With interest we read the article by Spaide about two patients (four eyes) with maternally inherited diabetes and deafness (MIDD) who presented with choriocapillary perfusion voids and consecutive retinal pigmentary epithelium loss and geographical atrophy.1 We have the following comments and concerns.
Although MIDD is due to the mutation m.3243A>G in the tRNA(Leu) gene in 85% of the cases, it is genetically heterogenous.2 In addition to the m3243A>G mutation, MIDD may be due to the m.9276G>C mutation in the COXIII gene, the m.1555A>G mutation in the 12S rRNA gene, the m.3308T>C mutation in the ND1 gene, the insertion m.^4535_14536 C or CC, the m.14709T>G mutation, the m.3421G>A mutation, the m14709T>C mutation, the 8383 mtDNA mutation, or due to a single mtDNA deletion.2 Which was the genetic background in the two presented patients? Which were the heteroplasmy rates and in which tissues were heteroplasmy rates determined? Were the mutations maternally inherited or did they occur de novo? About one quarter of the mtDNA point mutations are sporadic.3
Maternally inherited diabetes and deafness is usually not restricted to the pancreas and the ears but a mitochondrial multiorgan disorder syndrome (MIMODS) either already at onset or develops to a mitochondrial multiorgan disorder syndrome with progression of the disease. Which organs or tissues in addition to the pancreas, ears, and eyes were affected in the two included patients with MIDD? Did the two patients also present with short stature, stroke-like episodes, leucoencephalopathy, regional cerebral atrophy, cataract, macular abnormalities, cardiomyopathy, gastrointestinal compromise, renal insufficiency, or rhabdomyolysis?4
Which was the cause of the perfusion deficits? Patients with MIDD typically develop diabetes, and vasculopathy is a common finding in mitochondrial disorders in general manifesting as macroangiopathy or microangiopathy.5 Was impaired choriocapillary perfusion attributable to diabetic vasculopathy? Which were the HbA1c values in the two patients with MIDD? Which antidiabetic treatment was applied? Did the authors look for mitochondrial vasculopathy in body regions other than the retina? Did the patients have coronary heart disease or peripheral, occlusive artery disease? Which were the cardiovascular risk factors in addition to diabetes? Was low-density lipoprotein elevated, was there high blood pressure, did any of the two smoke?
A main disadvantage of the study is that no results of follow-up investigations were presented. Because no patients with MIDD with choriocapillary perfusion deficits have been reported in addition to the 2 cases reported by Spaide, it would be interesting to know if any of the two patients with MIDD reported developed clinically manifesting chorioretinal or retinal pigmentary epithelial disease with progression of the syndrome?
In the discussion, the authors mention that heteroplasmy rates of muscle correlate with retinal pigmentary epithelium abnormalities.1 However, correlation between heteroplasmic mtDNA point mutations and clinical severity is usually poor3 and associated with marked phenotypic heterogeneity between family members and between generations. Phenotypic and genotypic heterogeneity is attributed to the bottleneck effect during early oogenesis.
Overall, this interesting study evokes a number of questions and concerns which should be addressed to further strengthen the conclusions of this study.