Mitochondrial DNA (mtDNA) variant pathogenicity interpretation has special considerations given unique features of the mtDNA genome, including maternal inheritance, variant heteroplasmy, threshold effect, absence of splicing, and contextual effects of haplogroups. Currently, there are insufficient standardized criteria for mtDNA variant assessment, which leads to inconsistencies in clinical

Although mothers of chronically ill children are generally prone to depression and anxiety, clinical observation suggests that these symptoms are relatively increased in mothers of children with maternally inherited mitochondrial disorders (MIMD). In this study, the Beck Depression Inventory II (BDI), the Beck Anxiety Inventory (BAI), and a non-standardized mental health questionnaire were administered to 15 mothers of children with MIMD and 17 mothers of children with autosomal recessive metabolic disorders (ARMD) followed in one clinic. One half of the children in both groups suffer from mental retardation and/or > or = 2 hospitalizations/year related to their genetic disorder, and were labeled as severely affected. BDI and BAI scores were similar between mothers of severely affected MIMD and ARMD children, but BDI and BAI scores were threefold higher in mothers of mildly affected MIMD versus ARMD children (P = 0.001 and P = 0.003, respectively). Any mental health condition was self-reported in 10/15 MIMD and 2/17 ARMD mothers (P = 0.002), while at least one mental health condition per family was reported to be present in a matrilineal first-degree relative of the mother in 8/15 MIMD versus 1/17 ARMD families (P = 0.004). Our data confirm that mental health conditions, particularly depression, are diagnosed at an increased frequency among matrilineal relatives likely sharing the same mitochondrial DNA (mtDNA) as the affected proband. While previous studies have demonstrated that mtDNA sequences can affect brain function, our data suggests that in addition mtDNA sequences can predispose individuals towards the development of some "mental health" disorders. Thus, "genome-wide" studies to screen for genes associated with depression and anxiety should not neglect the small, yet important, mitochondrial genome.

We propose a mechanism in which RYR2 sequence variants result in aberrant stress-induced calcium release into the mitochondria of autonomic neurons, resulting in an increased risk to develop autonomic/functional disease such as CVS, and related conditions such as migraine and gut dysmotility. This model incorporates the existing hypotheses regarding CVS pathogenesis into a cohesive mechanism, and might have treatment implications.

We herein present an unrelated 20-year-old male with similar manifestations also with p.D59G in the RAB40AL gene, which supports the existence of this condition previously coined as Martin-Probst syndrome (OMIM: 300519).