A Novel Multisystem Proteinopathy Caused by a Missense ANXA11 Variant

Author(s):Show less -

Leoni, Tauana Bernardes ^[1] ; Gonzalez-Salazar, Carelis ^[1] ; Rezende, Thiago Junqueira R. ^[1] ; Hernandez, Ana Luisa C. ^[1] ; Mattos, Alexandre Hilario B. ^[1] ; Coimbra Neto, Antonio Rodrigues ^[1] ; da Graca, Felipe Franco ^[1] ; Nunes Goncalves, Joao Pedro ^[1] ; Martinez, Alberto R. M. ^[1] ; Taniguti, Lucas ^[2] ; Kitajima, Joao Paulo ^[2] ; Kok, Fernando ^{[3, 2]} ; Rogerio, Fabio ^[4] ; Serafim da Silva, Andre Macedo ^[3] ; Rodrigues de Oliveira, Alexandre Leite ^[5] ; Zanoteli, Edmar ^[3] ; Nucci, Anamarli ^[1] ; Franca Jr, Marcondes C.

Affiliation

^[1] Univ Campinas UNICAMP, Sch Med Sci, Dept Neurol, Campinas - Brazil

^[2] Mendel Genom Anal, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo - Brazil

^[4] Univ Campinas UNICAMP, Sch Med Sci, Dept Pathol, Campinas - Brazil

^[5] Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, Campinas - Brazil

• Document type: Journal article
• Source: ANNALS OF NEUROLOGY; v. 90, n. 2, p. 239-252, AUG 2021.
• Web of Science Citations: 0

Abstract

Objective Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). Methods We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. Results Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). Interpretation These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021 (AU)

• FAPESP's process: 13/07559-3 - BRAINN - The Brazilian Institute of Neuroscience and Neurotechnology
• Grantee: Fernando Cendes
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC