The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability

• Published in: American journal of medical genetics. Part A 2023-12, Vol.191 (12), p.2890-2897
• Main Authors: Strasser, Lauren, Doja, Asif, Davila, Jorge, Chakraborty, Pranesh, Bourque, Danielle K
• Format: Article
• Language: English
• Subjects: Adolescent; Aged, 80 and over; Blood; Child; Child, Preschool; DNA, Mitochondrial - genetics; Fatal Outcome; Female; Genetic diversity; Genetic Variation; Heteroplasmy; Heteroplasmy - genetics; Humans; Infant; Leigh Disease - blood; Leigh Disease - genetics; Leigh Disease - therapy; Male; MELAS syndrome; MELAS Syndrome - blood; MELAS Syndrome - genetics; MELAS Syndrome - therapy; MELAS Syndrome - urine; Middle Aged; Mitochondrial Diseases - blood; Mitochondrial Diseases - genetics; Mitochondrial Diseases - therapy; Mitochondrial Diseases - urine; Mitochondrial DNA; Neuroimaging; Pedigree; Phenotype; Phenotypes; RNA, Mitochondrial - genetics; RNA, Transfer - genetics; tRNA; Urine; Young Adult
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.63378

Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.