Abstract

Case presentation. A 34-year-old male with congenital clubfoot, post-exertional rhabdomyolysis, and a family history of sudden cardiac death in mid-life was evaluated for a severe rhabdomyolysis. Although muscle biopsy revealed desmin-dystrophin-positive cytosolic protein aggregates, no other signs were noted aside from persistently elevated CK levels (10x normal). After a mild SARS-CoV-2 infection at age 55, a mild cardiomyopathy was observed via cardiac MRI, without specific patterns indicative of myocarditis. Subsequently, NGS analysis identified a heterozygous likely damaging variant in the LDB3 gene, thus broadening the phenotypic spectrum of LDB3-related myopathies to potentially include congenital clubfoot and recurrent exertional rhabdomyolysis. Additionally, a possible link was suggested between the viral infection and the exacerbation of the otherwise subtle, undetected cardiomyopathy. In the context of hyperCKemia and a positive family history for unexplained cardiac abnormalities, broad-spectrum NGS testing, and cardiac MRI in selected cases, should be considered for timely diagnosis and interventions.

Introduction

Myofibrillar myopathies (MFMs) are a category of neuromuscular disorders defined by their histopathologic findings, namely focal areas of myofibrillar disorganization, accumulation of myofibrillar degradation products, and ectopic expression of numerous proteins in the sarcoplasm of muscle fibers, and they are being increasingly characterized, as demonstrated by the recent description by the Italian group 1,2. Among these, a still underdescribed subgroup is represented by MFMs caused by Z-band alternatively spliced PDZ-motif (ZASP)/Lim domain-binding 3 (LDB3) mutations, which are rare neuromuscular disorders characterized by slowly progressing late-onset distal weakness and structural cardiac abnormalities 3. Such cardiac manifestations render affected individuals more susceptible to life-threatening arrhythmias and significant reductions in ejection fraction, particularly when exposed to specific triggers 4,5. The objective of this study is to present an unusual case of ZASP/LDB3-related myopathy with COVID-19-exacerbated cardiomyopathy, highlighting the atypical phenotype and the potential connection between acute infection-related myocarditis and its impact on the cardiac presentation.

Methods

A cross-sectional evaluation was conducted, encompassing the patient’s medical history, skeletal muscle biopsy, muscle magnetic resonance imaging (MRI), cardiac assessments (including cardiac outpatient visits, electrocardiograms, trans-thoracic echocardiograms, cardiac magnetic resonance imaging 1.5 Tesla - MRI 1.5T), and next-generation sequencing (NGS) targeting a wide range of genes associated with myopathies and cardiomyopathies. Informed consent for genetic analysis and consent-to-disclose were obtained from the patient.

Results

We first evaluated the male patient at the age of 34, when he experienced a severe episode of post-exertional rhabdomyolysis (peak CK around 300,000 IU/L), requiring six cycles of inward dialysis. His family history revealed a myocardial infarction in his maternal grandfather at the age of 59, leading to a fatal outcome within one week, despite the absence of known cardiovascular risk factors. The patient reported being born with a clubfoot and experiencing multiple episodes of pigmenturia following moderate-intensity physical activities since adolescence. Neurological examination at that time, considering the post-rhabdomyolysis, revealed ankle retractions, modest dorsal scoliosis, and bilateral symmetrical hypotrophy of the medial gastrocnemius and lateral/posterior distal thighs. A quadriceps biopsy performed after the acute phase (still age 34) revealed notable myopathic alterations, including rod-like dystrophin and desmin positive cytoplasmic bodies in approximately 5% of muscle fibres (Fig. 1) and widespread myofibrillar disruption upon ultrastructural examination. Furthermore, immunohistochemical tests revealed a diffuse cytoplasmic positivity for desmin (around 10% of fibres) even outside cytoplasmic bodies, while the others comprising dystrophin (further analyzed via western blot), alfa- and gamma-sarcoglycan, merosin, and caveolin, yielded normal results. Additionally, carnitine palmitoyltransferase, acid alpha-glucosidase, and aerobic glycolysis enzymes activity resulted within the normal ranges. Based on these findings, a general diagnosis of “congenital myopathy” was made at the time.

Apart from a chronic high elevation of creatine kinase values (10-times the upper normal level, around 2500-3000 IU/L), regular annual instrumental (i.e., electrocardiograms and trans-thoracic echocardiograms) did not identify any significant abnormalities until the age of 55, when the patient complained of persistent cough and chest pain, occurring one month after a mild SARS-CoV-2 infection with minimal upper respiratory trait symptoms. Subsequent to a mild increase in troponin T levels, a cardiac MRI (1.5T Siemens) was performed three months from symptoms onset revealing moderate reduction in left ventricular ejection fraction (LVEF 39%). While subacute COVID-19-related myocarditis was suspected, no myocardial oedema was identified, likely due to the delay from the initial complaints. Treatment with a beta-blocker (nadolol 40 mg bid) and an angiotensin-receptor blocker (valsartan 160 mg bid) led to stabilization of LVEF values within the range of 42-47% during echocardiographic monitoring, with the most recent assessment performed 24 months after the COVID-19 infection. Concurrently, a subsequent cardiac MRI confirmed the mild reduction in LVEF and demonstrated persistent midwall fibrosis in the basal septum and inferior wall, a location atypical for myocarditis but consistent with cardiomyopathy.

During the patient’s last neuromuscular evaluation at age 57, CK was still ten times the upper normal value, and lower-limb muscle MRI revealed symmetrical bilateral alterations in T1-weighted images in the distal portion of the vastus lateralis, vastus intermedius, vastus medialis, as well as the entire medial gastrocnemius and soleus (Fig. 2). Short-TI Inversion Recovery (STIR) imaging exhibited positivity in the same regions. Neurological examination confirmed previously reported signs of distal myopathy and scoliosis, without evidence of significant focal weakness.

To further investigate the phenotype, an extended NGS panel targeting genes associated with myopathies and cardiomyopathies was performed (genes listed in Tab. I), revealing a variant in the LDB3 gene. Given the gene’s complexity and its pleiotropic expression in various tissues, including skeletal and cardiac muscles, the canonical transcript NM_007078.3 was considered. The identified variant, c.985G > A (p.Asp261Asn), was classified as a variant of uncertain significance based on a comprehensive genetic assessment; however, it remains highly relevant to the patient’s clinical, histological, and radiologic features. According to ACMG criteria 6, the variant was considered clinically relevant, as BP4 was deemed inconsistent due to conflicting results from multiple in silico predictors, while PP4 and PM2 supported the classification.

Discussion

ZASPopathies typically present with late-onset, distal-predominant weakness, initially affecting the intrinsic muscles of the hands and/or feet, with subsequent progression to proximal muscles, and cardiac involvement 3,7. Skeletal muscle biopsies often reveal cytosolic protein accumulations, and early muscle MRI findings demonstrate alterations in the medial gastrocnemius muscles 7,8. In our case, we observed a unique manifestation characterized by neonatal foot abnormalities and recurrent episodes of exertional rhabdomyolysis, along with an MRI pattern compatible with ZASP/LDB3-myopathy, potentially expanding the phenotypic spectrum of ZASPopathies.

Notably, cardiac involvement in our patient was only identified following SARS-CoV-2 infection. While establishing a definitive diagnosis of myocarditis may be challenging, such presumptive diagnosis may be plausible according to previous studies that have reported a direct association between SARS-CoV-2 infection and myocardial inflammation 5. In our case, the cardiac MRI revealed an abnormal distribution of endomyocardial fibrosis, suggesting the presence of a subtle pre-existing ZASP/LDB3-related cardiomyopathy that was not detected through routine transthoracic echocardiography and worsened after COVID-19-associated myocarditis.

Conclusion

Our case highlights a distinct presentation of ZASP/LDB3-related myopathy with atypical neonatal foot abnormalities and recurrent exertional rhabdomyolysis from early life, together with lower limbs distal hypotrophy. During his disease course, a viral infection unveiled a pre-existing mild cardiac involvement mimicking myocarditis. In order to timely identify such cases, cardiac and muscular MRI can be helpful in distinguishing disease-specific patterns and timely reveal signs of even subtle cardiomyopathy, especially when chronic hyperCKemia and remarkable personal or familial medical histories are present. Alongside, relevant hyperCKemias should be comprehensively assessed using wide genetic panels, such as NGS panels for myopathies, including genes linked to cardiomyopathy to aid in the early identification of variants that may lead to severe complications.

Acknowledgement

This study was initiated by the investigators without other external funding. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors of this publication are members of the European Reference Network for rare neuromuscular diseases (ERN EURO-NMD) - Project ID No. 739543.

Conflict of interest statament

The authors state that they have no Conflict of Interest (COI).

Funding

This research received no external funding.

Authors contribution

GG and SP manuscript preparation; GG, SP, GU data collection; GG, SP, DC interpretation and discussion of results; GG, SP, TM supervision and revision.

Ethical consideration

The present study was approved for publication in a scientific journal by the institutional ethical committee (Prot. n° 0027994, 03 Mar 2023). The local ethical committee also reviewed the written informed consent form (ICF) which was presented to the patient and collected for the same purpose.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

History

Received: November 11, 2024

Accepted: March 10, 2025

Figures and tables

Figure 1. Trichromic staining of quadriceps muscle biopsy showing fibre splitting (red arrows) and rod-like cytoplasmic bodies (black arrows) (scale bar 100 μm).

Figure 2. T1-weighted MRI images of legs showing symmetrical fatty infiltration of both medial gastrocnemi.

ABHD5 DNM2 LMOD3 SDHA
ACAD9 DOK7 LPIN1 SDHAF1
ACADM DPAGT1 LRP4 SDHB
ACADS DPM1 MAP3K20 SDHD
ACADVL DPM2 MATR3 SELENON
ACTA1 DPM3 MEGF10 SGCA
ACTN2 DYSF MGME1 SGCB
ADSS1 ECEL1 MSTO1 SGCD
AGL EMD MTM1 SGCG
AGRN ENO3 MTTP SIL1
ALDOA ETFA MUSK SLC12A3
ALG14 ETFB MYF6 SLC16A1
ALG2 ETFDH MYH14 SLC18A3
AMPD1 FHL1 MYH2 SLC22A5
AMPD3 FKRP MYH3 SLC25A20
ANO5 FKTN MYH7 SLC25A32
ATP2A1 FLAD1 MYH8 SLC5A7
B3GALNT2 FLNC MYO18B SMCHD1
B4GAT1 GAA MYO9A SNAP25
BAG3 GBE1 MYOT SPEG
BIN1 GFER MYPN SQSTM1
BVES GFPT1 NEB STAC3
CACNA1S GMPPB NEFL STIM1
CAPN3 GNE ORAI1 SUCLA2
CAV3 GOSR2 PFKM SYNE1
CCDC78 GYG1 PGAM2 SYNE2
CFL2 GYS1 1,00 PGK SYT2
CHAT HACD1 PGM1 TAFAZZIN
CHCHD10 HADHA PHKA1 TANGO2
CHKB HADHB PHKB TCAP
CHRNA1 HNRNPA1 PIEZO2 TIA1
CHRNB1 HNRNPA2B1 PLEC TK2
CHRND HNRNPDL PNPLA2 TMEM43
CHRNE HSPB1 POGLUT1 TNNT1
CHRNG HSPB8 POLG TNPO3
CLCN1 HSPG2 POLG2 TOR1AIP1
CNTN1 ISCU POMGNT1 TPM2
COL12A1 ITGA7 POMGNT2 TPM3
COL13A1 KBTBD13 POMK TRAPPC11
COL6A1 KCNJ12 POMT1 TRIM32
COL6A2 KCNJ2 POMT2 TRIP4
COL6A3 KCNJ5 PREPL TSFM
COLQ KLHL40 PRKAG2 TTN
COQ8A KLHL41 PUS1 TWNK
CPT2 KLHL9 PYGM TYMP
CRPPA LAMA2 PYROXD1 UNC45B
CRYAB LAMB2 RAPSN VAMP1
DAG1 LAMP2 RBCK1 VCP
DES LARGE1 RNASEH1 VMA21
DGUOK LDB3 RRM2B VWA1
DMD LDHA RXYLT1 YARS2
DNA2 LIMS2 RYR1
DNAJB6 LMNA SCN4A
Table I. Genes included in the NGS study. If not specified, both coverages > 10x and > 20x are assumed to be 100.00%. For the following genes: HSPG2 (coverage > 20x 99.83%); SELENON (coverage > 10x 89.96%, > 20x 87.87%); TSFM (coverage > 10x 93.95%, > 20x 93.95%).

References

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Authors

Giulio Gadaleta - Neuromuscular Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, Turin, Italy

Stefano Pidello - Division of Cardiology, Department of Cardiovascular and Thoracic Medicine, A.O.U. Città della Salute e della Scienza di Torino, 10126 Turin, Italy

Guido Urbano - Neuromuscular Unit, Department of Neurosciences “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy

Diana Carli - Department of Medical Sciences, University of Torino, Turin, Italy

Tiziana Mongini - Neuromuscular Unit, Department of Neurosciences “Rita Levi Montalcini”, University of Turin, 10126 Turin, Italy

How to Cite
Gadaleta, G., Pidello, S., Urbano, G., Carli, D., & Mongini, T. (2025). ZASP/LDB3-related atypical myopathy with subtle cardiac impairment unveiled by COVID-19 infection: a short report. Acta Myologica, 44(2). https://doi.org/10.36185/2532-1900-787
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