Genetic Spectrum and Phenotypic Variability in Chinese Patients with Multisystem Proteinopathy and Related Disorders.

Abstract

Objective: Multisystem proteinopathy (MSP) is a pleiotropic group of disorders initially presenting as inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and/or Paget disease of bone (PDB). Additional genes including MATR3, OPTN, and ANXA11, have recently been implicated in MSP-like disorders, further expanding the genetic spectrum. This research aims to study the genetic and clinical characteristics of MSP and related disorders in a large Chinese cohort.

Methods: Twenty-nine patients were identified in 953 patients diagnosed with ALS, IBM, or dementia at Huashan Hospital between 2000 and 2024. Variants in MSP-related genes were detected using next-generation sequencing and confirmed by Sanger sequencing. Clinical, pathological, imaging, and electromyography data were collected and analyzed.

Results: A total of 29 patients (3.0%) were identified as carrying MSP-related gene variants. Most patients were male (72.4%), with disease onset predominantly in the third to fifth decades of life. The majority of patients (21/29) presented with a single clinical phenotype. ALS was the most common phenotype (20/29), followed by IBM (10/29), FTD (7/29), and PDB (1/29). The most frequent variants were in ANXA11 (34.5%) and VCP (20.7%), followed by OPTN (17.2%), SQSTM1 (10.3%), MATR3 (10.3%), and HNRNPA1 (6.9%). All patients with VCP variants presented with initial lower limb involvement, whereas those carrying ANXA11 or OPTN variants predominantly showed upper limb or bulbar onset. Patients harboring OPTN variants had a later age at onset compared with those carrying VCP or MATR3 variants. Patients with ALS-onset exhibited faster progression compared with those with myopathy-onset, even when harboring identical variants.

Conclusion: This study broadens the clinical and genetic landscape of MSP and related disorders in a Chinese cohort. These results emphasize the clinical utility of next-generation sequencing for improving diagnostic accuracy in patients with unexplained neuromuscular or cognitive presentations, especially in the presence of multisystem involvement.