Sarcotubular Myopathy Due to Novel TRIM32 Mutation in Association with Multiple Sclerosis

Abstract

Azerbaijani 28-year-old female showed weakness (MRC (Medical Research Council Scale for Muscle Strength) grade 4 in the proximal part of the upper and MRC grade 2–3 in the lower extremities), difficulty in stair lifting, positive symptom of Hoover’s rising, «waddling gait», decline deep reflexes symmetrical, lack of surface reflexes, positive Babinsky’s reflex on the right, urinary incontinence during sneezing, prolonged walking and exercise from puberty. Additional methods made it possible to identify minor violations of conduction of the left ventricle, electromyography signs of primary muscular disease with predominant involvement of the proximal muscles of the lower extremities, elevation of serum creatine kinase (746.81 U/l), active foci of demyelination in the left frontal lobe, intrathecal synthesis of oligoclonal IgG bands (type 2) in cerebrospinal fluid, atrophy and fatty degeneration of all muscles of the shins, homozygous Variant of Uncertain Significance (VUS) c.1855C > T (p.Pro619Ser) in TRIM32 gene and heterozygous VUS c.2300C > G (p.Thr767Arg) in KIF5A, c.2840G > A (p.Arg947Lys) in MYH2, c.1502G > C (p.Gly501Ala) in POMT1 genes. Comparison of the phenotypes of the mutations that have been identified with the clinical picture of the patient suggests that VUS c.1855C > T (p.Pro619Ser) in the TRIM32 gene can be pathological. Summarizing, it can be argued that the cause of the identified disorders is a homozygous variant c.1855C > T (p.Pro619Ser) in TRIM32 gene that causes LGMDR8 in a patient with MS.

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

“…MMRI studies of the lower limbs were described in 49% (26/53) of the cases [our patient; ( 13 , 19 , 21 , 24 – 28 )]. Their images showed fibroadipose degeneration, with preferential affection of the posterior thigh compartment and selective sparing of specific muscles.…”

“…We conducted a literature review of the clinical data related to 26 TRIM32 variants, carried biallelically (in either compound heterozygosis or homozygosis) by 53 LGMDR8 patients (included our proband). Clinical and instrumental findings extracted from the 20 extant studies are reported in Table 1 , and a visual summary of the LGMDR8 typical phenotype, based on the literature, is displayed in Figure 1A ( 7 , 11 , 13 , 15 – 30 ).…”

“…Biallelic variants in the TRIM32 gene, on chromosome 9q33, have been associated with LGMDR8, which is caused by the homonymous protein deficiency ( 2 ). TRIM32 encodes the member 32 of the TRIpartite Motif-containing (TRIM) ubiquitin E3 ligase family, which ubiquitinates several muscle substrates, including sarcomeric proteins ( 13 ). However, the specific effect on the muscle of the so far identified TRIM32 variants has not been fully clarified yet.…”

“…Bioinformatic modeling suggests these variants may cause a potential misfolding of the TRIM32 protein, especially at the level of the C-terminal domain, leading to pathogenic consequences on the muscle physiology ( 14 ). Beside the first variant – c.1459G > A, p.(Asp487Asn) – identified in the Hutterite population with a founder effect ( 6 , 7 , 9 ), additional 25 variants of TRIM32 have been described to date in other 41 non-Hutterite LGMDR8 patients, worldwide ( 11 , 13 , 15 – 28 ).…”

“…He is the first LGMDR8 case in literature to be identified as compound heterozygous for two TRIM32 missense variants, whose pathogenicity has not been clarified yet. We describe his clinical, histopathological, muscle magnetic resonance imaging (MMRI) and molecular findings, against the backdrop of other 52 LGMDR8 patients harboring biallelic TRIM32 variants ( Table 1 ; Figure 1A ), reported across 19 published studies ( 7 , 11 , 13 , 15 – 30 ).…”