De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review

Magistrati, Martina; Zupin, Luisa; Lamantea, Eleonora; Baruffini, Enrico; Ghezzi, Daniele; Legati, Andrea; Celsi, Fulvio; Murru, Flora Maria; Capaci, Valeria; Pinamonti, Maurizio; Bussani, Rossana; Carrozzi, Marco; Dallabona, Cristina; Zeviani, Massimo; Bonati, Maria Teresa

doi:10.3390/ijms26020846

Open AccessCase Report

De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review

by

Martina Magistrati

^1,†

,

Luisa Zupin

^2,†

,

Eleonora Lamantea

³

,

Enrico Baruffini

¹

,

Daniele Ghezzi

^3,4

,

Andrea Legati

³

,

Fulvio Celsi

²

,

Flora Maria Murru

²,

Valeria Capaci

²

,

Maurizio Pinamonti

⁵

,

Rossana Bussani

^5,6

,

Marco Carrozzi

²

,

Cristina Dallabona

¹

,

Massimo Zeviani

² and

Maria Teresa Bonati

^2,*

¹

Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze, 11/A, 43124 Parma, Italy

²

Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria, 65, 34137 Trieste, Italy

³

Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133 Milan, Italy

⁴

Department of Pathophysiology and Transplantation, University of Milan, Via F. Sforza, 35, 20122 Milan, Italy

⁵

Institute of Pathological Anatomy and Histology, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), University of Trieste, Via Giacomo Puccini, 50, 34148 Trieste, Italy

⁶

Department of Medical, Surgical and Health Sciences, University of Trieste, Via Giacomo Puccini, 50, 34148 Trieste, Italy

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(2), 846; https://doi.org/10.3390/ijms26020846

Submission received: 4 December 2024 / Revised: 8 January 2025 / Accepted: 14 January 2025 / Published: 20 January 2025

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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Abstract

Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient’s death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus.

Keywords: DNM1L; lethal encephalocardiomyopathy; refractory status epilepticus (RSE); burst suppression; global developmental regression; hypertrophic cardiomyopathy (HC); retrospective post-mortem diagnosis

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MDPI and ACS Style

Magistrati, M.; Zupin, L.; Lamantea, E.; Baruffini, E.; Ghezzi, D.; Legati, A.; Celsi, F.; Murru, F.M.; Capaci, V.; Pinamonti, M.; et al. De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review. Int. J. Mol. Sci. 2025, 26, 846. https://doi.org/10.3390/ijms26020846

AMA Style

Magistrati M, Zupin L, Lamantea E, Baruffini E, Ghezzi D, Legati A, Celsi F, Murru FM, Capaci V, Pinamonti M, et al. De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review. International Journal of Molecular Sciences. 2025; 26(2):846. https://doi.org/10.3390/ijms26020846

Chicago/Turabian Style

Magistrati, Martina, Luisa Zupin, Eleonora Lamantea, Enrico Baruffini, Daniele Ghezzi, Andrea Legati, Fulvio Celsi, Flora Maria Murru, Valeria Capaci, Maurizio Pinamonti, and et al. 2025. "De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review" International Journal of Molecular Sciences 26, no. 2: 846. https://doi.org/10.3390/ijms26020846

APA Style

Magistrati, M., Zupin, L., Lamantea, E., Baruffini, E., Ghezzi, D., Legati, A., Celsi, F., Murru, F. M., Capaci, V., Pinamonti, M., Bussani, R., Carrozzi, M., Dallabona, C., Zeviani, M., & Bonati, M. T. (2025). De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review. International Journal of Molecular Sciences, 26(2), 846. https://doi.org/10.3390/ijms26020846

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De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review

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