Intra-familial phenotypic heterogeneity of m.3243A > G carriers remains elusive as long as heteroplasmy and mtDNA copy numbers are absent

I read with interest the article by Seiler et al.¹ on a 48-year-old male with a non-syndromic mitochondrial disorder (MID) due to the variant m.3243A > G in MT-TL1. The patient presented phenotypically with hearing loss, diabetes, and hypertrophic cardiomyopathy.¹ The causative variant was also detected in four first-degree relatives, who also manifested clinically but with partially different phenotypes.¹ Another family member had hypertrophic cardiomyopathy, two others dilated cardiomyopathy, and one half-brother also had renal insufficiency.¹ The study is excellent but has limitations that are cause for concerns and should be discussed.

A limitation of the study is that heteroplasmy rates among first-degree relatives were not reported.¹ Knowledge of heteroplasmy rates of first-degree relatives is crucial not only for explaining the individual phenotype but also for predicting an individual’s progression and outcome, for explaining the intra-familial phenotypic variability, and for genetic counselling. In addition, mitochondrial DNA (mtDNA) copy numbers should be reported as they contribute to the phenotypic variability between individuals carrying the same mtDNA mutation.

The diagnostic delay of 2 years should be explained. Patients with the combination of hearing impairment, diabetes, and hypertrophic cardiomyopathy are suspect of a MID. Especially in the light of the family history, primary MID should be considered. In addition, the pedigree in figure 4 shows that only females transmit the disease. A phenotype transmitted through the maternal line also indicates MID.

Because MIDs often present as multisystem diseases,² it is crucial that the index patient and his first-degree relatives were evaluated not only for cardiac involvement but also for subclinical or mildly manifesting abnormalities in other organs. Since MIDs particularly affect the central and peripheral nervous system, eyes, endocrine organs, the gastrointestinal tract, kidneys, bone marrow, and muscles, it is crucial that patients with a MID undergo prospective neurologic, endocrine, ophthalmologic, gastrointestinal, renal, and haematological examination. We should also know if there was dysmorphism or lactic acidosis in serum or cerebrospinal fluid (CSF). No mention is made of serum or CSF lactate.

Because the two half-sisters of the index patient with hearing loss and pre-diabetes most likely also carried the MT-TL1 variant, it is recommended that they are genetically tested. Did they refuse to be tested?

The index patient’s HbA1c of 7.3% was interpreted as pre-diabetes.¹ However, according to most laboratories, a HbA1c above 6.5% is regarded as diabetes.

Overall, the interesting study has limitations that call the results and their interpretation into question. Addressing these issues would strengthen the conclusions and could improve the status of the study. The intrafamilial phenotypic heterogeneity of m.3243A > G carriers remains elusive as long as heteroplasmy and mtDNA copy numbers are absent. Therefore, all family members of an m.3243A > G carrier should be prospectively screened for subclinical or clinically manifesting MID, as well as for heteroplasmy rates and mtDNA copy numbers. Furthermore, it is necessary that in a family with familial hypertrophic or dilative cardiomyopathy, the trait of inheritance be clarified before further genetic work-up is initiated to minimize costs and to save time. Because MIDs are commonly multiorgan, other specialists should be included in the work-up and management. Because MIDs are commonly transmitted via the maternal line, a family tree should be constructed.

 

Funding: None declared.

Data availability

All data are available from the corresponding author.

Compliance with ethics guidelines: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.