Biparental Mitochondrial Dna Transmission

Description

Although mitochondria and mitochondrial DNA (mtDNA) are typically maternally inherited, evidence exists for rare occurrences of paternal mtDNA transmission (Luo et al., 2018).

Clinical Features

Luo et al. (2018) reported a 4-year-old boy evaluated at the Cleveland Clinic for fatigue, hypotonia, muscle pain, and ptosis. He was suspected of having a mitochondrial disorder. Other family members showed varying clinical symptoms but were not suspected of having mitochondrial disorders. His twin sister had speech delay but was otherwise healthy, and his grandfather suffered a heart attack but had no other conditions. An older sister was healthy. The proband's mother was diagnosed with neuropathy and leg pain suspected to be due to multiple sclerosis. Whole mitochondrial DNA sequencing in the proband showed no pathogenic or likely pathogenic mutations, but identified 9 homoplasmic and 31 heteroplasmic variants. Among the 31 heteroplasmic variants, first blood sampling of the proband revealed an average heteroplasmy level of 29% for 10 variants and reciprocally 71% for the other 21 variants. Due to this abnormally high level of heteroplasmy, repeated sequencing and fresh blood sampling were performed, which confirmed the initial results. The proband and his 2 sisters were found to share the same mtDNA heteroplasmy pattern. Testing in the mother, grandmother, and grandfather of the proband indicated that the proband's mother had inherited 30 variants (60%) from her mother and 19 (40%) from her father. In all, 4 individuals in this family showed instances of biparental mtDNA transmission, with an autosomal dominant inheritance pattern. Luo et al. (2018) identified 2 additional families with biparental mtDNA transmission. The proband of family B, evaluated at the Cleveland Clinic, was a 35-year-old male with developmental delay, chronic fatigue, diabetes, congenital heart disease, supraventricular tachycardia, and status post ablation. The proband of family C, evaluated at the Mayo Clinic, was a 46-year-old female diagnosed with Guillain-Barre syndrome at 6 years of age who had presented with prematurity, hyperextensibility, thin translucent skin, chronic fatigue, diffuse body pain, and possible periodic fever. Both of these probands underwent mtDNA sequencing and showed high number and level of mtDNA heteroplasmy. Both family B and C showed strikingly similar mtDNA transmission pattern that segregated as an autosomal dominant phenotype.

Schwartz and Vissing (2002) reported a male with mitochondrial myopathy and exercise intolerance who possessed 2 different mtDNA haplotypes. One haplotype was inherited from the mother and the other from the father (with the exception of a de novo 2-basepair deletion in the ND2 gene of mtDNA; see 516001.0004). Paternal mtDNA was present only in the patient's skeletal muscle. Kraytsberg et al. (2004) confirmed the existence of the paternal haplotype in mtDNA from this patient.

Luo et al. (2018) stated that theirs and the report of Schwartz and Vissing (2002) were the only reports of biparental mitochondrial DNA inheritance.

Inheritance

The families studied by Luo et al. (2018) demonstrated biparental mtDNA transmission with an autosomal dominant mode of inheritance.

Molecular Genetics

Luo et al. (2018) stated that the mechanism of biparental mtDNA inheritance remained to be elucidated, although they hypothesized mutation in 1 nuclear gene involved in paternal mitochondrial elimination.