LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes

doi:10.1002/ajmg.a.63143

Case Reports

. 2023 May;191(5):1401-1411.

doi: 10.1002/ajmg.a.63143. Epub 2023 Feb 9.

LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes

Rita Alfattal¹, Maryam Alfarhan², Adeeb M Algaith³, Buthaina Albash⁴, Reem M Elshafie⁴, Asma Alshammari⁴, Ahmad Alahmad⁴, Fatima Dashti⁵, Rasha Alsafi⁶, Hind Alsharhan^{2

4

7

8}

Affiliations

¹ Department of Pediatrics, Al-Amiri Hospital, Ministry of Health, Kuwait.
² Department of Pediatrics, Health Sciences Centre, Faculty of Medicine, Kuwait University, Safat, Kuwait.
³ University of Szeged, Faculty of Medicine, Hungary.
⁴ Kuwait Medical Genetics Center, Ministry of Health, Sulaibikhat, Kuwait.
⁵ Department of Radiology, Ibn Sina Hospital, Ministry of Health, Safat, Kuwait.
⁶ Department of Pediatrics, Adan Hospital, Ministry of Health, Hadiya, Kuwait.
⁷ Department of Pediatrics, Farwaniya Hospital, Ministry of Health, Sabah Al-Nasser, Kuwait.
⁸ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 36757047
DOI: 10.1002/ajmg.a.63143

Case Reports

LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes

Rita Alfattal et al. Am J Med Genet A. 2023 May.

. 2023 May;191(5):1401-1411.

doi: 10.1002/ajmg.a.63143. Epub 2023 Feb 9.

Authors

Rita Alfattal¹, Maryam Alfarhan², Adeeb M Algaith³, Buthaina Albash⁴, Reem M Elshafie⁴, Asma Alshammari⁴, Ahmad Alahmad⁴, Fatima Dashti⁵, Rasha Alsafi⁶, Hind Alsharhan^{2

4

7

8}

Affiliations

¹ Department of Pediatrics, Al-Amiri Hospital, Ministry of Health, Kuwait.
² Department of Pediatrics, Health Sciences Centre, Faculty of Medicine, Kuwait University, Safat, Kuwait.
³ University of Szeged, Faculty of Medicine, Hungary.
⁴ Kuwait Medical Genetics Center, Ministry of Health, Sulaibikhat, Kuwait.
⁵ Department of Radiology, Ibn Sina Hospital, Ministry of Health, Safat, Kuwait.
⁶ Department of Pediatrics, Adan Hospital, Ministry of Health, Hadiya, Kuwait.
⁷ Department of Pediatrics, Farwaniya Hospital, Ministry of Health, Sabah Al-Nasser, Kuwait.
⁸ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 36757047
DOI: 10.1002/ajmg.a.63143

Abstract

Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.

Keywords: LYRM7; MRI; brain; lactic acidosis; leukoencephalopathy; mitochondria.

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Before diagnosing a stroke-like episode, a stroke-like lesion must be documented on multimodal cerebral MRI.
Finsterer J, Mehri S. Finsterer J, et al. Am J Med Genet A. 2023 Jun;191(6):1677-1678. doi: 10.1002/ajmg.a.63172. Epub 2023 Mar 2. Am J Med Genet A. 2023. PMID: 36863701 No abstract available.

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Neuroimaging in Primary Coenzyme-Q₁₀-Deficiency Disorders.
Münch J, Prasuhn J, Laugwitz L, Fung CW, Chung BH, Bellusci M, Mayatepek E, Klee D, Distelmaier F. Münch J, et al. Antioxidants (Basel). 2023 Mar 14;12(3):718. doi: 10.3390/antiox12030718. Antioxidants (Basel). 2023. PMID: 36978966 Free PMC article. Review.
Cavitating leukodystrophy in a case of mitochondrial complex III deficiency due to LYRM7 mutation.
Rezaei M, Dourandish Z, Kiani Mehr G, Ghorbani A, Fatehi F. Rezaei M, et al. Acta Neurol Belg. 2024 Aug;124(4):1409-1410. doi: 10.1007/s13760-024-02529-6. Epub 2024 Apr 9. Acta Neurol Belg. 2024. PMID: 38592654 No abstract available.
Dual diagnosis of UQCRFS1-related mitochondrial complex III deficiency and recessive GJA8-related cataracts.
Blue EE, Huang SJ, Khan A, Golden-Grant K, Boyd B, Rosenthal EA, Gillentine MA, Fleming LR, Adams DR, Wolfe L, Allworth A, Bamshad MJ, Caruana NJ, Chanprasert S, Chen J, Dargie N, Doherty D, Friederich MW, Hisama FM, Horike-Pyne M, Lee JC, Donovan TE, Hock DH, Leppig KA, Miller DE, Mirzaa G, Ranchalis J, Raskind WH, Michel CR, Reisdorph R, Schwarze U, Sheppeard S, Strohbehn S, Stroud DA, Sybert VP, Wener MH; University of Washington Center for Rare Disease Research, the Undiagnosed Diseases Network; Stergachis AB, Lam CT, Jarvik GP, Dipple KM, Van Hove JLK, Glass IA. Blue EE, et al. Rare. 2024;2:100040. doi: 10.1016/j.rare.2024.100040. Epub 2024 Aug 14. Rare. 2024. PMID: 39421685 Free PMC article.

References

REFERENCES

1. Alconada, A., Kübrich, M., Moczko, M., Hönlinger, A., & Pfanner, N. (1995). The mitochondrial receptor complex: The small subunit Mom8b/Isp6 supports association of receptors with the general insertion pore and transfer of preproteins. Molecular and Cellular Biology, 15, 6196-6205. https://doi.org/10.1128/MCB.15.11.6196
1. Cherian, A., Divya, K. P., Jose, J., & Thomas, B. (2021). Multifocal cavitating leukodystrophy-A distinct image in mitochondrial LYRM7 mutations. Multiple Sclerosis and Related Disorders, 47, 102615. https://doi.org/10.1016/J.MSARD.2020.102615
1. Dallabona, C., Abbink, T. E. M., Carrozzo, R., Torraco, A., Legati, A., van Berkel, C. G. M., Niceta, M., Langella, T., Verrigni, D., Rizza, T., Diodato, D., Piemonte, F., Lamantea, E., Fang, M., Zhang, J., Martinelli, D., Bevivino, E., Dionisi-Vici, C., Vanderver, A., … Bertini, E. (2016). LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain, 139, 782-794. https://doi.org/10.1093/BRAIN/AWV392
1. de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J. W., Benayoun, E., Chrétien, D., Kadhom, N., Lombès, A., de Baulny, H. O., Niaudet, P., Munnich, A., Rustin, P., & Rötig, A. (2001). A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature Genetics, 29, 57-60. https://doi.org/10.1038/NG706
1. de Meirleir, L., Seneca, S., Damis, E., Sepulchre, B., Hoorens, A., Gerlo, E., García Silva, M. T., Martín Hernandez, E., Lissens, W., & van Coster, R. (2003). Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. American Journal of Medical Genetics. Part A, 121A, 126-131. https://doi.org/10.1002/AJMG.A.20171

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[1] Alconada, A., Kübrich, M., Moczko, M., Hönlinger, A., & Pfanner, N. (1995). The mitochondrial receptor complex: The small subunit Mom8b/Isp6 supports association of receptors with the general insertion pore and transfer of preproteins. Molecular and Cellular Biology, 15, 6196-6205. https://doi.org/10.1128/MCB.15.11.6196

[2] Alconada, A., Kübrich, M., Moczko, M., Hönlinger, A., & Pfanner, N. (1995). The mitochondrial receptor complex: The small subunit Mom8b/Isp6 supports association of receptors with the general insertion pore and transfer of preproteins. Molecular and Cellular Biology, 15, 6196-6205. https://doi.org/10.1128/MCB.15.11.6196

[3] Cherian, A., Divya, K. P., Jose, J., & Thomas, B. (2021). Multifocal cavitating leukodystrophy-A distinct image in mitochondrial LYRM7 mutations. Multiple Sclerosis and Related Disorders, 47, 102615. https://doi.org/10.1016/J.MSARD.2020.102615

[4] Cherian, A., Divya, K. P., Jose, J., & Thomas, B. (2021). Multifocal cavitating leukodystrophy-A distinct image in mitochondrial LYRM7 mutations. Multiple Sclerosis and Related Disorders, 47, 102615. https://doi.org/10.1016/J.MSARD.2020.102615

[5] Dallabona, C., Abbink, T. E. M., Carrozzo, R., Torraco, A., Legati, A., van Berkel, C. G. M., Niceta, M., Langella, T., Verrigni, D., Rizza, T., Diodato, D., Piemonte, F., Lamantea, E., Fang, M., Zhang, J., Martinelli, D., Bevivino, E., Dionisi-Vici, C., Vanderver, A., … Bertini, E. (2016). LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain, 139, 782-794. https://doi.org/10.1093/BRAIN/AWV392

[6] Dallabona, C., Abbink, T. E. M., Carrozzo, R., Torraco, A., Legati, A., van Berkel, C. G. M., Niceta, M., Langella, T., Verrigni, D., Rizza, T., Diodato, D., Piemonte, F., Lamantea, E., Fang, M., Zhang, J., Martinelli, D., Bevivino, E., Dionisi-Vici, C., Vanderver, A., … Bertini, E. (2016). LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. Brain, 139, 782-794. https://doi.org/10.1093/BRAIN/AWV392

[7] de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J. W., Benayoun, E., Chrétien, D., Kadhom, N., Lombès, A., de Baulny, H. O., Niaudet, P., Munnich, A., Rustin, P., & Rötig, A. (2001). A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature Genetics, 29, 57-60. https://doi.org/10.1038/NG706

[8] de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J. W., Benayoun, E., Chrétien, D., Kadhom, N., Lombès, A., de Baulny, H. O., Niaudet, P., Munnich, A., Rustin, P., & Rötig, A. (2001). A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature Genetics, 29, 57-60. https://doi.org/10.1038/NG706

[9] de Meirleir, L., Seneca, S., Damis, E., Sepulchre, B., Hoorens, A., Gerlo, E., García Silva, M. T., Martín Hernandez, E., Lissens, W., & van Coster, R. (2003). Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. American Journal of Medical Genetics. Part A, 121A, 126-131. https://doi.org/10.1002/AJMG.A.20171

[10] de Meirleir, L., Seneca, S., Damis, E., Sepulchre, B., Hoorens, A., Gerlo, E., García Silva, M. T., Martín Hernandez, E., Lissens, W., & van Coster, R. (2003). Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. American Journal of Medical Genetics. Part A, 121A, 126-131. https://doi.org/10.1002/AJMG.A.20171

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LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes

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LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes

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