Preliminary communication
Mitochondrial inheritance in depression, dysmotility and migraine?

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Abstract

Background

Several studies have reported a high degree of association of the common conditions of depression, bowel dysmotility and migraine. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) sequence variants have been linked individually to each of these three conditions, providing a plausible hypothesis for the reported association. If this hypothesis is correct, the matrilineal relatives (who all share essentially the same mtDNA sequence) of patients with mitochondrial disease secondary to inherited mtDNA mutations would be expected to have an elevated prevalence of each of these three conditions.

Methods

Families were recruited by an advertisement posted on the United Mitochondrial Disease Foundation website and invited to participate in an on-line questionnaire if at least one member was diagnosed with mitochondrial disease by a physician. Based upon the reported family histories, families were assigned by the investigators to either the probable maternal inheritance (PMI) group (55 families) or the probable non-maternal inheritance (PnMI) group (111 families).

Results

Bowel disorders, migraine and depression were reported at very high prevalence in the PMI mothers (60%, 54% and 51%, respectively), but were present at significantly lower prevalence rates among the PnMI mothers (16%, 26% and 12%; P < 0.0001 for each) and the fathers of both groups (range 9–16%; P < 2 × 10 6 for each). Similar data was obtained comparing the prevalence rates among maternal and paternal grandmothers, aunts and uncles.

Limitations

Our data was obtained from families ascertained by the presence of a severely affected individual, and may not be applicable to families lacking this proband.

Conclusions

Depression, bowel dysmotility and migraine are common manifestations in individuals with mtDNA sequence-related mitochondrial dysfunction, which supports our hypothesis that mitochondrial dysfunction is a major common factor underlying the association of these three conditions.

Introduction

The association between depression and migraine has been known for over 100 years, and has been validated in multiple studies conducted in individuals from different cultures. Breslau et al. (2003) reported that the presence of major depression significantly increases the risk of migraine (odds ratio 3.4), but not of other severe headaches, and the presence of migraine significantly increases the risk of major depression (odds ratio 5.8). A form of bowel dysmotility, irritable bowel syndrome (IBS) has also been demonstrated to co-associate with depression in numerous studies. In one such study (Garakani et al., 2003), it was reported that 70% to 90% of patients with IBS who seek treatment have psychiatric comorbidity, most notably affective and anxiety disorders. An association between migraine and IBS has also been reported (Watson et al., 1978).

A number of studies demonstrate defective mitochondrial energy metabolism in both depression and migraine. Both conditions demonstrate decreased levels of high-energy phosphate compounds by 31P-magnetic resonance spectroscopy (Volz et al., 1998, Montagna et al., 1994), reduced electron transport chain activities (Gardner et al., 2003, Sangiorgi et al., 1994), preferential maternal inheritance (McMahon et al., 1995, Mortimer et al., 1992) and disease-associated mitochondrial DNA (mtDNA) polymorphisms (Kato et al., 2001, Wang et al., 2004). The latter two are important as 13 subunits of the mitochondrial electron transport chain (where most cellular ATP is produced) are encoded by mtDNA genes. In a manner known as mitochondrial inheritance or maternal inheritance, mtDNA is asexually transmitted from the mother without recombination. Thus, in the absence of a new mutation, individuals related exclusively through women share the same mtDNA sequence. These “matrilineal” relatives include the mother, siblings and maternal grandmother, aunts and uncles.

Mitochondrial function and mtDNA have not been systematically studied in IBS. However, in clinical practice, bowel disorders, generally functional disorders (dysmotility) including IBS, are among the most frequent complications of mitochondrial disorders (Chinnery and Turnbull, 1997), including in cases demonstrating the maternal inheritance of mtDNA mutations.

As depression, migraine and bowel dysmotility are associated with one another, and each are associated with mitochondrial dysfunction and maternal inheritance, the parsimonious conclusion is that mtDNA-sequence mediated mitochondrial dysfunction can predispose towards any or all of these three conditions. This provides a plausible hypothesis that mitochondrial dysfunction may be the common denominator behind these apparently unconnected conditions. If this hypothesis is correct, the matrilineal relatives (carrying essentially the identical mtDNA sequence) of patients with mitochondrial disease secondary to maternally inherited mtDNA mutations would be expected to have an elevated prevalence of these three conditions. Anecdotal data and clinical experience suggest that this is correct, although studies with sufficient numbers of subjects are lacking.

In this study, we have applied a novel approach seeking information about clinical conditions in relatives from a large group of families in which a member was diagnosed with a mitochondrial disorder. The population was dichotomized according to the probability of maternal inheritance. Comparisons of prevalence rates of “mitochondria-related disorders” were performed between the two groups in an attempt to highlight a putative background for the comorbidity of seemingly unrelated conditions.

Section snippets

Subjects

Families were recruited by an advertisement posted on the United Mitochondrial Disease Foundation (UMDF) website over a 12-month period, and invited to participate in the on-line questionnaire if at least one family member was diagnosed with mitochondrial disease by a physician. The UMDF is a family and professional led organization dedicated to advancing research, education and family support in mitochondrial disorders. The anonymous questionnaire included 27 questions regarding the health of

Probands

Among our 166 informative families, 55 (33%) met our criteria for probable maternal inheritance and were assigned to the PMI group, while the remaining 111 families were assigned to the PnMI group. There were no significant differences between the PMI and PnMI groups in terms of proband age (median 8 and 7 years), the proportion over age 18 years (27% and 30%), proband gender (47% and 51% male), subjective severity of the proband's disease as judged by the family on a 1 to 10 scale (median 7

Discussion

Family history alone cannot distinguish suspected mitochondrial disease cases into groups with and without maternal inheritance with complete accuracy. However, using our fairly simple protocol (Table 1), we separated the families into two groups: a probable non-maternally inherited (PnMI) group in which the prevalence rates among the mothers and fathers for several potentially-mitochondrial-disease-related conditions are at about the expected prevalence rates for the general population (Table 2

Acknowledgement

This study started as a Master's thesis by Ms. Burnett (Boldt) at California State University Northridge. The authors would like to thank her thesis committee, especially Dr. Aida Metzenberg, as well as the United Mitochondrial Disease Foundation, and all of the families that took the time to answer our 179 questions.

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Current address: California Pacific Medical Center, San Francisco, CA, United States.

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