Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

Abstract

Objectives: Mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1, encoding RNA-binding proteins or proteins in quality-control pathways, cause multisystem proteinopathies (MSP). They share pathological findings of protein aggregation and clinical combinations of inclusion body myopathy (IBM), neurodegeneration [motor neuron disorder (MND)/frontotemporal dementia (FTD)], and Paget disease of bone (PDB). Subsequently, additional genes were linked to similar but not full clinical-pathological spectrum (MSP-like disorders). We aimed to define the phenotypic-genotypic spectrum of MSP and MSP-like disorders at our institution, including long-term follow-up features. Methods: We searched the Mayo Clinic database (January 2010-June 2022) to identify patients with mutations in MSP and MSP-like disorders causative genes. Medical records were reviewed. Results: Thirty-one individuals (27 families) had pathogenic mutations in: VCP (n = 17), SQSTM1 + TIA1 (n = 5), TIA1 (n = 5), MATR3, HNRNPA1, HSPB8, and TFG (n = 1, each). Myopathy occurred in all but 2 VCP-MSP patients with disease onset at age 52 (median). Weakness pattern was limb-girdle in 12/15 VCP-MSP and HSPB8 patient, and distal-predominant in other MSP and MSP-like disorders. Twenty/24 muscle biopsies showed rimmed vacuolar myopathy. MND and FTD occurred in 5 (4 VCP, 1 TFG) and 4 (3 VCP, 1 SQSTM1 + TIA1) patients, respectively. PDB manifested in 4 VCP-MSP. Diastolic dysfunction occurred in 2 VCP-MSP. After 11.5 years (median) from symptom onset, 15 patients ambulated without gaitaids; loss of ambulation (n = 5) and death (n = 3) were recorded only in VCP-MSP. Interpretation: VCP-MSP was the most common disorder; rimmed vacuolar myopathy was the most frequent manifestation; distal-predominant weakness occurred frequently in non-VCP-MSP; and cardiac involvement was observed only in VCP-MSP.

ANXA11-related multisystem proteinopathy with inclusion body myopathy, ALS and FTD: A case report

“…He exhibited normal left ventricular systolic function (70%) but diastolic dysfunction and left ventricular hypertrophy, indicating myocardial involvement. Diastolic dysfunction was also reported to be observed in VCP-related MSP [2] . Our case expands the phenotype spectrum of ANXA11-related MSP.…”

“…Our case exhibited an onset age of 49 years, consistent with the previously reported onset typically occurring in the third to fth decade of life. His rapidly progression differs signi cantly from other subtype of MSP, such as VCP-related myopathy, which typically has an average disease duration of at least 12 years [2] . Initially, this patient was considered as simple IBM due his limbs weakness, EMG and muscle pathology.…”

“…Multisystem proteinopathy (MSP) is a rare group of genetically diverse degenerative disease characterized by co-occurrence of at least 2 of 4 conditions [inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Paget disease of bone (PDB)], within the same family [1] . To date, four genes have been identi ed as causative factors for MSP, namely VCP, HNRNPA1, HNRNPA2B1, SQSTM1 [2] . Annexin A11(ANXA11) is a newly discovered causative gene for both familial and sporadic ALS [3] .…”

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets

“…VDAC1 (voltage‐dependent anion channel 1): This gene is related to several skin conditions, including non‐melanoma skin cancer, psoriasis and eczema, potentially involved in cell death regulation, oxidative stress and inflammation 35 MATR3 (Matrin 3): Mutations in this gene have been linked to Charcot–Marie–Tooth disease (a hereditary peripheral neuropathy) and familial alopecia, potentially influencing keratin formation and neuronal cell function 36 OFD1 (oral‐facial‐digital syndrome 1): OFD1 mutations can cause oral‐facial‐digital syndrome, a rare genetic disorder with oral, facial and digital abnormalities, which can involve skin developmental issues 37 …”

Nationwide survey of patients with multisystem proteinopathy in Japan

“…Myopathy is found in MSP types 1–6 and MSP‐like disorders. It is probably the most frequent symptom, but its precise epidemiology is unclear 5,11 . Moreover, cases of pure IBM have been reported in most types of MSPs.…”