Brief reportAutosomal dominant psychiatric disorders and mitochondrial DNA multiple deletions: Report of a family☆
Introduction
Mutations in both mitochondrial (mtDNA) and nuclear genome cause heterogeneous and usually severe clinical phenotypes, which can be sporadic or inherited as maternal or autosomal traits. Common manifestations of mitochondrial disease (MD) include progressive external ophthalmoplegia, exercise intolerance, neuropathy, ataxia, hearing loss, weakness, and diabetes (DiMauro and Schon, 2003). Psychiatric symptoms are commonly associated with other symptoms/signs suggestive of MD, and often precede the diagnosis of MD (Inagaki et al., 1997, Koller et al., 2003, Mancuso et al., 2004a, Mancuso et al., 2004b, Siciliano et al., 2003, Thomeer et al., 1998). However, they are rarely the only persistent manifestation of a MD.
We report an Italian family in which bipolar disorders (BD), schizophrenia and depression represented the core phenotypic manifestation of the disease. The presence of multiple mtDNA deletions in the muscle of the proposita suggested a mitochondrial etiology despite the lack of non-psychiatric mitochondrial symptoms.
Section snippets
Case report
A 63-year-old woman (III1 in Fig. 1), developed normally until the age of 15 years, when she developed episodes of migraine. Since her childhood she has had depressive episodes (see below). In her 40s, she complained of memory problems. At the age of 58, she underwent resection of herniated disk at L3–L4.
She came to our attention because of mild exercise intolerance first noted in her 50s and attributed to fibromyalgia.
On examination, she was short and overweight. The neurological examination
Histochemical, biochemical and genetic studies
Histochemical analyses of muscle biopsy specimens and measure of the respiratory chain enzyme activities were performed as described (Filosto et al., 2003).
Southern-blot and Long-PCR analysis, as well as screening of mitochondrial tRNAs, ANT-1, Twinkle, POLG1 and POLG2 genes on DNA extracted from patient's muscle were performed as reported (Filosto et al., 2003).
Results
Muscle biopsy in the proband showed numerous ragged-red and cytochrome c oxidase-negative fibers. Activities of mitochondrial respiratory chain complexes I, III, and IV were markedly reduced in muscle (10–40% of mean control values). Multiple mtDNA deletions were detected by Southern-blot and Long-PCR analysis (Fig. 2). Screening of tRNAs, ANT-1, Twinkle, POLG1 and POLG2 genes was negative. Unfortunately, no tissues or DNA were available from the other family members, making additional genetic
Discussion
Compelling support for a major genetic influence in BD comes from twin and family studies (Gershon, 1990). Although the modes of inheritance of familial BD are unclear, it has been reported a preferential transmission of BD through the maternal lineage (McMahon et al., 1995). Since mitochondria are inherited from the mother, they might be directly involved in the transmission of the disease. Predominance of maternal transmission, altered energy metabolism in the brain (Kato et al., 1998),
Acknowledgments
The authors are grateful to Dr. S. Pini and M. Preve for their contribution in the analysis of the family.
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Authors Mancuso, Siciliano, DiMauro designed the study and wrote the protocol. Authors Ricci, Choub, Filosto managed the literature searches and analyses. Authors Mancuso, Filosto, Tessa, Santorelli, Davidzon performed the experiments. Authors Mancuso, Murri and Siciliano wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.