Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun;10(6):1035-1045.
doi: 10.1002/acn3.51787. Epub 2023 May 23.

A different pattern of clinical, muscle pathology and brain MRI findings in MELAS with mt-ND variants

Wei Wang #  1 , Yuying Zhao #  1 , Xuebi Xu  2 , Xiaotian Ma  3 , Yuan Sun  4 , Yan Lin  1 , Ying Zhao  1 , Zhihong Xu  1 , Jiayin Wang  1 , Hong Ren  1 , Bin Wang  1 , Dandan Zhao  1 , Dongdong Wang  1 , Fuchen Liu  1 , Wei Li  1 , Chuanzhu Yan  1   5   6 , Kunqian Ji  1
Affiliations

A different pattern of clinical, muscle pathology and brain MRI findings in MELAS with mt-ND variants

Wei Wang et al. Ann Clin Transl Neurol. 2023 Jun.

Abstract

Objective: To explore the clinical characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by mitochondrial DNA-encoded complex I subunit (mt-ND) variants.

Methods: In this retrospective study, the clinical, myopathological and brain MRI features of patients with MELAS caused by mt-ND variants (MELAS-mtND) were collected and compared with those of MELAS patients carrying the m.3243A > G variant (MELAS-A3243G).

Result: A total of 18 MELAS-mtND patients (female: 7; median age: 24.5 years) represented 15.9% (n = 113) of all patients with MELAS caused by mtDNA variants in our neuromuscular center from January 2012 to June 2022. In this MELAS-mtND cohort, the two most common variants were m.10191 T > C (4/18, 22.2%) and m.13513 G > A (3/18, 16.7%). The most frequent symptoms were seizures (14/18, 77.8%) and muscle weakness (11/18, 61.1%). Compared with 87 MELAS-A3243G patients, MELAS-mtND patients were significantly more likely to have a variant that was absent in blood cells (40% vs. 1.4%). Furthermore, MELAS-mtND patients had a significantly lower MDC score (7.8 ± 2.7 vs. 9.8 ± 1.9); less hearing loss (27.8% vs. 54.0%), diabetes (11.1% vs. 37.9%), and migraine (33.3% vs. 62.1%); less short stature (males ≤ 165 cm; females ≤ 155 cm; 23.1% vs. 60.8%) and higher body mass index (20.4 ± 2.5 vs. 17.8 ± 2.7). MELAS-mtND patients had significantly more normal muscle pathology (31.3% vs. 4.1%) and fewer RRFs/RBFs (62.5% vs. 91.9%), COX-deficient fibers/blue fibers (25.0% vs. 85.1%) and SSVs (50.0% vs. 81.1%). Moreover, brain MRI evaluated at the first stroke-like episode showed significantly more small cortical lesions in MELAS-mtND patients (66.7% vs. 12.2%).

Interpretation: Our results suggested that MELAS-mtND patients have distinct clinical, myopathological and brain MRI features compared with MELAS-A3243G patients.

PubMed Disclaimer

Conflict of interest statement

All authors report no competing interests.

Figures

Figure 1
Figure 1
Pedigree diagram for 18 unrelated Chinese families with mt‐ND variants. The arrow indicates the proband. Squares symbolize males, and circles symbolize females. Black symbols and gray symbols indicate symptomatic patients and asymptomatic carriers, respectively. Question marks indicate family members who refused to undergo genetic analysis. B, blood cells; M, muscle sample; O, oral mucosa; U, urothelium.
Figure 2
Figure 2
Genetic heteroplasmy and clinical findings in MELAS‐mtND patients. (A) Genetic heteroplasmy in different tissues of MELAS‐mtND patients. (B) Frequency of symptoms of 18 MELAS‐mtND patients. The gray column represents muscular involvement, the dark gray column represents the multisystem involvement, and the black column represents central nerve system involvement. (C) Comparison of BMI between MELAS‐mtND and MELAS‐A3243G patients. (D and E) Comparison of the MDC score between MELAS‐mtND and MELAS‐A3243G patients.
Figure 3
Figure 3
Classic and nonclassic SLLs of MELAS‐mtND patients. The white arrow indicates nonclassic SLLs. The black arrow indicates classic SLLs. (A) nonclassic SLLs with single small cortical lesion; (B) nonclassic SLLs with multiple isolated small cortical lesions; (C) nonclassic SLLs with disseminated cortical lesions; (D) classic SLLs with nonclassic basal ganglion lesion; (E) nonclassic SLLs with cerebellar lesions; (F) classic SLLs with lesions in the temporal lobe.
Figure 4
Figure 4
Comparison of muscle pathology between MELAS‐mtND and MELAS‐A3243G patients. Muscle pathology of one MELAS‐A3243G patient and two MELAS‐mtND patients (Family 5, II‐1 and Family 14, II‐2). Arrows represent RRFs with blue fibers. †Represent RRFs without blue fibers. *Represent COX decreased fibers presented with blue fibers but without RRFs.
See this image and copyright information in PMC

References

    1. La Morgia C, Maresca A, Caporali L, Valentino ML, Carelli V. Mitochondrial diseases in adults. J Intern Med. 2020;287(6):592‐608. - PubMed
    1. Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651‐653. - PubMed
    1. El‐Hattab AW, Adesina AM, Jones J, Scaglia F. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015. Sep‐Oct;116(1–2):4‐12. - PubMed
    1. Santorelli FM, Tanji K, Kulikova R, et al. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun. 1997;238(2):326‐328. - PubMed
    1. Valentino ML, Barboni P, Rengo C, et al. The 13042G→A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype. J Med Genet. 2006;43(7):e38. - PMC - PubMed

Publication types

Substances