Lewy body disease. (A) Hematoxylin and eosin (HE)-stained section from the locus coeruleus, 40× magnification; (B) phosphorylated α-synuclein [pS129]-stained section from the left amygdala, 20× magnification; (C) phosphorylated α-synuclein [pS129]-stained section from the right frontal cortex, 40× magnification.
Figure 2
Figure 2
Age and tau PET scans, according to amyloid deposition positivity, in Stanford ADRC participants. Family 1: affected son of the index case is reported as a blue square (LBSD). AB = beta-amyloid; AD = Alzheimer’s disease; HC = healthy control; MCI = mild cognitive impairment.
Figure 3
Figure 3
Pedigree of the reported LBSD families. Family 1 (panel (A)) and Family 2 (panel (B)). Arrows indicate the index cases.
Figure 4
Figure 4
Sanger sequencing results of GBA p.R202X in Family 1. The top panel shows the presence of the G/A (heterozygote) genotype in the affected son of the index case and its absence from the two unaffected sisters. No DNA was available for GBA p.R202X Sanger sequencing of the index case.
See this image and copyright information in PMC

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