Screening for the C9ORF72 Expansion in Greek Huntington Disease Phenocopies and Controls and Meta-analysis of Current Data

Abstract

Huntington-disease like disorders (HDL) are a rare cause of chorea, resembling Huntington's disease (HD) and its common triplet of symptoms-chorea, cognitive decline, and psychiatric symptoms, but lack the CAG expansion, responsible for the original disorder. Huntington's disease phenocopy syndromes, represent about 1% of the cases with a clinical suspicion of HD [3]. Several neurogenetic diseases are

C9orf72 Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis

“…This systematic review was conducted in four primary publication databases and found 10 studies that reported the C9orf72 pathogenic repeat expansion frequency among patients diagnosed with HLD (Hensman Moss et al, 2014a;Kostic et al, 2014;Koutsis et al, 2015;Fedotova et al, 2016;Mariani et al, 2016;Baine et al, 2018;Ida et al, 2018;Martins et al, 2018a;Rikos et al, 2020). Most of these cases were referred with a clinical diagnosis of Huntington Disease by an expert neurologist or neurogeneticist for the (CAG)n-HTT expansion test.…”

“…Most of these cases were referred with a clinical diagnosis of Huntington Disease by an expert neurologist or neurogeneticist for the (CAG)n-HTT expansion test. Most of these studies were conducted in European countries (Hensman Moss et al, 2014a;Kostic et al, 2014;Koutsis et al, 2015;Fedotova et al, 2016;Mariani et al, 2016;Martins et al, 2018a;Rikos et al, 2020). The estimated frequency of the expansion is around 1% among populations from Europe, South Africa, India, and the United States.…”

“…Two studies did not mention the diagnostic criteria for HLD (Fedotova et al, 2016;Kaur et al, 2020). At least six studies described a diagnostic workup that excluded other genetic causes of HLD including neuroacanthocytosis, neurodegeneration with brain iron accumulation, DJ-1 mutations, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease, HLD type 2, SCA-1, SCA-2, SCA-3, SCA-7, SCA-8, SCA-12, SCA-10, SCA-17, dentatorubral-pallidoluysian atrophy, and familial prion disease (Kostic et al, 2014;Koutsis et al, 2015;Mariani et al, 2016;Baine et al, 2018;Martins et al, 2018a;Rikos et al, 2020).…”

“…expansion was detected (Hensman Moss et al, 2014b;Kostic et al, 2014;Ida et al, 2018;Rikos et al, 2020). Six studies reported at least one HLD patient carrying the C9orf72 repeat expansion.…”

“…Previous systematic reviews found a 1.6 and 2% prevalence of C9orf72 repeat expansion in HLD patients (Marogianni et al, 2019;Rikos et al, 2020). However, we strictly followed PRISMA guidelines for systematic reviews and analyzed cases with intermediate alleles (<30 repeat range), which are cataloged as unclear clinical significance (Fedotova et al, 2016;Ida et al, 2018).…”