Case report: A novel patient presenting TRIM32-related limb-girdle muscular dystrophy

Abstract

Limb-girdle muscular dystrophy autosomal recessive 8 (LGMDR8) is a rare clinical manifestation caused by the presence of biallelic variants in the TRIM32 gene. We present the clinical, molecular, histopathological, and muscle magnetic resonance findings of a novel 63-years-old LGMDR8 patient of Italian origins, who went undiagnosed for 24 years. Clinical exome sequencing identified two TRIM32 missense variants, c.1181G > A p.(Arg394His) and c.1781G > A p.(Ser594Asp), located in the NHL1 and NHL4 structural domains, respectively, of the TRIM32 protein. We conducted a literature review of the clinical and instrumental data associated to the so far known 26 TRIM32 variants, carried biallelically by 53 LGMDR8 patients reported to date in 20 papers. Our proband's variants were previously identified only in three independent LGMDR8 patients in homozygosis, therefore our case is the first in literature to be described as compound heterozygous for such variants. Our report also provides additional data in support of their pathogenicity, since p.(Arg394His) is currently classified as a variant of uncertain significance, while p.(Ser594Asp) as likely pathogenic. Taken together, these findings might be useful to improve both the genetic counseling and the diagnostic accuracy of this rare neuromuscular condition.

Keywords: LGMDR8; TRIM32; clinical exome sequencing; limb-girdle muscular dystrophy; tripartite motif-containing proteins.

Figure 1

(A) Graphic of the typical LGMDR8 phenotype. The five sections summarize the most frequent clinical and instrumental features, drawn from the analysis of the 53 LGMDR8 TRIM32-mutated patients (including our case) reported in the literature; (B) timeline highlighting our patient's clinical history and diagnostic work-up. Figures (A, B) were created with BioRender.com.

Figure 2

Histological and immunohistochemical findings in muscle biopsy. (A, B) Hematoxylin and eosin (A) and modified Gomori trichrome (B) stains showing markedly increased fiber size variability, central nuclei, severe fibro-adipose replacement (asterisks), splitting fibers (arrowheads), internal vacuoles (arrow). (C) ATPase pH 9.4 stain showing predominant type 2 (darker) fibers atrophy. (D) NADH-TR stain showing preserved oxidative enzymes activity in most of the observed fibers, with darker stain of the atrophic fibers. (E, F) Immunofluorescence assay showing increased intracellular accumulation of myotilin (E) and desmin (F) proteins compared to control muscles (small frames). (G) Immmunofluorescence assay showing increased cytoplasmic p62 signal compared to control muscle (small frame). Scale bars: 100 μm (A–D) 25 μm (E–G).

Figure 3

Schematic representation of the TRIM32 gene (A) and TRIM32 protein (B), displaying the structural domains and intermediate regions with the LGMDR8-associated biallelic variants (that are listed with the same color coding in Table 1). The two variants (c.1181G > A, p.Arg394His; c.1781G > A, p.Ser594Asn) carried by our patient are outlined in red (B) and also shown in the chromatograms (C). Figures (A, B) were created with BioRender.com.