# Tracing neuropathological signatures: TARDBP and C9orf72 double mutations in a Sicilian family

## TL;DR

This study examines a rare case of a patient with both TARDBP and C9ORF72 mutations to understand their combined impact on amyotrophic lateral sclerosis.

## Contribution

The study is the first to document a patient with both TARDBP and C9ORF72 mutations and provides postmortem neuropathological data.

## Key findings

- The patient's clinical progression was consistent with typical C9ORF72 carriers.
- No heightened pathological burden was observed from the TARDBP mutation.
- Double heterozygosity did not exacerbate amyotrophic lateral sclerosis pathology.

## Abstract

Co-occurrence of double heterozygosity in TARDBP and C9ORF72 is exceedingly rare in amyotrophic lateral sclerosis. While TARDBP mutations and C9ORF72 hexanucleotide repeat expansions have each been independently implicated in disease pathogenesis, their combined effect on disease progression and neuropathology remains unclear. We present the first study documenting a patient harboring both a TARDBP mutation and a C9ORF72 expansion, with comprehensive postmortem data available, to elucidate any additive or synergistic effects on disease course and pathological burden. Detailed clinical assessments tracked the patient’s progression, and neuropathological examination was performed postmortem. The presence and extent of TDP-43 pathology and other hallmark features were evaluated and compared to known patterns in carriers of isolated C9ORF72 mutations. The patient’s clinical trajectory and pathological findings did not show evidence of a more aggressive disease course or heightened pathological burden attributable to the additional TARDBP mutation. Instead, the disease manifested in a manner consistent with other C9ORF72 carriers, suggesting that double heterozygosity do not necessarily exacerbate ALS pathology.