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

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.

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

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

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

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.