Hereditary gelsolin amyloidosis: a rare cause of cranial, peripheral and autonomic neuropathies linked to D187N and Y447H substitutions

Abstract

Introduction

Hereditary gelsolin (AGel) amyloidosis is a systemic disease that is characterised by neurologic, ophthalmologic, dermatologic, and other organ involvements. We describe the clinical features with a focus on neurological manifestations in a cohort of patients with AGel amyloidosis referred to the Amyloidosis Centre in the United States.

Methods

Fifteen patients with AGel amyloidosis were included in the study between 2005 and 2022 with the permission of the Institutional Review Board. Data were collected from the prospectively maintained clinical database, electronic medical records and telephone interviews.

Results

Neurologic manifestations were featured in 15 patients: cranial neuropathy in 93%, peripheral and autonomic neuropathy in 57% and bilateral carpal tunnel syndrome in 73% of cases. A novel p.Y474H gelsolin variant featured a unique clinical phenotype that differed from the one associated with the most common variant of AGel amyloidosis.

Discussion

We report high rates of cranial and peripheral neuropathy, carpal tunnel syndrome and autonomic dysfunction in patients with systemic AGel amyloidosis. The awareness of these features will enable earlier diagnosis and timely screening for end-organ dysfunction. The characterisation of pathophysiology will assist the development of therapeutic options in AGel amyloidosis.

Keywords:

• Hereditary amyloidosis
• gelsolin gene mutation
• cranial neuropathy
• carpal tunnel syndrome

Acknowledgements

The authors acknowledge all members of the Amyloidosis Center clinical team who took care of patients included into the study and patients who provided tissue samples.

Ethical approval

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Data deposition

The gene sequence of the GSN variant p.Y474H (Y447H) has been submitted in the ClinVar database (accession no. SCV002599112).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work has been supported by the Wildflower Foundation and Boston University Amyloid Research Fund to TP. The funding organisations had no role in study design; data collection; results interpretation; writing the manuscript; and decision to submit.