SYSTEMATIC REVIEW

published: 28 July 2020

doi: 10.3389/fpsyt.2020.00747

Neuropsychological and Psychiatric

Features of Children and
Adolescents Affected With
Mitochondrial Diseases:
A Systematic Review
Elise Riquin 1,2,3*, Philippe Duverger 1,3, Cindy Cariou 1, Magalie Barth 4,
Clément Prouteau 4, Patrick Van Bogaert 5, Dominique Bonneau 2,4 and Arnaud Roy 3,6
1 Department of Child and Adolescent Psychiatry, University Hospital of Angers, Angers, France, 2 Mitovasc Unit, UMR

Edited by: CNRS 6015-INSERM 1083, Angers, France, 3 Laboratory of Psychology, LPPL EA4638, University of Angers, Angers,
David Cohen, France, 4 Department of Biochemistry and Genetics, University Hospital of Angers, Angers, France, 5 Department of Pediatric
Université Pierre et Marie Curie, France Neurology, Angers University Hospital, Angers, France, 6 Reference Center for Learning Disabilities, Nantes University
Hospital, Nantes, France
Reviewed by:
Roberto Canitano,
Siena University Hospital, Italy
Mitochondrial diseases (MDs) are a group of clinically heterogeneous genetic disorders
Angele Consoli,
Assistance Publique Hopitaux De that arise as the result of dysfunctional mitochondria. Only few medical articles deal with
Paris, France neuropsychological or psychiatric aspects of MDs.
*Correspondence:
Elise Riquin
Aim: The present article aims to provide a systematic review of neuropsychological and
elise.riquin@chu-angers.fr psychiatric aspects of MDs.
orcid.org/0000-0002-5956-3014
Methods: In order to identify all studies dealing with psychiatric and neuropsychological
Specialty section: aspects of MDs in children and adolescents, we performed a search in the medical
This article was submitted to literature between April 2009 and April 2019 using PubMed, Cochrane, and Web of
Child and Adolescent Psychiatry,
a section of the journal
Science and we defined inclusion and exclusion criteria.
Frontiers in Psychiatry
Results: We found only seven studies that satisfy the inclusion requirements and criteria.
Received: 07 May 2020
The main psychiatric aspects reported in MDs were depressive and behavioral disorders.
Accepted: 16 July 2020
Published: 28 July 2020 With regard to the neuropsychological aspects of MDs, developmental analyses showed
Citation: an overall deterioration and developmental delay.
Riquin E, Duverger P, Cariou C,
Barth M, Prouteau C, Van Bogaert P,
Interpretation: Children and adolescents with MDs may present psychiatric symptoms
Bonneau D and Roy A (2020) and neuropsychological impairment. A more systematic investigation of psychiatric and
Neuropsychological and Psychiatric neuropsychological features of MDs is needed to foster a better understanding of the
Features of Children and Adolescents
Affected With Mitochondrial Diseases: phenotype of these diseases and their links with the genotype, which may have significant
A Systematic Review. implications for the developmental trajectories of patients.
Front. Psychiatry 11:747.
doi: 10.3389/fpsyt.2020.00747 Keywords: mitochondrial diseases, children, adolescent, neuropsychological profile, psychiatric profile

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Riquin et al. Psychiatric Features of Mitochondrial Diseases

INTRODUCTION In a second step, the articles previously found were selected

using inclusion and exclusion criteria. Inclusion criteria included:
Mitochondrial diseases (MDs) are a group of clinically 1) articles published in English; 2) articles reporting prospective
heterogeneous genetic disorders that arise as the result of and retrospective studies; 3) articles reporting longitudinal and
dysfunctional mitochondria (1). The forms of MDs affecting cross-sectional studies; 4) articles reporting studies with an
children (<16 years old) have an estimated prevalence ranging experimental group of children and/or adolescents with MD,
from 5 to 15 cases per 100,000 individuals (1). MDs can be caused and 5) articles published between April 2009 and April 2019.
either by mutations in the mitochondrial DNA (mtDNA) or in Articles reporting results from adults, literature reviews, and
genes from the nuclear genome encoding for mitochondrial case reports were excluded.
proteins (2). Many MDs often involve multiple organ systems During the review phase of the articles, data was summarized by
and typically affect organs that require the greatest amount of a primary reviewer (ER) who completed a data abstraction form.
energy (i.e. brain, heart, muscles, kidney) (3–5). The main central Then, a secondary reviewer (CC) checked the accuracy and
nervous system (CNS) symptoms of MDs include epilepsy, completeness of the primary review. Finally, two other reviewers
hearing loss, visual impairment, intellectual disability, fluctuating independently assessed the eligibility of the study for inclusion and
encephalopathy, stroke-like episodes, ataxia, and spasticity. unresolved disagreements between reviewers were adjudicated by a
Brain dysfunction in MDs can also result in neuropsychological or third reviewer (MB). The kappa coefficient, measuring the interrater
psychiatric disturbances including mood or behavior disorders, but reliability, was 0.84. Our local research ethics committee did not
few articles deal with this aspect of MDs (6, 7). Cognitive impairment consider that its approval was needed for this systematic review.
is a common feature in adults presenting with mitochondrial The PRISMA flow diagram of this bibliographic search is
encephalopathy, such as MELAS (mitochondrial encephalopathy shown in Figure 1.
lactic acidosis, and stroke-like episodes) (8) and psychiatric
symptoms are associated with MDs in up to 70% of the adult
population (9, 10). Along the same lines, a recent article suggested
that mitochondrial activity could regulate the availability in neurons
RESULTS
of GABA, an inhibitory neurotransmitter, leading to social deficits A total of 1,946 articles were retrieved during the first step of the
that can be rescued by the modulation of GABA level (11). review but only seven met the inclusion and exclusion criteria
In contrast, only few articles have dealt with the (Table 1). Two of these articles reported retrospective studies (21,
neuropsychological and psychiatric features of children and 23), four reported prospective studies (17–20), and one reported a
adolescents with MDs (12–15). It is, however, crucial to consider longitudinal study (22). The number of children included in these
this aspect of MDs in the pediatric population because the disease studies ranged from 14 (20) to 112 individuals (18). Two studies
occurs in developing brains and may have not only a significant were carried out in the Netherlands (17, 19), two in the Republic
impact on developmental trajectories, but also may lead to of Korea (21, 22), two in the USA (20, 23), and one in the UK
psychological disturbances affecting quality of life. (18). Quantitative data obtained from psychometric tests were
available in only six of these studies (Table 1) (19–23).

METHODS Psychiatric Features of

Mitochondrial Diseases
This review follows the 2019 Preferred Reporting Items for Psychiatric disorders were analyzed in four articles, (17–19, 21)
Systematic Reviews and Meta-Analyses (PRISMA) statements but only three of them (17, 19, 21) used rating scales to
for performing a systematic review (16). As a first step, studies objectively assess them. The scales used in these studies were
dealing with neuropsychological and psychiatric features of the Hamilton Depression Rating Scale (HDRS), the Zung
children and adolescents with MD were identified thanks to a depression scale (17), the Holmes and Rahe Social
computerized search in PubMed, Cochrane, and Web of Science Readjustment Rating Scale (17), and the child behavior
using the following keywords: (mitochondrial disorder OR checklist (CBCL) (19, 21). These studies, the main results of
mitochondria OR mitochondrial cytopathy OR mitochondrial which are shown in Table 1, primarily demonstrated the high
disease) AND (psychiatry OR psychiatric OR mental illness OR prevalence of depressive symptoms and behavioral disorders,
mental disorders OR major depression OR anxiety OR bipolar such as withdrawal, social problems, attention deficit, sleep
disorder OR schizophrenia OR psychosis OR neuropsychology disorders, and emotional response in children with MDs.
OR cognitive OR executive function OR development OR IQ OR In the study performed by Eom et al. (21), 28 children with
memory OR language OR learning abilities) AND (children OR behavioral disorders were tested using the CBCL. The most
adolescent OR pediatrics). severe features reported in this study were withdrawal, social
All articles found were registered using the bibliographic problems, attention deficit, sleep disorders, and emotional
management software EndNote. Duplicates were checked not response. In addition, a high level of parental stress was also
only digitally, but also manually in order to remove duplicates reported. Similarly, almost 65% of the mothers from this study
that could have been missed by the software. exhibited significant levels of depression.

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Riquin et al. Psychiatric Features of Mitochondrial Diseases

FIGURE 1 | Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

Morava et al. (19) evaluated the psychological characteristics of 18 (24), and that abnormal cerebral energy metabolism could be a
Dutch children with MDs who exhibited no developmental delays. In risk factor for mood disorders.
this study, a significantly high rate of withdrawal and depressive In another study conducted in the Netherlands, Koene et al.
behavior was observed in the MD group in comparison to not only (17) found that 5 children with MD out of 35 (14.3%)
the normal population, but also to children affected with other forms demonstrated major depressive behavior.
of inborn errors of metabolism and to children with Sotos syndrome. In a study conducted in the UK, Verity et al. (18) focused on
When comparing both these groups, the authors aimed to the clinical presentation, the way the diagnosis was made, and the
check whether factors such as the stress of being diagnosed with epidemiology of MD in children who exhibited progressive
such conditions, fatigue, and discomfort were major determinants intellectual and neurological deterioration. The methodology
of the depressive behavior. This study showed a strikingly high was based on the British Pediatric Surveillance Unit (BPSU)
incidence of depressive behavior in children with MDs, but the card, which asks pediatricians to report children presenting
occurrence of depression was not significantly correlated with the progressive intellectual and neurological deterioration (PIND).
degree of mitochondrial dysfunction and the clinical severity of The data reported by clinicians were classified and analyzed by
the disease or, more specifically, with muscle involvement or an expert group. In this study, 3 children out of 112 had autistic
severe CNS involvement. According to the authors, this lack of spectrum disorder (2.7%) and 1 had behavioral difficulties
correlation supported the hypothesis that depressive behavior (without specificities) (0.9%). In this study, however, no specific
could be genetically determined, as shown in multiple studies scales rating the psychiatric disorders were used.

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Riquin et al. Psychiatric Features of Mitochondrial Diseases

TABLE 1 | Main results of the studies included in the literature review.

References, Characteristics of the sample Tests used Results

country of origin

Koene, (17), The 35 children Depression diagnosis (DSM-IV Major depression (n=5; 14.3%)
Netherlands Inclusion criteria for MD: mutation in a mitochondrial (17) criteria) or HDRS for children older Psychotic symptoms (n=1; 2.9%)
or in a nuclear (13) gene. than 14 years old and/or Zung Life stress event score: increased susceptibility
5 children with suspected depression were analyzed depression scale (>50%) in 3 patients.
Age range: 2–18 years old, mean: 8.7 years old Holmes and Rahe Social
Readjustment Rating Scale (Life
Stress Event Scale)
Verity, (18), UK 2,493 children with PIND No tests used Developmental delay (n=43; 38.4%)
112 (4, 5) children with MD Data were obtained from medical Cognitive decline (n=1; 0.9%)
Inclusion criteria for MD diagnosis: 112 suspected MD in clinical observations Psychiatric symptoms:
the group of patients with PIND by a group of experts. Autistic spectrum (n=3; 2.7%)
Lactate levels increased in the blood and or CSF (n=87); Behavioral difficulties (n=1; 0.9%)
muscle biopsy (n=75) and measures of mitochondrial
respiratory chain enzymes: in 31 of these the result was
diagnostic; DNA studies (n=50) yielded a specific
diagnosis in 35; brain MRI (n=78)
Age range: birth–14 years 7 months; median: 12 months
15 Leigh syndrome, 5 MELAS, 24 nonspecific, 68 other
Morava, (19), The 18 children who exhibit no developmental delays WISC (version not provided) Depressive behavior (n=7; 38.9%)
Netherlands (individuals with IQ<70 were excluded) CBCL CBCL, in the MD group:
Inclusion criteria for MD: -Anxious/depressed (1–18 years Compared to norms:
A clinical and biochemical diagnosis of OXPHOS disease old), Higher rate of withdrawn and depressive
for more than 1 year; muscle disease with developmental - Withdrawn/depressed (only in behavior (p = 0.0001)
delay and variable systemic involvement. CBCL 6–18 years old) Higher levels of depressive behavior (p =
Control group: - Affective disorders (6–18 years 0.017)
18 children with inborn errors of metabolism old)/affective problems (1–5 years Compared to inborn errors of metabolism
19 children with Sotos syndrome (a Mendelian disorder old). group:
with non-progressive ID) Comparison to American norms Anxious, depressive behavior in MD disorder:
(sub-scale score of <65 is normal, ns
65–69 scores are borderline, and Withdrawn depressed behavior increased (p =
scores of >70 indicate a clinical 0.002) in the MD group
problem) Anxious depressive behavior: ns
Compared to Sotos syndrome group:
Withdrawn depressive behavior significantly
higher in patients diagnosed with MD
Anxious depressive behavior: ns
Schreiber, (20), 14 children were included BASC-2, for ages 12 to 21 years old Attitude to school associated with depression
USA Inclusion criteria for MD: selection via a website then BRIEF for older children/adolescents (p < 0.001), anxiety (P < 0.01), and internalizing
parental questionnaire about how the MD was diagnosed aged 13 to 18 years old or adult problems (P < 0.01).
(i.e. mutations identified or strongly suspected through report for patients older than 18 Students mothers rated somatization more
muscle biopsy and/or blood test, in addition to clinical years than a standard deviation above the mean
symptoms). Unspecified MD (n=5) (self-report: mean ¼ 62.21, SE ¼ 3.32; parent
Age range of children: not provided report: mean ¼ 78.86, SE ¼ 2.97).
7 male and 7 female adolescents/young adults. 5 of the BRIEF results were not analyzed because of
subjects were between the ages of 19 and 21 the age heterogeneity in the cohort
Eom, (21), South 70 children BSID-II Development (n=41): mental development =
Korea Age at diagnosis: mean: 1.78 ± 2.52 years old WPPSI (Korean version) 52.9 ± 11.3 (=significant level of delay);
Inclusion criteria for MD: WISC-III (Korean version) psychomotor development = 52.1 ± 10.5
biochemical enzyme assay of muscle tissues Children’s adaptive (=significant level of delay)
and modified mitochondrial Function: Social Maturity Scale IQ (n=15): FSIQ = 64.6 ± 21.8 (=mild levels of
diseases criteria (MDC) (Korean version); Parent responses intellectual disability); VIQ=70.5 ± 19.2 (=mild
Inclusion criteria for nonspecific MD: no classical clinical for 99-item CBCL (Korean version) levels of intellectual disability); PIQ = 58.6 ±
symptoms, biochemical results, or mitochondrial DNA for children 1.5–5 years of age or 16.9 (=mild to moderate levels of impairment)
(mtDNA) deletions/duplications/point mutations that 118-item CBCL for children and Daily living function (n=54); social quotient =
conform to known and established mitochondrial adolescents 6–18 years of age 50.2 ± 31.3 (significant impairments in adaptive
syndromes. Parental assessment (PSI; BDI for function)
16 Leigh syndrome, 3 MELAS, 51 nonspecific mothers) Behavioral difficulties (n=28): CBCL = 62.9 ±
17.1; 43% above the cutoff; internalizing
problems = 32%; externalizing problems =
25%; withdrawn = 46%; somatization = 11%;
anxiety/depression = 29%; social problems

(Continued)

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Riquin et al. Psychiatric Features of Mitochondrial Diseases

TABLE 1 | Continued

References, Characteristics of the sample Tests used Results

country of origin

55%; cognitive problems = 20%; attention

problems = 41%; delinquent behavior = 0%;
aggressive behavior = 15%; emotional
response = 31%; sleep problems = 38%; other
problems = 20%
PSI (n=32) = 88.6 ± 9.4; 75% above the cutoff
BDI (n=26) = 14.6 ± 9.1; 65% above the cutoff
Eom, (22), South 53 children KICDT Pre-diagnosis evaluation (n=18): DQ = 60.4 ±
Korea Inclusion criteria for MD: biochemical enzyme assay of DQ = (developmental age/ 34.4
muscle tissue samples and meeting the modified MDC chronological age) × 100] Diagnosis (n=37): DQ = 31.9 ± 25.8
11 Leigh syndrome, 2 MELAS, 40 nonspecific First visit prior to diagnosis, second Post-diagnosis (1 year after) (n=19): DQ = 27.8
Age at diagnosis: mean: 3.12 ± 2.49 years old; lead time visit prior to diagnosis, one-time ± 23.3
to diagnosis: 1.09 ± 1.15 years old (range, 0.6–1.46 years diagnostic evaluation, and six post-
old) diagnostic developmental
evaluations
Shurtleff, (23), USA 49 children WPPSI-III: 2½ to 7 years old WISC-III or –IV (n=40) Vineland (n=9) = 85
Age range: 61–250 months old WISC-III or -IV: 6 to 16 years old [interquartile range (IQR): 50, 102]
Inclusion criteria for MD: biochemical testing, muscle WAIS-III or -IV: 16 years of age and Group without seizures: FSIQ=100 (IQR: 86,
biopsy with electron transport chain enzyme assay, and/ older 109), PIQ =100 (IQR 94, 112)
or gene sequencing of mtDNA or nuclear genes involved FSIQ, VIQ, PIQ Group with seizures: FSIQ = 67 (IQR: 49.5,
in mitochondrial disease. When available, molecular WMI or FFD 89), PIQ = 63 (IQR 54, 84)
genetic testing that confirmed pathological variants in PSI Statistical and clinical difference (D=33; 95% CI:
either nuclear or mtDNA-encoded genes were obtained Vineland Adaptive Behavior Scales, 9, 52).
from Clinical Laboratory Improvement Amendments (CLIA) 2nd Edition Adaptive function measure = 43 (IQR: 37, 50)
approved laboratories. All patients met clinical criteria of (patients with intractable epilepsy only)
modified Walker criteria for diagnosing mitochondrial
disease

Acronyms used: BASC, Self-report and parent report Behavior Assessment for Children; BDI, Beck Depression Inventory; BRIEF, Behavior Rating Inventory of Executive Function self-
report and parent report; BSID, Bayley Scales of Infant Development; CBCL, Child Behavior Check List; CSF, cerebrospinal fluid; DQ, developmental quotient; FFD, Freedom From
Distractibility Index; IQ, intelligence quotient; FSIQ, Full Score Intelligence Quotient; HDRS, Hamilton Depression Rating Scale; ID, intellectual disability; KICDT, Korean Infant and Child
Development Test; MD, mitochondrial disorders; MDC, Mitochondrial Disease Criteria; MELAS, mitochodrial encephalopathy and lactate acidosis syndrome; OXPHOS, disorders of
oxidative phosphorylation; PIQ, performance intelligence; PIND, progressive intellectual and neurologic deterioration; PSI, Processing Speed Index; VIQ, verbal intelligence; WAIS,
Wechsler Adult Intelligence Scale; WISC, Wechsler Intelligence Scale for Children; WMI, Working Memory Index; WPPSI, Wechsler Preschool and Primary Scale of Intelligence.

Neuropsychological Features of overall developmental delay and had consistently varying signs of
Mitochondrial Diseases cognitive decline.
The neuropsychological profiles of children and adolescents with Verity et al. (18) found that 43 children with MDs among 112
MDs has been analyzed in five studies (18, 20–23), the main results showed developmental delay (38.4%), one of them having a cognitive
of which are shown in Table 1. However, only four of these studies decline (0.9%). In this study, however, no specific scales were used
used specific scales to evaluate the neuropsychological profiles of and the data was only obtained from clinical observations.
affected children. In the study by Eom et al. (22), which included 53 children, the
Regarding intelligence, there was a substantial heterogeneity developmental function was evaluated at nine different time points
among juvenile patients with MDs with mild levels of intellectual (two points before diagnosis, one at the time of diagnosis, and six
disability and a Full Scale Intelligence Quotient (FSIQ) ranging during the post-diagnosis phase) using the developmental quotient
from 64.6 to 100 in non-epileptic children (21, 23). By contrast, (DQ) from the Korean infant and child development test (KICDT),
the cognitive profile appeared to be more affected in individuals which assesses developmental age rather than chronological age.
with seizures and early onset of the disease (23). The overall DQ calculated for these 53 children showed a decline
In the study by Eom et al. (21), which included 70 children, from the pre-diagnostic period to the post-diagnostic periods,
several neuropsychological scales were used but not all measures suggesting an overall deterioration. However, even if declining
were complete for all patients due to the limited functioning of patterns were consistently present, the characteristics of
some individuals. The results for 41 patients showed a significant developmental deterioration were disparate. The authors
level of mental and psychomotor developmental delay. Due to described five phases: 1) pre-diagnostic initial decline phase; 2)
limited function, the intellectual quotient (IQ) measurement was pre-diagnostic accelerated decline phase; 3) post-diagnostic
performed for only 15 individuals and showed mild levels of alleviated phase; 4) post-diagnostic reaccelerated decline phase;
intellectual disability and mild to moderate levels of impairment. and 5) post-diagnostic stagnant phase. This study showed that
Regarding overall development, children with MD showed an diffuse brain atrophy, the clinical rating provided by the physician,

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Riquin et al. Psychiatric Features of Mitochondrial Diseases

and the age at which the first symptoms significantly affected the fact that data were only obtained through clinical observations. The
developmental level and decline. However, no significant effect was description of psychiatric symptoms is also very vague as
noted according to the type of syndrome and the severity of “behavioral difficulties.” Moreover, this study was aimed to
epilepsy, suggesting that these aspects may not directly reflect the analyze children with progressive intellectual and neurological
developmental condition of the patients. The authors stressed some deterioration and not to take into account children with stable
limitations in their study such as a preliminary study with a small conditions. In addition, this study relied on information obtained
number of patients, and the overall cohort that was not followed up from hospital records and on the diagnosis evaluation by
consistently as they reviewed the data retrospectively. pediatricians for children with developmental delay or autistic
Schreiber et al. (20) studied 14 children using the Behavior spectrum disorders. In the study by Eom et al. (21), the patient
Rating Inventory of Executive Function® (BRIEF®) scale to sample size was small and the data were collected retrospectively.
evaluate their behavior and executive functions. Unfortunately, Anglin et al. (9) described cases of adults with MDs that was
the results were not significant because the age of participants in diagnosed many years after the onset of the psychiatric symptoms,
the cohort was too heterogeneous. which occurred during childhood or adolescence. These
observations suggest that psychiatric symptoms could have been
DISCUSSION considered as early signs of the disease and could have led to an
earlier diagnosis, especially if there were linked with other symptoms,
In this systematic review, we found only three articles dealing with such as a cognitive decline (30). The majority of cases in the literature
the psychiatric features of children and adolescents affected by had personal and family histories of multiple medical symptoms,
MDs and only five articles reporting their neuropsychological including muscle weakness, hearing loss, fatigue, dysphagia,
outcomes. These studies were conducted in only five countries constipation, type 2 diabetes mellitus, migraines, and stroke-like
(Table 1) and their methodologies were heterogeneous. For episodes. From a psychiatric perspective, several patients had
example, some studies took all the children in the sample into atypical aspects to their presentation and did not conform to strict
account (19–23) whereas others only analyzed the individuals who DSM-IV diagnostic categories (9).
had psychiatric and behavior issues or had progressive intellectual Beyond mood disorders, some authors described psychotic
and neurologic deterioration (17, 18). In two studies (17, 18), no symptoms in adult populations (9) and Satogami (31) reported a
specific psychometric scales were used and in another (20), data case of Leigh syndrome who survived past adolescence and
were not collected for all individuals in the sample. presented schizophrenia-like symptoms, including persecutory
delusions and auditory hallucinations.
Psychiatric Features In addition, and in connection with analyses of adult
The main psychiatric features affecting children and adolescents populations, Rosebush (10) suggested that there could be a
with MDs include depressive (14.3 to 38.9%) and behavioral difference between sexes in the timing of onset of the psychiatric
disorders, such as withdrawal, social problems, attention deficit, manifestations of inherited MDs, with girls potentially having
sleep disorders, and emotional response (0.9 to 43%). This supports earlier onset of the psychiatric manifestations.
the fact that, even in children, mood disorders can be associated The treatment of psychiatric illness in patients with MDs can be
with abnormal cerebral energy metabolism (19). Koene et al. (17) associated with resistance to treatment and even clinical
stated that depression could affect 14.3% of their study group of deterioration. With some reported exceptions (32, 33), many
patients with MDs in comparison to 3 to 4% of the adolescents from psychotropic agents, including both typical and atypical anti-
the general population. However, in this study, only on children psychotic agents, selective serotonin reuptake inhibitors (SSRIs),
with a history of depression were evaluated and not all the 35 and tricyclic antidepressants, have been found to impair
children of their sample because many children were either too mitochondrial function, generally through inhibition of complex I
young or too severely affected. The authors therefore argued that the of the mitochondrial respiratory chain (10, 34). Nevertheless, it is
depression rate in children with MDs was probably underestimated challenging to delineate whether mitochondrial dysfunction occurs
(17). The prevalence of depression in MDs is similar to other secondary to pharmaceutical treatment or whether it is a result of the
chronic neurodegenerative disorders, although slightly higher, underlying disease process itself (34). Therefore, intensive research is
suggesting that the expression of major depression in these needed in psychiatric disorders to avoid malfunctioning of the
disorders is mostly dependent on the age of onset and clinical mitochondria (35). In addition, as shown before, a very high
severity of the condition and regulated by the coping mechanism of proportion of patients is supposed to receive antiepileptic
the child and the family (25). Koene et al. (17) proposed the medications and could suffer from the side effects of antiepileptic
abnormal energy metabolism of the central nervous system as the treatment (decrease of vigilance, attention disorders, speech
underlying cause of the mood disorder in pediatric patients. difficulties…). In this vulnerable population, additional iatrogenic
Schreiber et al. (20) added that the etiology of depression and symptoms should be carefully looked for and monitored over time.
anxiety in young students with MDs is likely complex and may
involve the biological and genetic substrates of these diseases. It is Neuropsychological Results
also well established that MDs lead to severe disabilities in most Regarding the neuropsychological consequences of MDs in the
pediatric patients, significantly affecting their quality of life (26) and pediatric population, the evaluation of intellectual abilities is not
mood. In fact, having a chronic disease is a risk factor of depression consensual. Overall, the studies showed that many affected children
(27–29). In the study by Verity et al. (18), the limitation is due to the have psychomotor and mental developmental delays (21) but the

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Riquin et al. Psychiatric Features of Mitochondrial Diseases

results of cognitive function evaluations are heterogeneous (20). The executive functions comprise all the processes that help to
The studies analyzed herein have many limitations. In the study by monitor and regulate cognitive processes during complex tasks and
Eom et al. (22), the analyzes were retrospective and included an include planning, self-regulation, behavior organization, cognitive
insufficient number of individuals to draw relevant conclusions. flexibility, working memory, error detection and correction,
Moreover, this study presented only the pre-diagnostic inhibition, sustained attention, and resistance to interference (41).
neuropsychological profiles of the children together with Disorders of executive functions are also linked to anxiety and
comorbidities in their mothers. In addition, direct measurement depression in children and adults (40, 42). Future studies should
of quality of life or long-term follow-up results were not provided. aim to understand the mechanisms underlying clinical symptoms in
The studies suggest deterioration of the DQ with a decline MDs in children and the adolescents by focusing on the analysis of
from the pre-diagnostic through the post-diagnostic periods the psychiatric profile and, more specifically, the anxiety and the
(22). When such deterioration occurs, it may be either very depression and the neuropsychological profile through the
quick and sudden, causing death or leading to a vegetative state, dysexecutive syndrome hypothesis.
or slow and progressive (36). According to Shurtleff et al. (23), an
early diagnosis of MD is essential to try to limit the cognitive loss
with a more effective control of seizures. However, Shurtleff et al.
(23) reported on only intelligence and adaptive functioning
CONCLUSION
without distinction between the different types of MDs. This systematic review shows that children and adolescents
affected with MDs may have psychiatric symptoms and
Future Direction for Research neuropsychological impairment that are similar to those
In the children and adolescents population, the difficulties, and in observed in adults highlighting the importance of considering
particular the psychiatric symptoms, must be identified and them as key clinical signs for the diagnosis of MDs in pediatric
analyzed in a developmental logic. The disorders presented at a practice. It seems of interest to better know the phenotype in
young age will have very different consequences from those children and adolescents and highlights the developmental
presented in adult population, particularly in terms of learning specificities in MD diseases.
abilities, but also quality of life. The issues of care and diagnosis are
therefore particularly not the same as adult population. Future
studies on neuropsychological and psychiatric features of MDs in
children and adolescents should focus on the cognitive profiles and DATA AVAILABILITY STATEMENT
executive functions for which data are lacking. Executive functions
All datasets presented in this study are included in the article/
are cognitive processes that assist the child in adapting their
supplementary material.
behavior to a specific purpose in a specific environment using
reasoning, planning, and problem solving. Frontal-subcortical
circuits are the effector mechanisms of executive functions and
mature progressively throughout childhood and adolescence (37). AUTHOR CONTRIBUTIONS
Executive control function should be evaluated in children with
MDs (20), considering that abnormal presence of intra-cerebral Design of the study: ER, CC, MB, AR. Data analysis: ER, CC, CP,
metabolites, such as lactate, could disrupt the development and the AR. Article writing and revising: ER, PD, CC, MB, CP, PB, DB, AR.
functioning of frontal-subcortical networks (20). Furthermore, the Revision of the manuscript: ER, PD, CC, MB, CP, PB, DB, AR.
presence of these metabolites could also cause psychiatric
symptoms, in particular in zones such as the caudate nucleus, the
cingulate cortex, and the hippocampus with regard to depression ACKNOWLEDGMENTS
and anxiety (38, 39). There is therefore a real interest in studying the
association between neuropsychological aspects, executive The authors thank the University of Angers and the Enjeu[x]
functions, and psychiatric symptoms in children with MDs (40) program for their financial support.

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