# Phenotypical Characterization of C9ALS Patients from the Emilia Romagna Registry of ALS: A Retrospective Case–Control Study

## TL;DR

This study compares the clinical features of ALS patients with and without C9ORF72 mutations, finding faster disease progression and sex-specific differences in C9ALS patients.

## Contribution

The study provides new insights into the phenotypic differences and sex-specific characteristics of C9ALS patients compared to nmALS patients.

## Key findings

- C9ALS patients showed faster disease progression and shorter times to gastrostomy and ventilation.
- Female C9ALS patients had more severe bulbar and upper motor neuron involvement.
- Cognitive symptoms were more common in C9ALS and were an independent prognostic factor.

## Abstract

Background/Objectives: C9ORF72 expansion is associated with significant phenotypic heterogeneity. This study aimed to characterize the clinical features of C9ALS patients from the Emilia Romagna ALS registry (ERRALS) and compare them with non-mutated ALS (nmALS) patients matched for sex, age at onset, and diagnostic delay, sourced from the same register. Methods: In total, 67 C9ALS patients were compared to 201 nmALS. Clinical data, phenotype, and prognostic factors were analyzed in the two groups and within the C9ALS group after stratification by sex. Results: C9ALS patients displayed a higher disease progression rate and shorter times to gastrostomy and invasive ventilation, despite no differences in overall survival. Female C9ALS had a more severe bulbar and upper motor neuron involvement compared to males. Cognitive and behavioral symptoms were more common in the C9ALS group, and the former was an independent prognostic factor. Prevalences of, autoimmune diseases, and dyslipidemia were significantly higher among C9ALS patients. Conclusions: In our dataset, we show an overall increased disease progression rate in C9ALS patients and hint at sex-specific discrepancies in some phenotypical characteristics. We also suggest a possible clinically relevant involvement of C9ORF72 expansion in metabolism and autoimmunity.