Case Reports
Volume XLIV n. 2 - June 2025
ZASP/LDB3-related atypical myopathy with subtle cardiac impairment unveiled by COVID-19 infection: a short report.
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 |
References
- Olivé M, Kley R, Goldfarb L. Myofibrillar myopathies. Curr Opin Neurol. 2013;26(5):527-35. doi:https://doi.org/10.1097/WCO.0b013e328364d6b1
- Bortolani S. Clinical, histopathologic, and genetic features of patients with myofibrillar and distal myopathies. Neurology. 2024;103(4). doi:https://doi.org/10.1212/WNL.0000000000209697
- Laneuville M, Woulfe J, Bourque P, McMillan H, Dyment D, Warman Chardon J. LDB3/ZASP-related myofibrillar myopathy associated with marked phenotypic variability. Neuromuscul Disord. 2016;26. doi:https://doi.org/10.1016/j.nmd.2016.06.383
- Limongelli G. COVID-19 pandemia and inherited cardiomyopathies and channelopathies: a short term and long term perspective. Orphanet J Rare Dis. 2020;15(1):1-7. doi:https://doi.org/10.1186/S13023-020-01444-2
- Castiello T. COVID-19 and myocarditis: a systematic review and overview of current challenges. Heart Fail Rev. 2022;27(1):251-61. doi:https://doi.org/10.1007/s10741-021-10087-9
- Richards S. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi:https://doi.org/10.1038/gim.2015.30
- Griggs R. Zaspopathy in a large classic late-onset distal myopathy family. Brain. 2007;130(6):1477-84. doi:https://doi.org/10.1093/brain/awm006
- Zheng J, Chen S, Chen Y, Zhu M, Hong D. A novel mutation in the PDZ-like motif of ZASP causes distal ZASP-related myofibrillar myopathy. Neuropathology. 2017;37(1):45-51. doi:https://doi.org/10.1111/neup.12328
Downloads
License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Copyright
Copyright (c) 2025 Acta Myologica
How to Cite
- Abstract viewed - 183 times
- PDF downloaded - 76 times