Mitochondrial Diseases VCEP
The m.3481G>A (p.E59K) variant in MT-ND1 has been reported in at least two unrelated individuals. The first, an 8-year-old male with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), exhibited muscle weakness, ragged red fibers on muscle biopsy, multiple acute encephalopathic episodes, and rod-cone-type retinal dystrophy. Heteroplasmy ranged from 50%-80% (PMID:17535832). The second individual was a female with severe developmental delay, spastic tetraparesis, joint contractures, type 2 fiber atrophy seen on muscle biopsy, severe visual impairment, and epilepsy with onset at 6 months. She developed hypertrophic cardiomyopathy at 16 years old and died from cardiac insufficiency at 26. Heteroplasmy ranged from 12%-61% (PMID: 18504678). Both individuals had elevated lactate and abnormalities on brain MRI. This variant may have been observed in a third individual with mitochondrial epilepsy; however the full text was unavailable for review (PMID:31665838). Haplogroup information was not reported for all cases precluding consideration for PS4. In the family of the proband with MELAS, the proband exhibited heteroplasmy levels ranging from 50-80% (lymphocytes: 55%). However, unaffected or less severely affected maternal relatives, including the mother, maternal aunt, and maternal cousin (who reported migraines), displayed lower heteroplasmy levels ranging from 15-20% in lymphocytes (PP1, PMID: 17535832). In the other case, the variant was absent in mother’s blood (PMID: 18504678), however the proband's blood was not tested. Complex I deficiency was demonstrated in both probands, however nuclear causes of disease were not excluded (PMIDs: 17535832, 18504678). Cybrid studies demonstrated a strong inverse correlation between heteroplasmy level and Complex I activity (PS3_supporting, PMID: 17535832). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic with raw scores of 0.69 and 0.754, respectively (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PS3_supporting, PM2_supporting, PP3.
