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Review
. 2021 Jun 4:12:679927.
doi: 10.3389/fneur.2021.679927. eCollection 2021.

Neurodegenerative Disease Risk in Carriers of Autosomal Recessive Disease

Sophia R L Vieira  1 , Huw R Morris  1
Affiliations
Review

Neurodegenerative Disease Risk in Carriers of Autosomal Recessive Disease

Sophia R L Vieira et al. Front Neurol. .

Abstract

Genetics has driven significant discoveries in the field of neurodegenerative diseases (NDDs). An emerging theme in neurodegeneration warrants an urgent and comprehensive update: that carrier status of early-onset autosomal recessive (AR) disease, typically considered benign, is associated with an increased risk of a spectrum of late-onset NDDs. Glucosylceramidase beta (GBA1) gene mutations, responsible for the AR lysosomal storage disorder Gaucher disease, are a prominent example of this principle, having been identified as an important genetic risk factor for Parkinson disease. Genetic analyses have revealed further examples, notably GRN, TREM2, EIF2AK3, and several other LSD and mitochondria function genes. In this Review, we discuss the evidence supporting the strikingly distinct allele-dependent clinical phenotypes observed in carriers of such gene mutations and its impact on the wider field of neurodegeneration.

Keywords: EIF2AK3; GBA1; GRN; TREM2; autosomal; carrier; neurodegenerative; recessive.

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Conflict of interest statement

HM is employed by UCL. In the last 24 months he reports paid consultancy from Biogen, Biohaven, Lundbeck; lecture fees/honoraria from Wellcome Trust, Movement Disorders Society. Research Grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council, Michael J Fox Foundation. HM is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Possible mechanisms linking GBA1 mutations to PD. (A) The loss-of-function theory postulates that In GBA1 mutation-positive patients, deficient GCase results in GlcCer accumulation, lipid dyshomeostasis and α-synuclein aggregation; (B) the gain-of-function model states that ER retention of mutant GCase leads to ER stress, enhancing α-synuclein aggregation and prevent its degradation via autophagy or the ubiquitin-proteasome pathway and (C) a bidirectional positive feedback loop, in which reduced GCase activity leads to an accumulation of α-synuclein and α-synuclein accumulation further contributes to a decrease in GCase activity.
Figure 2
Figure 2
Ceramide and glycolipid metabolism in lysosomes (enzymes in red, autosomal recessive disease in green): aCerase, acid ceramidase; ASM, acid sphingomyelinase; ARSA, arylsulfatase; GALC, galactocerebrosidase; GCase, glucocerebrosidase; aGLA, a-galactosidase; βGLA, β-galactosidase; HEX A/B, hexosaminidase A/B; NPD, Niemann-Pick disease.
See this image and copyright information in PMC

References

    1. Poolman EM, Galvani AP. Evaluating candidate agents of selective pressure for cystic fibrosis. J R Soc Interface. (2007) 4:91–8. 10.1098/rsif.2006.0154 - DOI - PMC - PubMed
    1. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. . Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. (2009) 361:1651–61. 10.1056/NEJMoa0901281 - DOI - PMC - PubMed
    1. Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, et al. . Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet. (2012) 90:1102–7. 10.1016/j.ajhg.2012.04.021 - DOI - PMC - PubMed
    1. Gambin T, Jhangiani SN, Below JE, Campbell IM, Wiszniewski W, Muzny DM, et al. . Secondary findings and carrier test frequencies in a large multiethnic sample. Genome Med. (2015) 7:54. 10.1186/s13073-015-0171-1 - DOI - PMC - PubMed
    1. Cassinerio E, Graziadei G, Poggiali E. Gaucher disease: a diagnostic challenge for internists. Eur J Intern Med. (2014) 25:117–24. 10.1016/j.ejim.2013.09.006 - DOI - PubMed