American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 137B:20 – 24 (2005)
A High Predisposition to Depression and Anxiety in
Mothers and Other Matrilineal Relatives of Children With
Presumed Maternally Inherited Mitochondrial Disorders
Richard G. Boles,1,2* Brittany B. Burnett,1 Katrina Gleditsch,1 Stacey Wong,1 Ariela Guedalia,1
Anneli Kaariainen,1 Judy Eloed,1 Alan Stern,1 and Virdette Brumm2
1
Division of Medical Genetics and the Saban Research Institute, Childrens Hospital Los Angeles, California
2
Department of Pediatrics, Keck School of Medicine at the University of Southern California, Los Angeles, California
Although mothers of chronically ill children are
generally prone to depression and anxiety, clin-
ical observation suggests that these symptoms are
relatively increased in mothers of children with
maternally inherited mitochondrial disorders
(MIMD). In this study, the Beck Depression In-
ventory II (BDI), the Beck Anxiety Inventory
(BAI), and a non-standardized mental health ques-
tionnaire 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 re-
tardation and/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 ¼ 0.001 and P ¼
0.003, respectively). Any mental health condition
was self-reported in 10/15 MIMD and 2/17 ARMD
mothers (P ¼ 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 ¼ 0.004). Our data confirm that mental health
conditions, particularly depression, are diagnos-
This article contains supplementary material, which may be
viewed at the American Journal of Medical Genetics website
at http://www.interscience.wiley.com/jpages/1552-4841/suppmat/
index.html.
Brittany B. Burnett’s present address is California Pacific
Medical Center, San Francisco, California.
Katrina Gleditsch’s present address is Davidson College,
Davidson, North Carolina.
Stacey Wong’s present address is Division of Genetics, Cedars-
Sinai Medical Center, Los Angeles, California.
Ariela Guedalia’s present address is Genzyme Corporation, 500
Kendall street, Cambridge, Massachusetts.
Anneli Kaariainen’s present address is Department of Pediatric
Neuropsychology, Long Island Jewish Medical Center, Schneider
Children’s Hospital, New Hyde Park, New York.
Virdette Brumm is in the Division of Neurology, Childrens
Hospital Los Angeles, California.
*Correspondence to: Richard G. Boles, Medical Genetics Box 90,
Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles,
CA 90027. E-mail: rboles@chla.usc.edu
Received 17 September 2004; Accepted 24 January 2005
DOI 10.1002/ajmg.b.30199
ß 2005 Wiley-Liss, Inc.
ed at an increased frequency among matrilineal
relatives likely sharing the same mitochondrial
DNA (mtDNA) as the affected proband. While pre-
vious 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.
ß 2005 Wiley-Liss, Inc.
KEY WORDS: anxiety; depression; maternal
inheritance; mitochondrial dis-
ease; mtDNA
INTRODUCTION
Depression and anxiety are prevalent in the general
population. Studies have shown that the mothers of chronically
ill children have higher levels of depression and anxiety, are
more prone to stress, and require increased social support
relative to the mothers of healthy children [Breslau et al.,
1982]. In particular, mothers of children with genetic meta-
bolic disorders must cope with their child’s chronic condition in
addition to stress related to the unpredictable nature of the
disease, complicated treatment regimens, and frequently, the
presence of more than one affected family member.
In our University—affiliated, busy urban metabolic disease
clinic, integrative clinical services are provided by a physician,
genetic counselor, social worker, nutritionist, and nurse to
children with a wide variety of different metabolic disorders
coming from diverse ethnic, racial, and socioeconomic back-
grounds. In this setting, it has been our clinical observation
that mothers of children with presumed maternally inherited
mitochondrial disorders (MIMDs) suffer from depression and
anxiety, have difficulty in coping with stress, and receive
mental health services at a far greater rate than the mothers of
children with autosomal recessive metabolic disorders
(ARMDs). However, in our judgment the latter disease group
is at least as severe in terms of cognitive deficits, inconvenience
in complying with medical/dietary treatments, the number of
hospitalizations, and mortality risk.
We propose that the same mitochondrial DNA (mtDNA)
sequence variants that predispose family members towards
the development of multi-system ‘‘physical’’ disease also pre-
dispose towards the development of ‘‘mental’’ disease, specifi-
cally depression and/or anxiety. Thus, we hypothesize that
matrilineal relatives sharing essentially the same mtDNA
sequence of children with MIMD would demonstrate depres-
sion and anxiety more frequently than in matrilineal relatives
of children with ARMD. If so, this information would be of
potential use regarding the clinical care for patients with

mitochondrial disorders and their families. In addition, this
would indicate that mtDNA sequences are risk factors in the
etiology of depression and/or anxiety disorders, at least in some
families.
MATERIALS AND METHODS
Subjects
Subjects consist of mothers who had at least one child
(<18 years at time of study) diagnosed with a metabolic
disorder and followed in the Metabolic Clinic of Childrens
Hospital Los Angeles (CHLA) for a minimum of 1 year after
the diagnosis had been established. In both groups, severe
disease was defined as mental retardation (IQ < 70) and/or
multiple hospitalizations (an average of two or more per year).
By this criterion, the disease burden was classified as ‘‘severe’’
in 7/15 MIMD cases and in 8/17 ARMD cases.
The experimental MIMD group consists of 15 subjects who
had at least one child previously diagnosed with a maternally
inherited mitochondrial disorder based upon presumptive
diagnoses of mitochondrial dysfunction and maternal inheri-
tance by meeting at a minimum all five criteria listed in Table I.
The severe MIMD group is comprised of the mothers of one
child each with MELAS and Leigh syndrome with the A3243G
and T8993C mtDNA mutations, respectively, both with rela-
tively static disease, two children with severe mental retarda-
tion and other neuromuscular conditions, two children with
primary dysautonomic presentations resulting in frequent
hospitalizations (for cyclic vomiting and/or intestinal pseudo-
obstruction), and one child with dysautonomia and mental
retardation. The remaining MIMD children, labeled as mild,
suffer from intermittent migraine-related symptoms (head-
aches, cyclic vomiting, and/or extremity pain) under good
control on amitriptyline, mild to moderate gastrointestinal
TABLE I. Study Criteria for Presumed ‘‘Maternally Inherited
Mitochondrial Disease’’
(1) Neuromuscular or multi-system involvement
(2) Elevated (>97th centile) body fluid lactate levels in blood, CSF
or urine (if blood, >2.5 mM)
(3) One or more of the following:
(a) Elevation (>97th centile) in two or more of the following
organic acids in urine: lactate, glutamate, b-hydroxybutryrate,
ethylmalonate, and a Krebs cycle intermediate (fumarate
or malate)
(b) Two or more of the following findings on muscle biopsy:
excessive variation in muscle fiber sizes, elevated lipids,
decreased electron transport chain activity, mitochondrial
proliferation
(c) A known heteroplasmic mitochondrial DNA mutation not
found in 100 controls (not including control region variants)
(4) Two or more matrilineal relatives (mother of the affected
patient or her first degree relative) having two or more
features common in mitochondrial disease, as defined by the
following list: migraine headaches (perceptional disturbances,
aura, prominent nausea/vomiting/abdominal pain, and/or
stroke-like episodes), functional bowel disease (severe and
requiring ongoing treatment), hypothyroidism, hypoglycemia,
seizures, peripheral neuropathy, cranial nerve abnormalities,
severe exercise intolerance with muscle weakness, renal
tubular dysfunction, vital sign changes (e.g., tachycardia,
abnormal thermoregulation), or neurovascular dysfunction
(intermittent pain, color changes, and/or swelling of the
extremities); mental health conditions were excluded from all
inclusion criteria for the purpose of this study
(5) Lack of another diagnosis following a complete genetics clinic
workup; the actual tests performed vary in each case, but
minimally consist of a high-resolution karyotype, plasma
amino acids, and urine organic acids.
Depression in mtDNA Disease Relatives 21
dysmotility (reflux, delayed gastric emptying, and/or irritable
bowel), exercise intolerance, and/or static neurological abnor-
malities (learning disabilities with a normal IQ, hypotonia in
infancy, cranial nerve palsies, partial hemiparesis yet ambu-
latory, and/or well-controlled seizure disorders). All MIMD
children are instructed to avoid fasting with few, if any, addi-
tional dietary constraints.
The control group consists of 17 mothers whose children
were confirmed to have an autosomal recessive metabolic
disorder by the appropriate diagnostic testing. The severe
ARMD group is comprised of two cases each with methylma-
lonic acidemia and propionic acidemia; and one case each with
maple syrup urine disease, glutaric acidemia type 1, 3-
hydroxy-3-methyl glutaryl co-enzyme A lyase deficiency, and
glucose transporter deficiency. These children are mentally
retarded, most severely so, are monitored on synthetic diets,
and many are frequently hospitalized for episodes of metabolic
decompensation. The remaining ARMD children were labeled
as mild, including two cases each with phenylketonuria, very-
long-chain acyl co-enzyme A dehydrogenase deficiency and
galactosemia; and one case each with late-onset methylma-
lonic acidemia, isovaleric acidemia, and tyrosinemia type 1.
These children are monitored on special (generally synthetic)
diets that take great care to administer have few, if any,
hospitalizations and have normal intelligence, although
learning disabilities are present in a minority. No mildly
affected child in either group was reported to have ADHD. Only
one mother approached, declined to participate. This study was
approved by the CHLA Institutional Review Board.
Heteroplasmy refers to the presence of two or more mtDNA
species in the same individual; most mtDNA disease-causing
sequence variants (mutations) reported to date are hetero-
plasmic, although many homoplasmic (only one mtDNA type
present) mutations also are known [MITOMAP]. Excluding
the A3243G and T8993C cases, eight of our MIMD children
were screened for heteroplasmy by temporal temperature
gradient gel electrophoresis (TTGE), revealing rare control
region heteroplasmic variants in five [Ito et al., 2001].
Additional information regarding the subjects, ascertainment,
and molecular analyses is accessible on the web site http://
www3.interscience.wiley.com/cgi-bin/jhome/99018626/.
Questionnaires and Data Analyses
During routine outpatient visits at the Metabolic Clinic,
informed consent was obtained from all subjects after which
subjects completed three questionnaires: the Beck Depression
Inventory II (BDI), the Beck Anxiety Inventory (BAI; both
indexes by The Psychological Corporation, published by
Harcourt Brace and Company, San Antonio, TX), and a four
page, double-spaced questionnaire entitled ‘‘Questionnaire for
Mothers of Children With Genetic Metabolic Disease.’’ The
latter ‘‘questionnaire’’ was designed specifically for this study,
and included both multiple choice and short fill-in-the blank
type questions regarding mental health diagnoses and related
treatment in the subject, as well as all of the subject’s matri-
lineal first and second-degree relatives (defined below). On
the questionnaire, a ‘‘mental health condition’’ is defined as
‘‘(A) one of the following, or similar conditions: schizophrenia,
bipolar/manic depression, depression, any type of phobia,
catatonia, obsessive-compulsive disorder, anxiety disorder,
amnesia, or psychosis, and (B) that condition affects everyday
function or happiness.’’
Matrilineal relatives consist of those individuals who are
related completely through women, and since mtDNA is in-
herited exclusively from the ovum without recombination
[Taylor et al., 2003], matrilineal relatives all presumably
share essentially the same mtDNA sequence. However, since
mtDNA exists at high copy number within cells and mitotic
22 Boles et al.

segregation is generally random, in the case of a heteroplasmic
mutation each relative is likely to harbor different proportions
of the mutant and wild-type sequences, including possibly ab-
sent or near-absent mutant mtDNA proportions. Matrilineal
first-degree relatives of the mother consist of her mother,
siblings, and children; for the purposes of this study the pro-
band (the affected child that brought the family to attention)
was excluded. Matrilineal second-degree relatives of the mother
consist of her maternal grandmother, aunts, uncles, nieces,
and nephews.
Statistics were performed by WinSTAT Statistics for
Windows (Kalmia Co., Inc., Cambridge, MA), using indepen-
dent Student’s t-test, Chi-square, or Fisher exact test, as ap-
propriate. Significance was defined as a P-value 0.05.
RESULTS
Overall, depression and anxiety scores were higher in the
MIMD group compared to the ARMD group, which was
statistical significant for anxiety (Table II). Among the ARMD
cases, depression and anxiety scores were significantly higher
(more symptoms) in cases with greater disease severity as
judged by the investigators, a relationship that was not noted
among MIMD cases (Table II). Among severely affected cases,
BDI and BAI scores were very similar between the MIMD and
ARMD groups, while among mildly affected cases, MIMD cases
demonstrated significantly higher levels of depression and
anxiety (Table II). This finding was particularly evident in that
0/8 versus 7/9 mildly affected MIMD and ARMD cases, res-
pectively, had very low scores (6) for depression, and 1/8
versus 7/9 mildly affected MIMD and ARMD cases, respec-
tively, had very low scores (6) for anxiety.
Per our study questionnaire, mental health conditions were
more commonly diagnosed in MIMD mothers than in ARMD
mothers (40% vs. 12%), a trend that reached statistical signi-
ficant when suspected cases were included (67% vs. 12%)
(Table II). Among the matrilineal relatives of the mothers,
there was a significantly elevated, several-fold higher, re-
ported prevalence of mental health conditions among the
matrilineal first-degree relatives of the mothers (53% vs. 6%,
not including the proband), among the matrilineal second-
degree relatives of the mothers (33% vs. 0%), and in the
probands themselves (33% vs. 0%) (Table II). Among the MIMD
first-degree matrilineal relatives, specific write-in diagnoses
included: depression (8, designated as bipolar in 2), anxiety
disorder (1) and schizophrenia (1, also with bipolar), while
among the second-degree matrilineal relatives depression
again dominated (3/5) the write-in diagnoses. Altogether, a
mental health disorder was diagnosed by a healthcare profes-
sional in at least one matrilineal relative of 87% of MIMD and
18% of ARMD probands (P ¼ 0.0001).
Among our MIMD families, severe illness in the proband was
not associated with an increase in the prevalence of mental
illness in the mother (4/7 mothers of severely vs. 6/8 mothers of
mildly affected probands reported having mental illness) or in
any matrilineal relative other than the mother (4/7 severe
versus 7/8 mild). Our questionnaire was limited in that neither
did the fathers of metabolic patients participate nor did we
query for mental health conditions in the father or any other
paternal relatives.
DISCUSSION
An increased level of depression and anxiety among the
mothers of severely ill children is both intuitive and supported
by research. Associated with caring for a severely affected
child, both the mothers of children with MIMD and ARMD in
our study showed similar degrees of depression and anxiety as
self reported by the Beck scales. However, while most mothers
of children with mildly affected ARMDs report very low
levels of depression and anxiety, almost none of the mothers
of children with mildly affected MIMDs did so. The levels of
depression and anxiety reported by these mothers was essen-
tially equal to that reported in the mothers of children with

TABLE II. Results of Beck Inventories and Our Non-Standardized Mental Health Questionnaire

MIMD ARMD
mothers mothers Statistical test P-value*

Beck Depression Inventory II (BDI)

BDI scores 13.6  7.4 9.3  8.6 Student’s t-test 0.1
BDI scores, severely affected children 12.7  9.7a 14.8  8.8b Student’s t-test 0.7
BDI scores, mildly affected children 14.4  5.3a 4.4  5.0b Student’s t-test 0.001
Low BDI scores (6) in mothers of mildly affected children 0/8 7/9 Fisher exact test 0.002
Beck Anxiety Inventory (BAI)
BAI scores 12.0  4.8 6.2  6.8 Student’s t-test 0.01
BAI scores, severely affected children 11.6  5.1c 9.3  7.4d Student’s t-test 0.5
BAI scores, mildly affected children 12.4  4.7c 3.6  5.3d Student’s t-test 0.003
Low BAI scores (6) in mothers of mildly affected children 1/8 7/9 Fisher exact test 0.01
Questionnaire for mothers of children with genetic metabolic disease
Mother ever diagnosed with a mental health condition by a health 6/15 2/17 Fisher exact test 0.08
care professional
Mother diagnosed with or suspects that she may have a mental 10/15 2/17 Chi–square df ¼ 1 0.001
health conditione
Current pyschotropic usage in motherf 4/15 2/17 Fisher exact test 0.3
Any mental health disorder in first-degree matilineal relatives 8/15 1/17 Fisher exact test 0.004
Any mental health disorder in proband 5/15 0/17 Fisher exact test 0.01
Any mental health disorder in sibling other than proband 5/15 1/17 Fisher exact test 0.06
Any mental health disorder in at least one second-degree 5/15 0/17 Fisher exact test 0.01
matrilineal relative
Any mental disorder in at least one matrilineal relative 13/15 3/17 Chi-square df ¼ 1 0.0001
a–d
Statistical evaluation of BDI and BAI scores comparing mothers of severely affected children to mothers of mildly affected children within our two subject
groups: aP ¼ 0.7, bP ¼ 0.01, cP ¼ 0.8, dP ¼ 0.009.
*Bold P-values are significant (P  0.05).
e
Four additional MIMD and no ARMD mothers indicated that they ‘‘suspect’’ that they ‘‘have a mental health condition not yet diagnosed by a healthcare
professional.’’
f
Dominated by serotonin selective reuptake inhibitor medications.

severely affected metabolic disease, whether MIMD or ARMD.
One potential explanation is that while these children are
‘‘mildly affected’’ as per the investigators’ criteria, they are
considered to be severely affected by their mothers, and pos-
sibly per the child and other family members as well. Unlike
children in the ARMD group, most of the MIMD children report
the frequent occurrence of signs and symptoms such as chronic
fatigue, functional bowel disorders, and episodic pain, that
while they may not threaten ‘‘life or limb,’’ may be very dis-
turbing to the mother and/or the child. In addition, one-third of
our MIMD, and none of our ARMD, children themselves suffer
from a diagnosed mental illness, again the diagnoses were
dominated by depression (3/5 cases). Our present data sup-
ports our clinical impression that conditions that appear to be
mild per the medical community are frequently very disturbing
to many mothers of children affected with mitochondrial dis-
ease. However, the Beck data does not address whether this
higher level of depression and anxiety in the mothers of ‘‘mildly
affected’’ MIMD children is a result of a difference in pers-
pective regarding the degree of disease burden, the presence of
many of the same ‘‘mild’’ disease manifestations in the mothers
themselves, or a biologically-derived higher level of depression
and anxiety in the mothers.
In the only study that we are aware of that addressed mental
health in the mothers of children with mitochondrial disease
[Varvogli and Waisbren, 1999], 56% of the mothers were noted
to have Minnesota Multiphasic Personality Inventory (MMPI-
2) scores in the pathological range on three or more scales,
most notably on the Hypochondriasis, Hysteria, and Paranoia
scales. Only 36% had an elevated depression scale, although
mothers were apparently studied from families with a variety
of inheritance patterns, thus likely diluting any findings re-
levant to the maternally inherited subset. However, this study
does agree with our present data in the very basic sense that
significant proportions of mothers of patients with mitochon-
drial disease demonstrate mental health abnormalities.
The most striking result of the present study is the very high
incidence of mental illness, predominately depression, among
the matrilineal relatives of MIMD versus ARMD children. Not
only was this finding striking in the mothers, 50% of whom had
received a provider-given mental health-related diagnosis
(which is 4.8-fold higher than the incidence in the ARMD
group), but this finding was also apparent among the mothers’
first and second-degree matrilineal relatives. These findings
were unrelated to the perceived severity of the proband’s
illness. Even if all MIMD children are designated as ‘‘severe’’
and these families are compared only against severely affected
ARMD children, the same relationship holds (13/15 versus 2/6
have a matrilineal relative reported to have mental illness,
P ¼ 0.006). Our data suggests that the matrilineal relatives of
MIMD children have a very high incidence of mental illness,
predominately depression, and that this finding cannot be
explained entirely by the burden of caring for a chronically ill
child. Depression has been reported to be present in multiple
case reports of individuals with mitochondrial disease
[reviewed in Gardner et al., 2003], and the association is
mentioned in at least two review articles [Fadic and Johns,
1996; Chinnery and Turnbull, 1997]. Thus, our first conclusion
is that clinics providing medical services to individuals with
mitochondrial disease should consider these findings in the
course of developing treatment plans in order to address
possible depression and anxiety in the patients and mothers, as
well as possibly in the siblings and other matrilineal relatives,
and to make referrals for additional evaluation and manage-
ment as clinically indicated.
We hypothesize that the significantly higher prevalence of
depression and/or anxiety among the matrilineal relatives of
our MIMD probands is due to a genetic, mtDNA-sequence
mediated, predisposition. One potentially confounding vari-
Depression in mtDNA Disease Relatives 23
able is that, by definition, more than one individual is affected
with protean ‘‘physical’’ disease symptoms likely related to
mitochondrial dysfunction in each of the MIMD families,
including 13/15 of the mothers, and 1–3 affected siblings in
7/15 families. Non-mental health, possibly energy metabolism-
related conditions in the mothers include migraine (8 cases),
gastrointestinal dysmotility (6), exercise intolerance/chronic
fatigue (4), other dysautonomias (4), and seizure disorders
(2). However, none of the mothers have significant cognitive
deficits, physical disability, or disease requiring hospitaliza-
tion. In contrast, the proband is the only affected member in all
but two of the ARMD families, in which there is a similarly
affected sibling. Thus, this variable cannot be controlled for in
the present study design, and could account for a higher degree
of reported mental illness among the mothers and siblings of
probands. However, it is less likely that this effect would apply
to relatives who generally do not live with the proband, mother
or siblings, including many of the first-degree and likely all
of the second-degree relatives whereas the same relationship
was found.
Another study limitation is that the true prevalence of
mental health disorders among family members other than the
mother cannot be accurately accounted for by reporting on
behalf of the mothers. However, the latter limitation should
apply equally to both the MIMD and ARMD groups, would tend
to support the null hypothesis (no maternal bias), and is very
unlikely to account for the striking differences in prevalence
reported between the two subject groups. The current study
was designed as a pilot in order to verify the validity of the main
hypothesis, and a more rigorous follow-up study is indicated in
which individual family members are individually queried.
This proposed follow-up study could also sub-categorize in-
dividuals into specific recognized entities unipolar, bipolar,
severe depression associated with anxiety, depression with
chronic physical problems, which was not feasible with our
current study design. Both unipolar and bipolar depressions
were reported among the mothers and other matrilineal rela-
tives in the present study.
Families were assigned to the MIMD group based in part
upon meeting our strict criteria for maternal inheritance
(Table I and thus it is presumed that at least most of
the children in this group carry causal/predisposing mtDNA
sequence variants. We propose that these mtDNA sequence
variants, in addition to predisposing individuals towards the
development of ‘‘physical’’ disease, may also predispose to-
wards the development of ‘‘mental’’ disease, in particular de-
pression and/or anxiety. Control region variants were found in
one half of the MIMD families assayed upon screening of most
of the mtDNA for heteroplasmy, and thus control region vari-
ants, either heteroplasmic or homoplasmic, may account for at
least some of the depression/anxiety predisposing mtDNA
sequences that we propose herein. While our hypothesis may
appear far-fetched, given that mtDNA-encoded genes are
strictly involved with energy metabolism, most mtDNA muta-
tions in humans result primarily in brain disorders [Wallace,
1999] including mental retardation, learning disabilities, and
sensory and movement disorders, and a mtDNA polymorphism
has been associated with human intelligence [Skuder et al.,
1995]. In addition, backcrossing two strains of mice has recently
shown, against a constant nuclear background, that the mtDNA
type affects ‘‘gross brain anatomy, sensory development,
learning, and exploration’’ [Roubertoux et al., 2003].
While our data demonstrates that mtDNA sequence variants
likely predispose some individuals to develop depression, it
does not address the larger question: In what proportion of
patients with depression do mtDNA sequences play a role, and
to what extent? Several studies suggest that the mtDNA
contribution towards depression may be substantial, including
demonstrating a maternal bias in the inheritance of bipolar
24 Boles et al.
disease [McMahon et al., 1995; Gershon et al., 1996], and
decreased high-energy phosphate compounds in basal ganglia
[Moore et al., 1997] and cerebral cortex [Volz et al., 1998] of
depressed subjects by 31P-magnetic resonance spectroscopy. In
a group of patients with longstanding depression and chronic
physical (generally audiological) symptoms, multiple mito-
chondrial abnormalities were noted relative to controls,
including impaired oxidation of a-ketoglutarate and succinate,
decreased complex I þ III/IV and II þ III/IV enzymatic ratios,
and an increase in mtDNA deletions detected by long PCR
[Gardner et al., 2003]. Thus, ‘‘genome-wide’’ studies to screen
for genes associated with depression and anxiety disorder
should not neglect the small, yet important, mitochondrial
genome.
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