Mitochondrial diabetes plus phenotypes due to the m.3243A > G variant require correlation with heteroplasmy rates

We read with interest Zheng et al's article on a family with mitochondrial diabetes due to the mtDNA variant m.3243A > G in MT-TL1.1 The index patient, a 33-year-old male, exhibited not only diabetes but also hypoacusis, which is why maternally inherited diabetes and deafness (MIDD) syndrome was diagnosed.1 In addition to MIDD, the index patient suffered from hyperuricemia, abdominal pain, vomiting, myocloni, and limb spams (MIDD plus).1 The index patient benefited significantly from insulin and coenzyme-Q.1 Six other family members also had MIDD and two additional family members had myocloni.1 The work is compelling, but some points should be discussed. The first point is that a heteroplasmy rate was provided only for the index patient (31%), although the mother was also genetically tested. Knowledge of heteroplasmy rates in other clinically affected and unaffected family members is crucial as they strongly determine the phenotype and therefore disease course and outcome of m.3243A > G carriers. It would also be desirable to have heteroplasmy rates from different affected tissues to assess whether the phenotype correlates with mutational load. Heteroplasmy rates of different generations would also be desirable in order to be able to assess whether heteroplasmy rates increase in successive generations. A second point is that MIDD plus has not been studied in detail among affected family members. MIDD is known to manifest phenotypically either as classic MIDD with diabetes and hypoacusis, or as MIDD plus, in which organs other than the pancreas and the ears are additionally affected, such as the brain, heart, the kidney, peripheral nerves, or skeletal muscles.2, 3 In the brain, MIDD can manifest as seizures, leukoencephalopathy, atrophy, basal ganglia calcifications, or cognitive impairment.4 In the peripheral nervous system, MIDD can manifest as neuropathy or myopathy. A third point is that the clinical onset of MIDD is not always accompanied by the onset of diabetes or impaired hearing. If, for example, short stature is a feature of MIDD, it must be assumed that MIDD begins significantly earlier than with diabetes or hypoacusis, since short stature usually develops in early childhood. A fourth point is that the index patient also had abdominal pain and vomiting. We should know whether these gastrointestinal symptoms were due to pancreatitis, gastritis, reflux esophagitis, intestinal pseudo-obstruction, liver disease, or due to the current medication the patient was taking regularly. A fifth point is that the "limb spasms" were not adequately explained. Do the authors mean muscle cramps, myoclonus, clonus, seizures, spasticity, rigidity or dystonia? Clear assignment of these manifestations is crucial because m.3243A > G carriers can also manifest with cerebral involvement, including epilepsy, migraines, extrapyramidal disease, cognitive decline, stroke-like episode, and cerebrovascular disease. In summary, the excellent study has limitations, which complicate the interpretation of the results. Addressing these limitations could strengthen and reinforce the statement of the study. MIDD patients require a comprehensive clinical, instrumental, and genetic workup. Of particular interest is the relation between phenotypic heterogeneity and heteroplasmy rates. Josef Finsterer: Conceptualization; data curation; investigation; writing – original draft. None. None received. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All data are available from the corresponding author. Not applicable. Not applicable.