Phenotypic Heterogeneity in 5 Family Members with the Mitochondrial Variant m.3243A>G

Objective: Rare disease Background: The pathogenic mitochondrial DNA variant m.3243A>G is associated with a wide range of clinical features, making disease course and prognosis extremely difficult to predict. We aimed to understand the cause of this broad intra-familial phenotypic heterogeneity in a large family carrying the variant m.3243A>G. Cases Reports: Thirteen family members were clinically affected. Clinical manifestations occurred in the brain, eyes, ears, endocrine organs, myocardium, intestines, kidneys, muscle, and nerves. Five family members carried the m.3243A>G variant. The 2 most severely affected patients were the index patient, a 60-year-old woman, and her sister, who was deceased. The phenotypic features most frequently found were hypoacusis and cerebellar atrophy. Hypertrophic cardiomyopathy was diagnosed in 3 family members. Short PQ syndrome and gestosis had not been reported to date. The broad phenotypic heterogeneity was attributed to variable heteroplasmy rates and variable mtDNA copy numbers. All affected patients benefited from symptomatic treatment. Conclusions: The mitochondrial DNA variant m.3243A>G can manifest phenotypically with a non-syndromic, multisystem phenotype with wide intra-familial heterogeneity. Rare manifestations of the m.3243A>G variant are gestosis and short PQ syndrome. The broad intra-familial phenotypic heterogeneity may be related to fluctuating heteroplasmy rates or mitochondrial DNA copy numbers and may lead to misdiagnosis for years.