Original Article

Journal of Child Neurology

27(12) 1506-1516
Pilot Study on Executive Function and ª The Author(s) 2012
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Adaptive Skills in Adolescents and Young DOI: 10.1177/0883073812442589
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Adults With Mitochondrial Disease

Hope Schreiber, PsyD, ABPP/CN1

Abstract
High-functioning adolescents and young adults with mitochondrial disease are now attempting transitions to postsecondary
environments. This pilot and case study explores factors that interfere with their successful transition through behavior-
rating scales addressing academic skills and behavior. In the Behavior Assessment System for Children, Second Edition, Spear-
man correlation matrices showed that students’ attitude to school was associated with depression and anxiety. Mothers’
reports linked internalizing disorders with somatic symptoms. Two case studies, with Behavior Rating Inventory of Exec-
utive Function profiles, show the role executive functions play in academic success. Attention to both cognitive and psy-
chiatric concerns may increase success in academics and enhance the sense of well-being in older students with
mitochondrial disease.

Keywords
mitochondrial disease, executive function, postsecondary education, depression, BRIEF, BASC-2, anxiety, academic

Received January 29, 2012. Accepted for publication February 24, 2012.

Mitochondrial diseases, a large heterogeneous collection of
disorders that involve disruption of energy production, are
now considered to be the most common metabolic disease.
The population prevalence is estimated at 1 in 5000
births.1-4 High-functioning adolescents with mitochondrial
disease are now attempting to navigate high school and col-
lege experiences with a unique array of cognitive and med-
ical concerns. Familiarity with the range and course of
cognitive and behavioral patterns associated with these ill-
nesses is critical to facilitate effective transitions through
high school and to college. Targeted strategies and accom-
modations may then support a successful college experi-
ence. The late adolescent and young adult population, in
particular, may ‘‘fall through the cracks,’’ between pediatric
and adult primary care.5 Unique difficulties they may face
as they attempt to perform developmentally expected activ-
ities such as going to college may not be anticipated by
physicians, mental health providers, academic support staff,
or their families.
This article will describe a pilot study of adolescents and
young adults with mitochondrial disease, and suggestions to
help facilitate effective transition to higher educational envir-
onments will be offered. Two case studies will be presented,
illustrating the need for an integrated approach to support post-
secondary study, as well as support for transitions, in general,
for these students.
What Is Mitochondrial Disease and How
Does It Affect Students?
Through advances in molecular biology, biochemical meth-
odologies, and genetics, inborn errors of metabolism have been
recognized with greater frequency over the past decades. Many
can produce serious or life-threatening illness early in life.
Known mitochondrial syndromes have clusters of symptoms
that are readily identifiable to the physician, although they may
not be easily recognizable unless they present in their most
severe form. More mild variants can be found in individuals
who may struggle with a multiplicity of medical issues, but
who continue to have the resources and determination to seek
postsecondary education and employment.
Neuropsychological evaluation can be valuable in delineat-
ing where accommodation is needed. Although some metabolic
disorders, such as phenylketonuria (PKU) and galactosemia,
1
Department of Psychiatry, Tufts Medical Center, Tufts University School of
Medicine, Boston, MA, USA
Corresponding Author:
Hope Schreiber, PsyD, ABPP/CN, Department of Psychiatry, Tufts
University School of Medicine, Tufts Medical Center, #1007, 800
Washington Street, Boston, MA 02111
Email: hschreiber@tuftsmedicalcenter.org
Schreiber
have specific patterns of cognitive dysfunction associated with
them,6-10 mitochondrial diseases are a very heterogeneous
group, with variation not only among types of disease but also
among individuals with the same genetic mutation. Under these
conditions, the role of the neuropsychologist is that of a team
member, delineating cognitive strengths and weaknesses at a
particular point in time, and then providing recommendations
not only to school but also to family and work settings. These
recommendations are part of a team ‘‘package,’’ where atten-
tion to other factors such as intermittent fatigue, autonomic
dysfunction, and a wide variety of central nervous system and
medical problems are the norm. An understanding of the basic
nature of mitochondrial disorders and types of deficits that can
be associated with them is crucial to the individuals working in
a postsecondary environment. Educators, neuropsychologists,
and learning specialists may then participate as team members,
pairing with their health service colleagues on campus, as well
as with metabolic and genetic specialists and neurologists, in
the support of these young adults.
Mitochondria in the cell serve to convert chemical energy
provided by food to adenosine triphosphate (ATP) through oxi-
dative phosphorylation. Electrons that result are passed through
the electron transport chain complexes that are intimately
involved in ATP synthesis. The energy from mitochondria
powers muscular action and other energy-demanding organs
such as the brain. Most individuals with primary mitochondrial
disease have deficits in the 5 multiprotein complexes (complex
I-V) found on the inner membrane of mitochondria. Most of the
87 genes known to be involved are of the nuclear genome; the
potential role of additional regulatory genes is currently
unknown. Thirteen are derived from mitochondrial DNA.11
Mitochondrial DNA is circular and double stranded, inherited
solely through the maternal line. Thus, although most mito-
chondrial diseases are inherited through Mendelian genetics,
and the majority are inherited through autosomal recessive
mechanisms, the mechanism of inheritance can be diverse:
Some are also autosomal dominant, X-linked, or inherited
through maternal mitochondrial DNA alone. Mitochondrial
dysfunction can not only be found when there are problems that
genetically impact on the electron transport chain but also
when other pathways in the mitochondria, such as fatty acid
oxidation or amino acid metabolism, are affected. Medications
and toxins can affect mitochondrial activity.12 In addition,
spontaneous or sporadic mutations in adulthood can lead to
such disease.13,14
Individuals, even those in the same family with the same
mutation, can show great variety in the clinical manifestation
of disease. When the disease is transmitted through Mendelian
genetics, the severity of the disease may be relatively consistent
among family members. However, if inherited through mito-
chondrial DNA, the concept of heteroplasmy may apply. In het-
eroplasmy, a single cell may contain a mix of mutant and
normal DNA. The proportion of mutated mitochondria passed
on to a child may be different in each pregnancy, depending on
which mitochondria go into egg cells. Then, when a threshold
for the disease is reached, that is, when the load of mutated
1507
DNA reaches a critical level, symptoms appear.15 In addition,
mutated mitochondria may segregate differently in each off-
spring, resulting in an extraordinarily broad array of symptoms
differing in each affected.
Characteristic neuropsychological and psychiatric patterns
can be associated with certain syndromes but are not confined
to them. The syndromes below are a far from exhaustive list,
but supply examples of the most common, illustrating the range
of presentation in these disorders.
Mitochondrial encephalopathy, lactic acidosis, and stroke-
like episodes (MELAS) has onset that is often in late childhood
or young adulthood but can be present earlier. Transient
ischemic episodes, and cognitive dysfunction related to infarcts
can be found associated with the middle cerebral artery or
related to multiple small infarcts. Both cortical and subcortical
white matter can be affected, especially in the parietal and occi-
pital lobes, thalamus, corpus striatum, globus pallidus, brain-
stem, and cerebellum. Although progressive cognitive
dysfunction is often reported, discrete deficits or a
schizophrenia-like syndrome may more rarely be observed.16
Stroke-like episodes or events, sometimes known as ‘‘meta-
bolic strokes,’’ appear related to regional defect in cellular
energy production. Because the injury is not due to reduced
blood supply, the lesions do not always follow a vascular dis-
tribution.17,18 Seizures and early-onset hearing loss are com-
mon phenomena. Mitochondrial encephalopathy, lactic
acidosis, and stroke-like episodes may present as migraines
with visual auras. Visual hallucinations and bipolar disorder
have been described in patients with mitochondrial encephalo-
pathy, lactic acidosis, and stroke-like episodes and other mito-
chondrial patients with cognitive decline.18,19
Myoclonic epilepsy with ragged-red fibers (MERRF),
characterized by myoclonus, myoclonic epilepsy, progressive
ataxia and myopathy, is seen in childhood and young adult-
hood. Cerebellar ataxia and dementia can lead to retardation,
but infarcts are uncommon. Clinical symptoms may include
deafness, optic atrophy, peripheral neuropathy, and others.
Eighty percent of patients have a point mutation in mitochon-
drial DNA.17 Kearns-Sayre syndrome is also associated with
mitochondrial DNA point mutations. With beginnings in child-
hood, this syndrome involves progressive degeneration of optic
muscles, retina, cardiac conduction, cerebellar deficits, and
myopathy.
Leigh syndrome is characterized by bilateral symmetric
lesions of the basal ganglia. Most common in children, symp-
toms include dyskinesia, dystonia, somnolence, nystagmus,
respiratory abnormalities, and ataxia. The patient may appear
as if he or she has cerebral palsy. Although the syndrome is
usually progressive, symptoms may wax and wane depending
on the degree of metabolic or catabolic stress.18 Neuroimaging
findings include periventricular leukomalacia and hyperinten-
sities in the basal ganglia and thalamus.17
Mitochondrial cytopathies appear less consistently syndromal
in nature and may show waxing and waning cognitive symptoms
and fatigue, thus proving more difficult to document neuropsy-
chologically despite a progressive course. Dysregulation of the
1508
autonomic nervous system (controlling heart rate, respiration,
temperature, and digestion), debilitating fatigue, and multiple
organ systems affected can result in severe functional disabilities.
In addition, psychiatric symptoms can be found, sometimes as
first symptoms of these complex disorders that occur prior to the
diagnosis of mitochondrial disease.19 Bipolar disorder, major
depression, anxiety disorders, schizophrenia, and autism have
been related to impaired mitochondrial dysfunction.19-23 Given
that mitochondrial disease is so specific to the individual, it has
been difficult for cognitive patterns of strength and weakness to
be characterized by type of illness. Case studies have been infor-
mative but limited in their ability to provide generalizations about
cognitive and psychiatric profile or prognosis.16,24-26
Methods
Subjects and Procedure
A national sample of high-functioning adolescents and young adults,
ages 13 to 21 years was sought through a flier posted on the website
of MitoAction.org, an advocacy organization that has wide participa-
tion by children and their families with mitochondrial disease. A Goo-
gle connection was offered by MitoAction.org for 3 months in which
individuals who Googled mitochondrial disease saw a link to this flier.
The same flier was placed in offices of several physicians who manage
patients with energy disorders. Institutional Review Board (IRB)
approval was obtained for the flier, forms, and all contact, mailing,
and database procedures. Information from new subjects was immedi-
ately deidentified on receipt and added to the database in Excel. As
information about general intellectual functioning was often not avail-
able, adolescents and young adults who were able to complete forms
independently were included in the study. Parents were permitted to
physically help with completion but not with provision of answers
to questionnaires.
Sent to the participating adolescent/young adult and their mother
were a self-report and parent report Behavior Assessment for Chil-
dren, second edition (BASC-2), for ages 12 to 21 years, a Behavior
Rating Inventory of Executive Function (BRIEF) self-report and par-
ent report for older children/adolescents aged 13 to 18 years or an
adult report and informant report for those aged 18 to 21 years. In
addition, each parent was asked to complete a questionnaire about the
nature of their child’s disorder, how it had been diagnosed, and accom-
modations and other supports needed. These were mailed to the fam-
ilies who wished to participate with stamped addressed return
envelopes. In each case, first contact was initiated by the parent inquir-
ing about the study by email or telephone.
The Behavior Assessment for Children, second edition, and Beha-
vior Rating Inventory of Executive Function are rating scales widely
used to collect psychiatric and behavioral data on adolescents and
young adults. The Behavior Assessment for Children, second edition,
is intended to be ‘‘sensitive to both obvious and subtle behavioral and
emotional disorders as expressed in school and clinical settings, and to
academic and familial demands on child and adolescent develop-
ment.’’27 As such, it appeared singularly appropriate to explore the
effects not only of a disorder that may have the stresses one might
expect in individuals struggling with medical and academic problems
but in a disorder where psychiatric issues may be intrinsic in some
individuals. In addition, a single normative base can be used for sub-
jects and their parents from ages 12 to 21 years. The Behavior Assess-
ment for Children, second edition, is available in versions for parent,
Journal of Child Neurology 27(12)
teacher, and self-report. As many children with mitochondrial disease
are home-schooled for at least periods of time, only the parent and
self-report versions were used. Spearman correlation matrices and lin-
ear regression graphs were completed with SAS to isolate important
factors affecting the subjects’ function from the perspective of the sub-
ject and parent.
Similarly, the Behavior Rating Inventory of Executive Function
addresses subdomains of executive functioning in a fashion that
appears related to skills affecting daily living and academics.28 The
scales are informative about how the child is perceived in their every-
day real-world setting, with increased ecological validity, whereas
tests tell us something about how the student can perform over a short
time frame on a specific task.29 Although the Behavior Rating Inven-
tory of Executive Function is clinically useful in describing a wide
array of such daily activity, there is not a clear one-to-one relationship
between Behavior Rating Inventory of Executive Function results and
the results of neuropsychological tests.30-32 The term executive
function, referring to a broad range of self-regulatory and cognitive
processes, is defined and operationalized in a wide variety of ways,
and associated with more than 1 brain-behavior pathway.33-35 In the
Behavior Rating Inventory of Executive Function, executive function
is broken down into domains divided into 2 groups, self-regulation
(inhibition, shift, emotional control, self-monitor) and metacognition
(initiate, working memory, plan/organize, task monitor, organization
of materials).
Results
All but 2 families who contacted the author found the study
flier on the MitoAction.org website. Two additional families
found study information through their metabolic physician.
Of those families inquiring about the study, 2 were identified
as not filling study criteria. These 2 parents indicated that their
children would not be able to complete the questionnaires inde-
pendently because of their cognitive limits and were clearly not
appropriate for a study related to transition to higher educa-
tional settings; therefore, they were not sent the packet. Of ini-
tial contact of 20 subjects who filled research criteria, all
requested research packets, and 15 returned completed ques-
tionnaires; 1 individual was later removed from the sample
as it was found he had a different sort of metabolic disorder.
Thus, 70% of the distributed packets were returned and utiliz-
able for this study. On their return, the responses were deiden-
tified and entered into an Excel file. Two case studies had been
identified prior to the beginning of the study and releases were
obtained. Although these individuals also participated in the
study, they also cannot be identified through the database. The
demographics of each individual were changed significantly to
preserve their anonymous status.
Parents indicated the ways in which the mitochondrial disor-
der had been diagnosed on the Parent Questionnaire (see
appendix); all had mutations identified or strongly suspected
through muscle biopsy and/or blood test, in addition to clinical
symptoms. Identification of specific mutations responsible for
mitochondrial diseases is an evolving science, and new tests
and strategies are emerging. Thus the type of mitochondrial
disease each subject’s parent reported only carries a level of
specificity available to the parent at the time of this study.
Schreiber
Although 5 subjects had unspecified cytopathies, represented
in the group was 1 unspecified point mutation, 1 individual
with carnitine palmitoyl transferase deficiency, 1 individual
with mitochondrial encephalopathy, lactic acidosis, and
stroke-like episodes, and mutations in complex I, III, IV, and
possibly II. Two individuals had more than 1 complex identi-
fied. The sample included 7 male adolescents/young adults and
7 female. Five of the subjects were between the ages of 19 and
21 years, and thus utilized the adult form of the Behavior Rat-
ing Inventory of Executive Function. Consequently, it was dif-
ficult to derive statistics from the Behavior Rating Inventory of
Executive Function at this stage. Behavior Rating Inventory of
Executive Function results will be viewed in the case studies.
The same version of the Behavior Assessment for Children,
second edition, was completed by all subjects, however.
Parents were asked to qualitatively ‘‘Describe how your
child (adolescents and young adults) struggles with mitochon-
drial disease.’’ All of the parents lamented the extreme fatigue
their children experienced and the unpredictability of their
symptoms, ‘‘leading to academic and social issues,’’ according
to 1 parent. All but 1 parent described multiple medical prob-
lems leading to modified school experiences and home school-
ing in several cases. Cognitive or academic problems were
identified as central experiences of their children by 11 of the
parents. Quite touching assessments of the situation were
offered: ‘‘Her mind is capable but her body is unable to do what
she strives to achieve in life.’’ Dysautonomia with fluctuations
in cognition, energy, fatigue, and serious threats to ongoing
well-being were described. Individuals experienced specific
difficulty with muscle strength, gastrointestinal motility,
migraines, seizures, hearing loss, sleep disorders, and poor
attention and concentration, depression, and learning disabil-
ities and Asperger syndrome.
Spearman correlation matrices were computed for the Beha-
vior Assessment for Children, second edition, self-report
(Table 1) and parent report forms (Table 2) using SAS. Mixed
gender clinical norms were used such that the entire sample
could be analyzed from the same normative database. There
was a significant correlation between Somatization and Inter-
nalizing Disorders (but not individually with either depression
or anxiety) on the parent form at P .01 (Figure 1). Strong
adaptive skills were associated with strong functional commu-
nication, leadership, activities of daily living, social skills, and
negatively correlated with attention problems.
In the self-report form, attitude to school was significantly
associated with depression (P < .001) and anxiety (P < .01),
as well as internalizing problems (P < .01; Figure 2). Somatiza-
tion was not significantly associated with any other variable in
the self-report. Although students did not appear to be as
directly concerned about their somatic symptoms as their moth-
ers, both groups rated somatization more than a standard devia-
tion above the mean (self-report: mean ¼ 62.21, SE ¼ 3.32;
parent report: mean ¼ 78.86, SE ¼ 2.97). T scores between
60 and 70 are rated as at risk, and greater than 70 as clinically
significant. Even at-risk scores are related to considerable dis-
comfort in school: ‘‘Because school is so prominent in the lives
1509
of children and young adults, high scorers in the Attitude to
School scale often have other problems.’’27
Discussion
The purpose of this pilot study was to gather information about
what challenges adolescents and young adults with mitochon-
drial disease face, as they transition to higher grades and col-
lege. Given the cognitive heterogeneity of this group, this
study used behavior rating scales rather than neuropsychologi-
cal testing. In this way, the functional limits that affect success
in challenging environments could be identified.
The size of the sample limits the statistical information one
may derive from it. However, there was a highly significant
correlation between students’ attitude to school and depression
and anxiety in the Behavior Assessment for Children, second
edition. The developmental task of these students is success
in school, separation and seeking the future, despite uncer-
tainty. Challenges in these domains certainly cause distress.
It follows that improvement of the school experience and opti-
mization of success could provide a mitigating variable in the
development of depression and anxiety as well as a positive
feeling of efficacy. Those students with strong social, commu-
nication, and leadership skills may more easily adapt to fre-
quent changes in their medical status. Yet their vulnerability
to internalizing disorders is understandable.
The etiology of depression and anxiety in young students
with mitochondrial disease is likely to be complex. Not only
are the developmental tasks of adolescence and young adult-
hood challenged but the biological and genetic substrate of
these diseases may also be involved. Mitochondrial deletions
have been found in some individuals with psychiatric symp-
toms, including schizophrenia and mood disorders.36 A higher
incidence of depressed behavior (including fatigue) has been
found in children with disorders of oxidative phosphoryla-
tion,37 and a high incidence of psychiatric comorbidity in
adults is associated with mitochondrial disease.22 In addition,
the role of intermittent fatigue experienced by these students
and its direct relationship to metabolic change in the brain has
not been mapped out well yet. The presence of depression,
anxiety, and stress in mothers of children with mitochondrial
disorders has also been addressed.38,39 Yet Boles et al note that
although mothers of chronically ill children may be prone to
depression and anxiety, depression is more frequently observed
in matrilineal relatives who likely share the same mitochon-
drial DNA as the affected children themselves.38 Certainly, a
high index of suspicion for mood and anxiety disorders in these
students and their families can lead to more specific supportive
intervention.
Although with a larger sample it might have been possible to
correlate variables from the Behavior Rating Inventory of
Executive Function to the Behavior Assessment for Children,
second edition, as there are correlation coefficients available,
the age range of the sample resulted in even smaller groups
than the Behavior Assessment for Children, second edition,
thus limiting its utility in this way. The self-report Behavior
1510
Table 1. Spearman Correlation Matrix: Behavior Assessment for Children, Second Edition, Self-Report Scores (N ¼ 14)a

ats att sens atyp lc Socst anx dep inad som attp hyp relp Intr se sr SchP IntP In/Hyp EMI PAdj

ats 1.00
att 0.75y 1.00
sens 0.07 –0.22 1.00
atyp 0.54 0.59 –0.13 1.00
lc 0.67y 0.53 0.15 0.66 1.00
socst 0.58 0.77* –0.05 0.71y 0.60 1.00
anx 0.75y 0.69y –0.51 0.58 0.43 0.61 1.00
dep 0.89* 0.75y –0.23 0.57 0.58 0.57 0.89* 1.00
inad 0.56 0.61 –0.04 0.63 0.83* 0.71y 0.49 0.49 1.00
som 0.37 0.42 –0.04 0.02 0.05 0.30 0.45 0.55 0.09 1.00
attp 0.78* 0.54 0.04 0.49 0.47 0.70y 0.76y 0.69y 0.49 0.34 1.00
hyp 0.66y 0.64 –0.18 0.62 0.73y 0.61 0.56 0.53 0.69y –0.16 0.49 1.00
relp –0.34 –0.47 0.25 –0.64 –0.42 –0.65 –0.46 –0.30 –0.50 0.26 –0.55 –0.67y 1.00
intp –0.33 –0.78* 0.34 –0.41 –0.23 –0.71y –0.44 –0.36 –0.29 –0.17 –0.32 –0.56 0.58 1.00
se –0.44 –0.43 0.06 –0.25 –0.45 –0.58 –0.33 –0.27 –0.40 0.15 –0.57 –0.69y 0.75y 0.59 1.00
sr –0.58 –0.33 0.25 –0.26 –0.53 –0.35 –0.56 –0.64 –0.41 –0.10 –0.49 –0.54 0.29 0.23 0.49 1.00
SchP 0.91* 0.83* 0.27 0.52 0.61 0.65 0.55 0.77* 0.52 0.46 0.66y 0.55 –0.30 –0.45 –0.39 –0.34 1.00
IntP 0.82* 0.86* –0.19 0.73y 0.74y 0.81* 0.83* 0.89* 0.74y 0.52 0.68y 0.66y –0.42 –0.54 –0.35 –0.54 0.79* 1.00
In/Hyp 0.91* 0.75y –0.05 0.61 0.63 0.75y 0.85* 0.86* 0.61 0.40 0.93* 0.65 –0.54 –0.47 –0.52 –0.58 0.81* 0.87* 1.00
EMI 0.80* 0.74y –0.29 0.65 0.69y 0.79* 0.86* 0.80* 0.72y 0.22 0.83* 0.77* –0.69y –0.55 –0.67y –0.73y 0.64 0.86* 0.91* 1.00
PAdj –0.55 –0.72y 0.31 –0.56 –0.54 –0.75y –0.58 –0.51 –0.56 0.03 –0.57 –0.80* 0.87* 0.80* 0.88* 0.50 –0.52 –0.62 –0.65 –0.82* 1.00
Abbreviations: ats, attitude to school; att, attitude to teacher; sens, sensation seeking; lc, locus of control; socst, social stress; anx, anxiety; dep, depression; inad, sense of inadequacy; som, somatization; attp,
attention problems; hyp, hyperactivity; relp, relations with parents; intr, interpersonal relations; se, self-esteem; sr, self reliance; SchP, School Problems; IntP, Internalizing Problems; In/Hyp, Inattention/
Hyperactivity; EMI, Emotional Symptoms Index; PAdj, Personal Adjustment.
a
Bold numbers indicate the Spearman correlation coefficient is greater than 0.7 (either in positive or negative).
*P  .001; yP  .01.
 Table 2. Spearman Correlation Matrix: Behavior Assessment for Children, Second Edition, Parent Scores (N ¼ 14)a

hyp agg conp anx dep som atyp withdr attp adapt soc leadr adl fc ExtP IntP BSI

hyp 1
agg 0.81* 1
conp 0.41 0.41 1
anx 0.26 0.28 0.36 1
dep 0.62 0.62 0.20 0.78y 1
som 0.55 0.61 0.33 0.33 0.63 1
atyp 0.63 0.64 0.13 0.28 0.64 0.21 1
withdr 0.57 0.50 0.27 0.71y 0.86* 0.38 0.74y 1
attp 0.64 0.39 0.30 0.34 0.51 0.30 0.49 0.61 1
adapt –0.36 –0.36 –0.07 0.07 –0.38 –0.35 –0.37 –0.13 –0.24 1
soc –0.77y –0.62 –0.60 –0.32 –0.54 –0.39 –0.57 –0.58 –0.75y 0.43 1
leadr –0.36 –0.24 –0.07 –0.55 –0.64 –0.22 –0.42 –0.56 –0.77y 0.42 0.60 1
adl –0.48 –0.40 –0.24 –0.53 –0.69y –0.68y –0.17 –0.55 –0.74y 0.33 0.53 0.72y 1
fc –0.45 –0.20 0.10 –0.29 –0.55 –0.24 –0.43 –0.54 –0.77y 0.45 0.46 0.83* 0.71y 1
ExtP 0.95* 0.88* 0.61 0.41 0.68y 0.67y 0.59 0.63 0.63 –0.31 –0.79* –0.34 –0.57 –0.37 1
IntPr 0.54 0.57 0.34 0.84* 0.94* 0.74y 0.44 0.78y 0.50 –0.27 –0.49 –0.60 –0.78* –0.46 0.67y 1
BSI 0.89* 0.77y 0.40 0.52 0.81* 0.54 0.74y 0.84* 0.75y –0.28 –0.79* –0.52 –0.62 –0.51 0.90* 0.73y 1
AdSk –0.48 –0.29 –0.18 –0.40 –0.63 –0.40 –0.45 –0.54 –0.80* 0.59 0.68y 0.92* 0.78* 0.89* –0.47 –0.60 –0.56
Abbreviations: hyp, hyperactivity; agg, aggression; conp, conduct problems; anx, anxiety; dep, depression; som, somatization; atyp, atypicality; withdr, withdrawal; attp, attention problems; adapt, adaptability; soc,
social skills; leadr, leadership; adl, activities of daily living; fc, functional communication; ExtP, Externalizing Problems; IntP, Internalizing Problems; BSI, Behavioral Symptoms Index; AdSk, Adaptive Skills.
a
Bold numbers represent the Spearman correlation coefficient is greater than 0.7(either in positive or negative).
*
P  .001; yP  .01.

1511
1512
Figure 1. Behavior Assessment for Children, Second Edition,
somatization vs internalizing problems by parent report.
Assessment for Children, second edition, is based on a different
normative sample, but a validation study27 showed significant
correlations to the self-report version of the Behavior Rating
Inventory of Executive Function (N ¼ 104). In addition, utili-
zation of a comparison group of adolescents and young adults
with other medical illnesses might provide further information
about how specifically these disorders have impact, and how
that impact may be compared to the effect of chronic illness,
in general. This sample was self-selected in the sense that those
families who responded to information about the study already
were sensitive to cognitive and emotional issues related to the
transitions experienced by high-functioning adolescents and
young adults with mitochondrial disease. Thus, these findings
are difficult to generalize to more severely affected individuals
or, conversely, to individuals for whom transitions have not
been problematic. Case studies remain a strong tool for better
understanding what may be needed to support success in tran-
sition to postsecondary education.
Case Studies
Case 1. Case 1 was diagnosed with mitochondrial encepha-
lopathy, lactic acidosis, and stroke-like episodes (MELAS) in
early childhood by muscle biopsy and clinical evaluation, as
was his twin sister. When younger, he had several types of
seizures: he fell down and lost consciousness, on occasion.
He also had ‘‘catatonic seizures,’’ where he was unable to speak
and his muscles became stiff and tight, both now controlled
with medication (Lamictal). He has struggled with exhaustion
and a sleep disorder, difficulty sustaining attention and focus,
and spastic diplegia and acid reflux. He has 70% hearing loss
and chose a college with robust resources to support hearing-
impaired individuals. He had accommodations throughout
secondary school, including extended time for testing, a low-
distraction environment, shorter days, extra time for getting
to classes and obtaining class notes, and medical absences were
allowed. He had hearing aids, braces, and surgeries. In college,
he was able to register for classes early so that he could plan his
schedule. He received a note taker and speech-to-print technol-
ogy, where he could read lectures on a computer screen. He
relied on accommodations available for the deaf, rather than
Journal of Child Neurology 27(12)
Figure 2. Behavior Assessment for Children, Second Edition, school
attitude vs internalizing problems by self-report.
those that might have been delineated by neuropsychological
testing. A full battery was never administered; rather, only
limited testing in childhood had been completed.
College offered new and sometimes unexpected challenges.
He noted that his support structure of family and friends was no
longer in place, and he realized he had to rely on himself; he
had to be ‘‘independent and an adult all at the same time—it’s
a reality check.’’ He had roommates at the beginning of the
school year and got little sleep. Although he enjoyed meeting
new people, he found he was not entirely tolerant of ‘‘immature
behavior.’’ He got sick and missed a month of school and his
grades reflected that. He transferred to a single room and
switched his major to psychology, an area that interested him
far more than his original choice.
He noted that he can be very organized and uses a schedule.
However, he is capable of putting off certain kinds of assign-
ments such as papers until close to the deadline. He believes
he takes longer to learn things and learns through ‘‘busy work’’
over and over until he finally takes it in. He may become anx-
ious before tests, anticipating difficulty.
Review of the Behavior Assessment for Children, second edi-
tion, showed an elevation on the anxiety and internalizing prob-
lems scales by self-report, as well as elevation of the Somatic
scale. His mother indicated mild elevations in depression and
withdrawal but not anxiety; somatization was also high (T ¼
72). In the Behavior Rating Inventory of Executive Function,
both he and his mother indicated difficulties in behavioral regu-
lation. Inhibition, shifting, and emotional control scales were a
standard deviation or more above the mean (Table 3). His
mother also noted that working memory, in particular, was pro-
blematic leading to a mild elevation in the Metacognition Index.
Such difficulty is likely to be related to his experience of needing
to review material repeatedly before learning it.
In follow-up contact a year later, he reported that his health
varied and colder weather negatively affected him. He contin-
ued to need to watch his sleep and schedule carefully: when he
had an early morning class, it was difficult for him to get
enough sleep to function well. He was taking a reduced course
load, had extended time on tests and quizzes, and used an inter-
preter and note taker. He has learned to write his teachers in
advance of beginning a new class so as to warn them of his
Schreiber 1513

Table 3. Case 1 Behavior Rating Inventory of Executive Function Table 4. Case 2 Behavior Rating Inventory of Executive Function Self-
Self- and Informant Reports (T Scores) and Informant Reports (T Scores)

Scale/Index Self-Report Informant Report Scale/Index Self- Report Informant Report

Behavior regulation Behavior regulation

Inhibit 63 60 Inhibit 60 48
Shift 64 61 Shift 51 46
Emotional control 60 65 Emotional control 43 39
Self-monitor 67 58 Self-monitor 50 37
Metacognition Metacognition
Initiate 47 60 Initiate 60 54
Working memory 56 64 Working memory 59 58
Plan/organize 46 60 Plan/organize 65 58
Task monitor 54 61 Task monitor 54 45
Organization of materials 53 56 Organization of materials 56 44
Behavioral regulation index 66 63 Behavioral regulation index 50 40
Metacognition index 51 61 Metacognition index 61 52
Global executive function 58 63 Global executive function 57 47

condition, noting that this ‘‘makes them more likely to work
with me in case anything does happen.’’
When asked what was the most important thing for a college
student with mitochondrial disease to consider, he replied, ‘‘I
would recommend that they start with a lighter course load at
the beginning and try to figure out how much they can han-
dle—if they could handle an extra class later, then they could
add one in the future. I strongly suggest starting out this way
because I did very badly my freshman year trying to keep up
with people who simply had 2 times or more the amount of
energy I did.’’ In addition, he reported that living with a room-
mate was not feasible as it interfered with his sleep.
Thus, although he had sophistication in the potential accom-
modations available to him and knowledge about how to put
them in place, he was less able to anticipate the effects of a new
social environment in combination with the loss of his usual
family and friend network. Although he had some skill at man-
aging accommodations, his usual strategy of waiting until the
last moment to do some sorts of work was problematic. His
learning strategy, requiring repetition and review of material,
required more expense of energy than he observed was required
by his peers. It took time and a trial-and-error approach to find
a reasonable strategy for his college experience. He does
believe he will graduate with his current plan and hopes to
work with minority populations in a rehabilitation context.
Case 2. Case 2 had a late onset of mitochondrial disease, a
probable deficit in complex I, as do her mother and sister. Her
condition was diagnosed during an evaluation for intense
migraines, staring spells, and worsening memory in school
activity. When in high school she completed 60% of her curri-
culum at home with tutorial support under a 504 plan. She
remained a strong student but she easily became fatigued and
had variable visual acuity apparently related to eye muscle fati-
gue. Epilepsy was diagnosed at age 19 years and she was begun
on Lamictal. Two administrations of neuropsychological test-
ing over time indicated deficits in working memory and in her
ability to organize complex auditory-verbal and visuospatial
material to facilitate reliable and consistent learning of new
information and retrieval.
She complained of difficulty keeping track of tasks for
which she was responsible, remembering facts and recalling
pieces of conversation, even after beginning medication. Her
tutor described ‘‘debilitating fatigue’’ in addition to her
migraines, noting that it took her 3 times as long to complete
writing projects as her peers. Although she had initially hoped
to become a physician, she was attending community college
part time while living at home. She had changed her major
to secondary education in biology and history. She reported
sleeping a great deal, and struggling with having sufficient
energy to complete academic tasks. Accommodations included
extended time on tests, a note taker (which she often did not
use), no penalty for absences, and assistive technology such
as books on CD-Rom and an electronic reader. She was proud
that she had passed her Emergency Medical Technician (EMT)
certification for which she had been studying for a long while.
Although her mother did not record any concerns in the Adult
Behavior Rating Inventory of Executive Function, she indicated
particular concern with planning/organizing (T ¼ 65), and mild
concern with initiating behavior (T ¼ 60; Table 4). In the Beha-
vior Assessment for Children, second edition, both she and her
mother indicate somatic concerns a standard deviation above the
mean, but did not endorse other indicators. It was of interest that
her mother indicated that she had particularly strong social and
adaptive skills on the same scale (T ¼ 76 and 66, respectively).
A year after initial contact, she had a setback when her sister
and mother both became ill; her grades plummeted. She noted,
‘‘I hit a wall emotionally.’’ She was taking 3 courses and attempt-
ing to get her grades back up, but remained concerned about her
family members. Although strong interpersonal skills appeared
to be an asset in helping this young woman manage her medical
issues and school, when the health of family members also became
a concern, her resources were taxed. It was hard for her to consider
that she might need emotional as well as academic support.
1514
Conclusions
In both the above cases, only a planned strategy, along with a
system of accommodations and support that address medical,
psychosocial, and academic concerns together, adequately
address the challenges these young people face on a daily basis.
The importance of college as a vehicle for a simple belief in a
future is clear. This pilot study suggests it is certainly a primary
developmental focus. Yet these students not only face the
developmental challenges all teens and young adults face, they
also live with a degree of uncertainty that is difficult to imagine
for most. The need for all disciplines to work together to pro-
vide a cogent and flexible plan to optimize their success and
health is a challenge in itself. Protocols for health crises involv-
ing local and home-based physicians specific to the individual
needs of the student are only the beginning. Integration of
health and academic components of a college plan mean that
academic support services and health services communicate
regularly and more effectively support the student. Standard
academic accommodations such as extended time, note takers,
audiotaping, scribes, use of laptop, and books on CD or mp3
may be worthy of consideration in some individuals. Alterna-
tive technologies include the Kurzweil reader (text to voice)
and Dragon Naturally Speaking for dictation to text. The
sophisticated technologies available to the dyslexic, blind, or
deaf student bring a new dimension to such aids. In addition,
medical demands may point in the direction of alternative test
taking methods for some individuals.
It is more the rule rather than the exception that navigation
changes and course corrections will be a part of the college
experience for students with mitochondrial disease. In addi-
tion, feelings of fatigue and intermittent illness should be
expected. Although flexible programming can be helpful in
this regard, there can be a tension between the need for rea-
sonable accommodation and maintaining consistent educa-
tional standards that may affect how some universities and
colleges choose to develop accommodation plans. As is the
case in high school, variable energy level can be mistaken for
deliberately withheld effort; a familiarity with mitochondrial
disease is helpful. Education of faculty and staff about mito-
chondrial disease will promote support at the salient moment.
For some students, meeting with an academic support service
can promote organizational skill development, improved
study and test preparation skills, and more facility in devel-
oping long projects such as papers.
Students with mitochondrial disease understandably feel
the same lure of meeting new people, and being drawn to
social activities, as do all students. Yet with more interest
than energy, realistic appraisal of the situation is impor-
tant. Counseling support can help students begin to gauge
for themselves, for the first time, what is doable and what
is not, how to achieve the aspirations they have, and prior-
itize their short- and long-term goals. The interaction
between the particular cognitive challenges each student
may have and the ever-changing demands of a complex
environment such as a college will be different for each
Journal of Child Neurology 27(12)
student. Comprehensive neuropsychological evaluation,
along with functionally based rating scales, may serve to
anticipate areas of difficulty and identify areas of strength,
thus reducing frustrating moments such as those discussed
in case 1. For those students who successfully complete
their college education, careful thought about what types
of environments for work play to their strengths and mini-
mize the impact of their illness and cognitive concerns
would enhance the likelihood of success. Research further
exploring the needs of this late adolescent young adult
population with mitochondrial disease is sparse and much
needed.
Appendix
Parent Questionnaire
Please answer the questions below as best you can. Once
we receive this information, your child will be assigned a
code number. Demographic information will be removed
before information is entered into a database. It will not be pos-
sible to identify your child once the study is underway; identi-
fying information will not be accessible to others and will be
destroyed at the end of the study. If you wish to receive a sum-
mary of the study at its completion, please provide your name
and address below.
1. Name of child__________________________________
2. Date of Birth___________________________________
3. Date forms completed____________________________
4. Type of mitochondrial disorder, if known______________
5. How was it diagnosed (e.g., muscle biopsy, blood tests,
clinical diagnosis)_______________________________
6. Is the student home schooled, in private or public
school?_______________________________________
7. Top 5 academic accommodations___________________
8. Top 5 medical accommodations____________________
9. IQ scores, if available____________________________
10. Any known learning disorders or ADHD_____________
11. Describe how your child struggles with mitochondrial
disease________________________________________
Optional: If you wish to receive a study summary at the end of
this study, please add your name and address below. This infor-
mation will not be shared and will not be entered into the
research database.
____________________________
____________________________
____________________________
____________________________
Pilot Study on Executive Function and Adaptive Skills in Adolescents
and Young Adults with Mitochondrial Disease
Clinical experience has shown that teens and adolescents with
mitochondrial disease often face learning challenges as they
transition to high school and college. Many may have limited
organizational skills and may experience new difficulties when
Schreiber
their work becomes more complex and time-consuming. Such
challenges have not been well researched to date.
Teenagers and young adults with mitochondrial disease,
ages 13 to 21 years, need to better understand what their learn-
ing needs are especially when they make big academic transi-
tions. Each participant will be asked to fill out 2 standardized
questionnaires. Their parents will be asked to complete 2 par-
allel questionnaires, and a short form about the nature of their
child’s mitochondrial disease.
With the results from these questionnaires, a database will
be constructed in which participating individuals cannot be
identified. We hope to learn about the overall pattern of
strengths and weaknesses in our participants. With this infor-
mation we may develop more sophisticated accommodations
for students with mitochondrial disorders, for the transition
from grade to grade, and to college.
Please contact Dr Schreiber by phone or email if your
family is interested in participating in this study.
Acknowledgments
The author thanks Mark Korson, MD, Chief of the Metabolism Ser-
vice; John Sargent, MD, Chief of Child and Adolescent Psychiatry;
and David Griesemer, MD, Chief of the Division of Pediatric Neurol-
ogy, all at Tufts Medical Center, for reviewing this manuscript.
Thanks to Yoojin Lee of the Biostatistics Research Center at Tufts for
statistical support, and to Susan Meagher, PhD, for her thoughtful
review of the statistics. The author wishes to thank MitoAction.org for
their wise counsel and support in recruitment of subjects. Finally, the
author particularly wishes to thank the young participants with mito-
chondrial disease and their families for their valuable time and energy
in completing this study.
Author’s Note
Although there has been no direct financial support for this research,
MitoAction.org ran recruitment information on their website, and set
up Google to direct to their website for recruitment for 3 months. The
author is solely responsible for this article.
Declaration of Conflicting Interests
The author declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author received no financial support for the research, authorship,
and/or publication of this article.
Ethical Approval
All the research herein has been reviewed by the IRB at Tufts Medical
Center, has met their ethical standards, and has been approved by
them.
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