Clinical spectrum of C9orf72 expansion in a cohort of Huntington’s disease phenocopies

Abstract

The expansion in the C9orf72 gene has been recently reported as a genetic cause of Huntington's disease (HD) phenocopies. We aim to assess the frequency of the C9orf72 gene expansion in a Portuguese HD phenocopies cohort. Twenty HD phenotype-like patients without diagnosis were identified in our institutional database. C9orf72 gene expansion was detected using repeat-primed PCR. Clinical files were reviewed to characterize the phenotype of expansion-positive cases. One patient (5%) was positive for the C9orf72 expansion. A second patient presented 27 repeats-within the intermediate size interval. Both had familial neuropsychiatric disease characterized by diverse movement disorders, dementia, and psychiatric dysfunction that was distinct in severity and clinical expression. C9orf72 disease is clinically heterogeneous and without evident imaging markers. The definition of the role of intermediate alleles and of the pathological threshold for C9orf72 repeat expansions may have diagnostic implications.

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

“…These studies were conducted on patients who presented with an HD‐like phenotype and tested negative for pathogenic expansions in the huntingtin gene. Reported frequencies range from 1.75% to 5%, and all studies included populations of European origin: British, Serbian, Greek, and Portuguese . A study of the French population did not identify any C9orf72 positives .…”

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).…”

“…The overall frequency of the expansion was 1.0% (95% CI: 0-2%, I 2 = 0%, p = 0.51) (Figure 2). Also, we conducted a cumulative analysis of three studies reporting HLD patients carrying "intermediate" alleles of C9orf 72 (Fedotova et al, 2016;Ida et al, 2018;Martins et al, 2018a). The overall frequency of the C9orf72 intermediate allele was 3% (95% CI: 0-14%; I 2 = 78.48%; p = 0.01) (Figure 3).…”