Table 1.

Main results of the studies included in the literature review.

References, country of origin	Characteristics of the sample	Tests used	Results
Koene, (17), The Netherlands	35 children Inclusion criteria for MD: mutation in a mitochondrial (17) or in a nuclear (13) gene. 5 children with suspected depression were analyzed Age range: 2–18 years old, mean: 8.7 years old	Depression diagnosis (DSM-IV criteria) or HDRS for children older than 14 years old and/or Zung depression scale Holmes and Rahe Social Readjustment Rating Scale (Life Stress Event Scale)	Major depression (n=5; 14.3%) Psychotic symptoms (n=1; 2.9%) Life stress event score: increased susceptibility (>50%) in 3 patients.
Verity, (18), UK	2,493 children with PIND 112 (4, 5) children with MD Inclusion criteria for MD diagnosis: 112 suspected MD in the group of patients with PIND by a group of experts. Lactate levels increased in the blood and or CSF (n=87); 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	No tests used Data were obtained from medical clinical observations	Developmental delay (n=43; 38.4%) Cognitive decline (n=1; 0.9%) Psychiatric symptoms: Autistic spectrum (n=3; 2.7%) Behavioral difficulties (n=1; 0.9%)
Morava, (19), The Netherlands	18 children who exhibit no developmental delays (individuals with IQ<70 were excluded) Inclusion criteria for MD: A clinical and biochemical diagnosis of OXPHOS disease for more than 1 year; muscle disease with developmental delay and variable systemic involvement. Control group: 18 children with inborn errors of metabolism 19 children with Sotos syndrome (a Mendelian disorder with non-progressive ID)	WISC (version not provided) CBCL -Anxious/depressed (1–18 years old), - Withdrawn/depressed (only in CBCL 6–18 years old) - Affective disorders (6–18 years old)/affective problems (1–5 years old). Comparison to American norms (sub-scale score of <65 is normal, 65–69 scores are borderline, and scores of >70 indicate a clinical problem)	Depressive behavior (n=7; 38.9%) CBCL, in the MD group: Compared to norms: Higher rate of withdrawn and depressive behavior (p = 0.0001) Higher levels of depressive behavior (p = 0.017) Compared to inborn errors of metabolism group: Anxious, depressive behavior in MD disorder: ns Withdrawn depressed behavior increased (p = 0.002) in the MD group 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), USA	14 children were included Inclusion criteria for MD: selection via a website then parental questionnaire about how the MD was diagnosed (i.e. mutations identified or strongly suspected through muscle biopsy and/or blood test, in addition to clinical symptoms). Unspecified MD (n=5) Age range of children: not provided 7 male and 7 female adolescents/young adults. 5 of the subjects were between the ages of 19 and 21	BASC-2, for ages 12 to 21 years old BRIEF for older children/adolescents aged 13 to 18 years old or adult report for patients older than 18 years	Attitude to school associated with depression (p < 0.001), anxiety (P < 0.01), and internalizing problems (P < 0.01). Students mothers rated somatization more than a standard deviation above the mean (self-report: mean ¼ 62.21, SE ¼ 3.32; parent report: mean ¼ 78.86, SE ¼ 2.97). BRIEF results were not analyzed because of the age heterogeneity in the cohort
Eom, (21), South Korea	70 children Age at diagnosis: mean: 1.78 ± 2.52 years old Inclusion criteria for MD: biochemical enzyme assay of muscle tissues and modified mitochondrial diseases criteria (MDC) Inclusion criteria for nonspecific MD: no classical clinical symptoms, biochemical results, or mitochondrial DNA (mtDNA) deletions/duplications/point mutations that conform to known and established mitochondrial syndromes. 16 Leigh syndrome, 3 MELAS, 51 nonspecific	BSID-II WPPSI (Korean version) WISC-III (Korean version) Children’s adaptive Function: Social Maturity Scale (Korean version); Parent responses for 99-item CBCL (Korean version) for children 1.5–5 years of age or 118-item CBCL for children and adolescents 6–18 years of age Parental assessment (PSI; BDI for mothers)	Development (n=41): mental development = 52.9 ± 11.3 (=significant level of delay); psychomotor development = 52.1 ± 10.5 (=significant level of delay) IQ (n=15): FSIQ = 64.6 ± 21.8 (=mild levels of intellectual disability); VIQ=70.5 ± 19.2 (=mild levels of intellectual disability); PIQ = 58.6 ± 16.9 (=mild to moderate levels of impairment) Daily living function (n=54); social quotient = 50.2 ± 31.3 (significant impairments in adaptive function) 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 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 Korea	53 children Inclusion criteria for MD: biochemical enzyme assay of muscle tissue samples and meeting the modified MDC 11 Leigh syndrome, 2 MELAS, 40 nonspecific Age at diagnosis: mean: 3.12 ± 2.49 years old; lead time to diagnosis: 1.09 ± 1.15 years old (range, 0.6–1.46 years old)	KICDT DQ = (developmental age/chronological age) × 100] First visit prior to diagnosis, second visit prior to diagnosis, one-time diagnostic evaluation, and six post-diagnostic developmental evaluations	Pre-diagnosis evaluation (n=18): DQ = 60.4 ± 34.4 Diagnosis (n=37): DQ = 31.9 ± 25.8 Post-diagnosis (1 year after) (n=19): DQ = 27.8 ± 23.3
Shurtleff, (23), USA	49 children Age range: 61–250 months old Inclusion criteria for MD: biochemical testing, muscle biopsy with electron transport chain enzyme assay, and/or gene sequencing of mtDNA or nuclear genes involved in mitochondrial disease. When available, molecular genetic testing that confirmed pathological variants in either nuclear or mtDNA-encoded genes were obtained from Clinical Laboratory Improvement Amendments (CLIA) approved laboratories. All patients met clinical criteria of modified Walker criteria for diagnosing mitochondrial disease	WPPSI-III: 2½ to 7 years old WISC-III or -IV: 6 to 16 years old WAIS-III or -IV: 16 years of age and older FSIQ, VIQ, PIQ WMI or FFD PSI Vineland Adaptive Behavior Scales, 2nd Edition	WISC-III or –IV (n=40) Vineland (n=9) = 85 [interquartile range (IQR): 50, 102] Group without seizures: FSIQ=100 (IQR: 86, 109), PIQ =100 (IQR 94, 112) Group with seizures: FSIQ = 67 (IQR: 49.5, 89), PIQ = 63 (IQR 54, 84) Statistical and clinical difference (Δ=33; 95% CI: 9, 52). Adaptive function measure = 43 (IQR: 37, 50) (patients with intractable epilepsy only)

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.