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

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.