Psychiatric symptoms of patients with primary mitochondrial DNA disorders

Inczedy-Farkas Gabriella, Remenyi Viktoria, Gal Aniko, Varga Zsofia, Balla Petra, Udvardy-Meszaros Agnes, Bereznai Benjamin, Molnar, Molnar Maria

Description

The aim of our study was to assess psychiatric symptoms in patients with genetically proven primary mutation of the mitochondrial DNA. Methods 19 adults with known mitochondrial mutation (MT) have been assessed with the Stanford Health Assessment Questionnaire 20-item Disability Index (HAQ-DI), the Symptom Check List-90-Revised (SCL-90-R), the Beck Depression Inventory-Short Form (BDI-SF), the Hamilton Depression Rating Scale (HDRS) and the clinical version of the Structured Clinical Interview for the the DSM-IV (SCID-I and SCID-II) As control, 10 patients with hereditary sensorimotor neuropathy (HN), harboring the peripheral myelin protein-22 (PMP22) mutation were examined with the same tools. Results The two groups did not differ significantly in gender, age or education. Mean HAQ-DI score was 0.82 in the MT (range: 0-1.625) and 0.71 in the HN group (range: 0-1.625). Level of disability between the two groups did not differ significantly ( p = 0.6076). MT patients scored significantly higher on the BDI-SF and HDRS than HN patients (12.85 versus 4.40, p = 0.031, and 15.62 vs 7.30, p = 0.043, respectively). The Global Severity Index (GSI) of SCL-90-R also showed significant difference (1.44 vs 0.46, p = 0.013) as well as the subscales except for somatization. SCID-I interview yielded a variety of mood disorders in both groups. Eight MT patient (42%) had past, 6 (31%) had current, 5 (26%) had both past and current psychiatric diagnosis, yielding a lifetime prevalence of 9/19 (47%) in the MT group. In the HN group, 3 patients had both past and current diagnosis showing a lifetime prevalence of 3/10 (30%) in this group. SCID-II detected personality disorder in 8 MT cases (42%), yielding 3 avoidant, 2 obsessive-compulsive and 3 personality disorder not otherwise specified (NOS) diagnosis. No personality disorder was identified in the HN group. Conclusions Clinicians should be aware of the high prevalence of psychiatric symptoms in patients with mitochondrial mutation which has both etiologic and therapeutic relevance.

Sujets

• Mental disorder
• Dépression

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 6
• Langue: English

Extrait

Inczedy-Farkas
etal
.
BehavioralandBrainFunctions
2012,
8
:9
http://www.behavioralandbrainfunctions.com/content/8/1/9

RESEARCH

OpenAccess

Psychiatricsymptomsofpatientswithprimary
mitochondrialDNAdisorders
GabriellaInczedy-Farkas
1
,ViktoriaRemenyi
1
,AnikoGal
1
,ZsofiaVarga
2
,PetraBalla
3
,AgnesUdvardy-Meszaros
4
,
BenjaminBereznai
1
andMariaJuditMolnar
1*

Abstract
Background:
Theaimofourstudywastoassesspsychiatricsymptomsinpatientswithgeneticallyprovenprimary
mutationofthemitochondrialDNA.
Methods:
19adultswithknownmitochondrialmutation(MT)havebeenassessedwiththeStanfordHealth
AssessmentQuestionnaire20-itemDisabilityIndex(HAQ-DI),theSymptomCheckList-90-Revised(SCL-90-R),the
BeckDepressionInventory-ShortForm(BDI-SF),theHamiltonDepressionRatingScale(HDRS)andtheclinical
versionoftheStructuredClinicalInterviewforthetheDSM-IV(SCID-IandSCID-II)Ascontrol,10patientswith
hereditarysensorimotorneuropathy(HN),harboringtheperipheralmyelinprotein-22(PMP22)mutationwere
examinedwiththesametools.
Results:
Thetwogroupsdidnotdiffersignificantlyingender,ageoreducation.MeanHAQ-DIscorewas0.82in
theMT(range:0-1.625)and0.71intheHNgroup(range:0-1.625).Levelofdisabilitybetweenthetwogroupsdid
notdiffersignificantly(
p
=0.6076).MTpatientsscoredsignificantlyhigherontheBDI-SFandHDRSthanHN
patients(12.85versus4.40,
p
=0.031,and15.62vs7.30,
p
=0.043,respectively).TheGlobalSeverityIndex(GSI)of
SCL-90-Ralsoshowedsignificantdifference(1.44vs0.46,
p
=0.013)aswellasthesubscalesexceptfor
somatization.SCID-Iinterviewyieldedavarietyofmooddisordersinbothgroups.EightMTpatient(42%)hadpast,
6(31%)hadcurrent,5(26%)hadbothpastandcurrentpsychiatricdiagnosis,yieldingalifetimeprevalenceof9/19
(47%)intheMTgroup.IntheHNgroup,3patientshadbothpastandcurrentdiagnosisshowingalifetime
prevalenceof3/10(30%)inthisgroup.SCID-IIdetectedpersonalitydisorderin8MTcases(42%),yielding3
avoidant,2obsessive-compulsiveand3personalitydisordernototherwisespecified(NOS)diagnosis.No
personalitydisorderwasidentifiedintheHNgroup.
Conclusions:
Cliniciansshouldbeawareofthehighprevalenceofpsychiatricsymptomsinpatientswith
mitochondrialmutationwhichhasbothetiologicandtherapeuticrelevance.
Keywords:
Mitochondrialmutation,Mentaldisorders,Depression

Background
mutantandwildtypemtDNA)andthresholdlevel(the
Mitochondrialdisordersaremetabolicconditionswithproportionofmutatedmitochondriarequiredtocause
chronicdeteriorationandmultipleorganinvolvement.dysfunction)variesfromtissuetotissue,resultingina
PrimarymutationsofthemitochondrialDNA(mtDNA)widevarietyofclinicalphenotypes[1].Somepresenta-
areinheritedmaternallywhilemitochondrialdiseasestionsofmtDNAmutationsareclusteredintosyndromes
duetomutationsinnuclearDNAaretransmittedassuchasMELAS(mitochondrialencephalomyopathylac-
mendeliantraits.Theratioofheteroplasmy(ratiooftheticacidosisandstroke-likeepisodes)orCPEO(chronic
progressiveexternalophthalmoplegia),butmostofthem
showgreatheterogeneity.Inthebackgroundofthelate
*Correspondence:[e-mail]
1
ClinicalandResearchCenterforMolecularNeurology,Departmentof
onsetandtheprogressionofsomemtDNAdisorders
Neurology,SemmelweisUniversity,1083BudapestTöm
ő
Str.25-29.,
thereisgoodevidenceforincreasesintheproportionof
Budapest,Hungary
somepathogenicmutations-includingpathogeniclarge
Fulllistofauthorinformationisavailableattheendofthearticle
©2012Inczedy-Farkasetal;BioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons
AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin
anymedium,providedtheoriginalworkisproperlycited.

Inczedy-Farkas
etal
.
BehavioralandBrainFunctions
2012,
8
:9
http://www.behavioralandbrainfunctions.com/content/8/1/9

scaledeletionsandtRNApointmutations-withagein
skeletalmuscle,howeverthisisnotageneralphenom-
enon[2].TheinabilitytoincreaseATPproductionat
timesofhigherenergydemandexplainswhyclinical
symptomatologytypicallyoccursinassociationwith
physiological[3]orpsychological[4]stressors.
Braintissuedependstoalargeextentonmitochon-
drialfunctionforitsmetabolism,includingthemainte-
nanceofthetransmembranepotential[5],calcium
homeostasis[6],signaltransduction[7]andsynaptic
plasticity[8].Therefore,impairmentsinoxidativephos-
phorylationtendtomanifestinneurologic,psychiatric
orneuropsychologicsymptomatology[9].
Thereisagrowingnumberofevidencefortheasso-
ciationofmitochondrialdysfunctionandpsychiatricill-
nessesbothinvitroandinvivo.Morphologicalchanges
[10],alteredcellularlocation[11],decreasednumber
[12]andfunction[13]ofmitochondriahasbeenfound
indiversepsychiatricconditions.Downregulationof
mtDNAgenes[14,15],reducedexpressionprofilesof
electrontransportchainsubunits[3,15],impaired
defenseagainstoxidativestress[16]andanoveralldys-
functionofbrainmetabolismatmitochondriallevel[17]
hasalsobeendescribedinassociationwithpsychiatric
disorders.
Whilemanycasereportsuggeststheneweraof
‘
mito-
chondrialpsychiatry
’
[18],aPubMedsearchyieldedonly
onestudywherepsychiatricassessmenthasbeencarried
outsystematicallywithanadultpatientpopulation
selectedbythepresenceofmajorandminorcriteriaof
mitochondrialdisease[19].Theaimofourstudywasto
assesspsychiatricsymptomsinacohortofpatientswith
geneticallyprovenprimarymtDNAmutationswhichto
ourknowledgehasnotyetbeenperformed.
Methods
Patients
NineteenpatientswithprimarymutationofthemtDNA
wereevaluated(MTpatients,Patient1-19,13female,6
male).Meanageforthe13probands,includedinthe
statisticalanalysiswas34±8.43years(male:
μ
=27.25,
s
=6.8;female:
μ
=36.66,
s
=7.65),averageyearsof
educationwas12.84±1.21years(male:
μ
=13.25,
s
=
1.5;female:
μ
=12.66,
s
=1.12).Ascontrol,10patients
(HNpatients,Patient20-29,4female,6male,meanage:
40±10.99,averageyearsofeducation:14.2±3.85
years)withhereditarysensorimotorneuropathywere
examined.Diagnosiswasbasedonclinicalfeaturessup-
portedbythepresenceofprimarymtDNAmutationsin
MTpatientsandbythepresenceofthePMP22gene
mutationinHNpatients.
AllparticipantsofthestudywereCaucasianandvis-
itedtheclinicwithin1year.Written,informedconsent
wasobtainedfromallparticipants.Thisstudywas

Page2of9

carriedoutaccordingtotheHelsinkiDeclarationand
wasapprovedbytheResearchandEthicscommitteeof
SemmelweisUniversity.
Neurologicalandpsychiatricassessment
NeurologicalassessmentwascarriedoutwithallMT
andHNpatients.Functionalabilitywasassessedusing
theHungarianvalidatedversionoftheStanfordHealth
AssessmentQuestionnaire20-itemDisabilityIndex
(HAQ-DI)[20].Detailedpsychiatricassessmentusedthe
SymptomChecklist-90-Revised(SCL-90-R)[21],the
BeckDepressionInventory-ShortForm(BDI-SF)[22]
selfreportinventoriesaswellastheclinician-adminis-
tered21-itemHamiltonDepressionRatingScale
(HDRS)[23]andtheclinicalversionoftheStructured
ClinicalInterviewfortheDSM-IVaxis-I(SCID-I)[24]
andaxis-IIdisorders(SCID-II)[25].
TheSCL-90-Rhelpsevaluateabroadrangeofpsycho-
pathologicalsymptoms.Ityields9scoresofprimary
symptomdimensions(somatization,obsession-compul-
sion,interpersonalsensitivity,depression,anxiety,
hostility,phobicanxiety,paranoidideationandpsychoti-
cism),anadditionalitemsubscalereferringtosleepand
memoryproblemsandthearithmeticmeanofallofthe
above,theglobalseverityindex(GSI).TheBDI-SFisa
13-itemquestionnairescoredona4-pointscale,from0
to3,withoverallscoresrangingfrom0to39.TheBDI-
SFhasbeenfoundtohaveagoodcorrelationwiththe
standard21-itemBDI(r=0.96,
p
=0.001)andrelates
theclinicaldepth-of-depression(r=0.61)[22].The
emphasisofthe21-itemHDRSisonmelancholicand
physicalsymptomsofdepression.Inordertocontrolfor
theconfoundingeffectofcognitiveimpairment,we
includedpatientswithanIQof70andabove,as
assessedbytheHungarianvalidatedversionofthe
WechslerAdultIntelligenceScale(WAIS-III-Rversion).
Scalesandinterviewswereadministeredbytrainedclini-
cians.Patientchartswerealsoreviewed.
Statisticalanalysis
TheShapiro-Wilktestwasemployedtotestfornormal-
ityofthedata(datanotshown).Mann-Whitney
U
-test
wasperformed,p-valueswerecorrectedbytheHolm-
Bonferronimethod.Alltestsweretwotailedand
p
values
≤
0.05weredeemedsignificant.Differences
betweenthetwogroupswereassessedusingChi-Square
test(gender)and
t
-test(ageandeducation).SCL-90-R
wasanalysedwithSASSystemforWindows(Release
9.1TSLevel1M3,StatisticalAnalysisSystem,SAS-
InstituteUSA).CorrelationoftotalscoresinGSI,BDI
andHDRSwithHAQ-DIinbothgroupswasevaluated
usingPearson
’
scorrelation.Independentvariablescould
beobtainedselectingonlytheproband(indexcase)
fromeachfamilyfromthecohortofMTpatients.HN

Inczedy-Farkas
etal
.
BehavioralandBrainFunctions
2012,
8
:9
http://www.behavioralandbrainfunctions.com/content/8/1/9

patientswereallunrelated,statisticswerethusper-
formedusingdatafrom13MT(Patient1,2,3,5,8,10,
11,13,14,15,16,18,19)and10HNpatients.
Geneticanalysis
DNAwa