ARTICLE OPEN ACCESS

Mitochondrial diseases in North AmericaAn analysis of the NAMDC Registry

Emanuele Barca MD PhD Yuelin Long MS Victoria Cooley MS Robert Schoenaker MD BS

Valentina Emmanuele MD PhD Salvatore DiMauro MD Bruce H Cohen MD Amel Karaa MD

Georgirene D Vladutiu PhD Richard Haas MBBChir Johan LK Van Hove MD PhD Fernando Scaglia MD

Sumit Parikh MD Jirair K Bedoyan MD PhD Susanne D DeBrosse MD Ralitza H Gavrilova MD

Russell P Saneto DO PhD Gregory M Enns MBChB Peter W Stacpoole MD PhD Jaya Ganesh MD

Austin Larson MD Zarazuela Zolkipli-Cunningham MD Marni J Falk MD Amy C Goldstein MD

Mark Tarnopolsky MD PhD Andrea Gropman MD Kathryn Camp MS RD Danuta Krotoski PhD

Kristin Engelstad MS Xiomara Q Rosales MD Joshua Kriger MS Johnston Grier MS Richard Buchsbaum

John LP Thompson PhD and Michio Hirano MD

Neurol Genet 20206e402 doi101212NXG0000000000000402

Correspondence

Dr Hirano

mh29columbiaedu

AbstractObjectiveTo describe clinical biochemical and genetic features of participants with mitochondrial diseases(MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry

MethodsThis cross-sectional multicenter retrospective database analysis evaluates the phenotypic andmolecular characteristics of participants enrolled in the NAMDC Registry from September 2011 toDecember 2018 The NAMDC is a network of 17 centers with expertise in MtDs and includes bothadult and pediatric specialists

ResultsOne thousand four hundred ten of 1553 participants had sufficient clinical data for analysis For thisstudy we included only participants with molecular genetic diagnoses (n = 666) Age at onsetranged from infancy to adulthood The most common diagnosis was multisystemic disorder (113participants) and only a minority of participants were diagnosed with a classical mitochondrialsyndrome The most frequent classical syndromes were Leigh syndrome (97 individuals) andmitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (71 individuals)Pathogenic variants in the mitochondrial DNA were more frequently observed (414 participants)than pathogenic nuclear gene variants (252 participants) Pathogenic variants in 65 nuclear geneswere identified with POLG1 and PDHA1 being the most commonly affected Pathogenic variants in38 genes were reported only in single participants

ConclusionsThe NAMDC Registry data confirm the high variability of clinical biochemical and genetic featuresof participants with MtDs This study serves as an important resource for future enhancement ofMtD research and clinical care by providing the first comprehensive description of participant withMtD in North America

From the Department of Neurology (EB VE SD KE XQR MH) Columbia University Medical Center New York Department of Biostatistics (YL VC JK J Grier RB JLPT) MailmanSchool of Public Health Columbia University New York Radboudumc (RS) Nijmegen The Netherlands Department of Pediatrics (BHC) Northeast Ohio Medical University and AkronChildrenrsquos Hospital Genetics Unit (AK) Massachusetts General Hospital Boston Department of Pediatrics (GDV) State University of New York at Buffalo Departments of Neurosciences andPediatrics (RH) University of California at San Diego Department of Pediatrics (JLKVH AL) University of Colorado School of Medicine Aurora Department of Molecular and Human Genetics(FS) Baylor College of Medicine Houston TX Texas Childrenrsquos Hospital (FS) Houston Joint BCM-CUHK Center of Medical Genetics (FS) Prince of Wales Hospital ShaTin New Territories HongKong Department of Neurology (SP) Cleveland Clinic OH Departments of Genetics and Genome Sciences and Pediatrics (JKB SDD) and Center for Human Genetics University HospitalsClevelandMedical Center CaseWesternReserveUniversityOHDepartmentsofNeurologyandClinicalGenomics (RHG)MayoClinic RochesterMNDepartmentofNeurology (RPS) Universityof Washington Seattle Childrenrsquos Hospital Department of Pediatrics (GME) Stanford University Palo Alto CA Department of Medicine (PWS) University of Florida at Gainesville Genetics andGenomic Sciences at the Icahn School ofMedicine atMount Sinai (J Ganesh) NewYorkMitochondrialMedicine Frontier Program (ZZ-CMJF ACG) Division of HumanGenetics The ChildrenrsquosHospitalofPhiladelphiaandUniversityofPennsylvaniaPerelmanSchoolofMedicineUniversityofPennsylvaniaPerelmanSchoolofMedicine (ZZ-C) PhiladelphiaDepartmentofNeurology (MT)McMasters University Toronto Ontario Canada Department of Neurology (AG) Childrenrsquos National Health Network Washington DC Office of Dietary Supplements (KC) National Institutes ofHealth Bethesda MD and Eunice Kennedy Shriver National Institute of Child Health and Human Development (DK) National Institutes of Health Bethesda MD

Go to NeurologyorgNG for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by NIH U54 NS078059

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Mitochondria are the organelles that generate cellular energy(adenosine triphosphate) via oxidative phosphorylation(OxPhos) OxPhos is an elaborate multiprotein machinecomposed of a series of enzyme complexes embedded in theinner mitochondrial membrane (complex IndashV)1 Becausevirtually all tissues require mitochondria to function mito-chondrial dysfunction manifests commonly as multisystemdisorders with frequent involvement of high-energy demandtissues such as brain muscle and heart2 The OxPhos systemconsists of 85 subunits and is under the control of 2 genomesthe nuclear DNA (nDNA) and mitochondrial DNA(mtDNA) Mitochondrial diseases (MtDs) can arise due topathogenic variants in either of the 2 genomes3 Because ofthe genetic complexity and themultiple biochemical functionsof these organelles MtDs are phenotypically and geneticallyheterogeneous Because of this vast diversity these disordersare challenging to diagnose manage clinically and investigatescientifically Epidemiologically MtDs are considered rarediseases but among rare disorders they are relatively fre-quent with an overall estimated prevalence of 1151000003

In totality MtDs represent the most prevalent group ofinherited neurologic disorders4 Disease registries constitutea cornerstone of MtDs patient care because they help to es-tablish a reliable picture of the distribution and characteristicsof the participants focus resources and gather accurate datafor efficient clinical mechanistic studies and therapeutic trials5

This article reviews the spectrum of clinical biochemical andmolecular genetic features of MtD participants enrolled in theNorth American Mitochondrial Disease Consortium(NAMDC) Registry (hereafter referred to as the Registry)

MethodsStandard protocol approvals registrationsand patient consentsThe NAMDC is an NIH-funded collaborative effort of 17North American medical centers which work in close part-nership with the United Mitochondrial Disease Foundationand other patient advocacy groups Since 2011 the NAMDChas maintained a Registry that has collected clinical bio-chemical histologic and molecular genetic data on partic-ipants with MtDs The Registry protocol was approved by theNIH and the NAMDC central Institutional Review Board(IRB) with local context review at each NAMDC site(NCT01694940) To enroll participants had to visit an ex-perienced clinician at one of the sites for a review of medical

history physical examination and laboratory tests and pro-vide written consent using IRB-approved forms Cliniciansinput data using a secure web-based data entry system Datawere collected through December 1 2018

Data availabilityThe NAMDC Clinical Registry data are stored in a securedatabase and are available to other investigators on sub-mission of a data use application and approval by theNAMDC Data Use Committee

Clinical diagnosisParticipants are enrolled in the Registry based on theNAMDC site investigatorsrsquo clinical diagnoses of MtDs Di-agnoses are based on established and published clinicalcriteria67 Twenty-five different clinical diagnoses werecoded 15 classical mitochondrial clinical syndromes and 8with an association of symptoms and signs commonly ob-served in mitochondrial participants (table 1)8ndash12 Some ofthe syndromes require an association of clinical and radiologicfindings eg for the diagnosis of leukoencephalopathy whitematter lesions evident on brain MRI are typically associatedwith cognitive impairment long-tract signs or both En-cephalopathy was defined by the presence of dementia seiz-ures corticospinal tract dysfunction movement disorders orcombinations of these manifestations due to cerebralpathology

Two nonspecific groups of participants with complex clinicalmanifestations that do not fall in any of the other categoriesare (1) multisystemic and (2) other clinical disorders Formultisystemic disease clinical manifestations must involve atleast 3 organs with a progressive clinical course that does nototherwise conform to a classical phenotype Participantswithout clinical manifestations were classified as asymptom-atic carriers which are not included in this analysis

Clinical biochemical and laboratory dataClinical laboratory and biochemical data were collecteddeficiencies of OxPhos activities coenzyme Q10 (CoQ10)pyruvate dehydrogenase complex (PDC) or thymidinephosphorylase (TP)

Molecular geneticsnDNA pathogenic variants as well as mtDNA pathogenic pointvariants single andmultiple large-scale deletions and depletionwere recorded All genetic variants in the database were also

GlossaryCoQ10 = coenzyme Q10 COX = cytochrome c oxidase cPEO = chronic progressive external ophthalmoplegia IRB =institutional review board LS = Leigh syndrome LHON = Leber hereditary optic neuropathy MELAS = mitochondrialencephalomyopathy lactic acidosis and stroke-like episodes MERRF = myoclonus epilepsy with ragged red fibers MtD =mitochondrial disease mtDNA = mitochondrial DNA NAMDC = North American Mitochondrial Disease ConsortiumnDNA = nuclear DNA OxPhos = oxidative phosphorylation PDC = pyruvate dehydrogenase complex SLE = stroke-likeepisode TP = thymidine phosphorylase

2 Neurology Genetics | Volume 6 Number 2 | April 2020 NeurologyorgNG

assessed for pathogenicity using MseqDR (mseqdrorg) andvariants in the POLG1 gene were assessed using theNIH-basedPOLG1 mutation database (toolsniehsnihgovpolg)

Statistical analysisThe Fisher exact test (SAS 94 SAS Institute Inc Cary NC)was used in the comparisons of participants with differentgenetic features and Holm adjustment (R 351 Bell Labo-ratories New Providence NJ) for multiple comparisons

Table 1 Demographic clinical biochemical and geneticcharacteristics of the North AmericanMitochondrial Disease Consortium ClinicalRegistry participants (N = 666)

Characteristic (participants) Frequency ()

Sex

Female 380 (571)

Male 285 (428)

Missing 1 (02)

Racial composition

White 567 (851)

Asian 24 (36)

More than one 22 (33)

BlackAfrican American 19 (29)

Other 33 (50)

Missing 1 (02)

Age at onset

lt2 y 198 (297)

ge2 to lt5 y 83 (125)

ge5 to lt12 y 76 (114)

ge12 to lt18 y 52 (78)

ge18 y 180 (270)

Missing 77 (116)

Clinical syndrome

Multisystemic syndrome 113 (170)

LSa 97 (146)

Other clinical syndrome 75 (113)

MELASa 71 (107)

Encephalopathy 38 (57)

cPEO+a 37 (56)

Encephalomyopathy 32 (48)

LHONa 28 (42)

Myopathy 25 (38)

SANDOa 19 (29)

cPEOa 18 (27)

KSSa 17 (26)

MIDDa 16 (24)

Alpers syndromea 15 (23)

MERRFa 13 (20)

Pearson syndromea 10 (15)

MNGIEa 10 (15)

Table 1 Demographic clinical biochemical and geneticcharacteristics of the North AmericanMitochondrial Disease Consortium ClinicalRegistry participants (N = 666) (continued)

Characteristic (participants) Frequency ()

NARPa 8 (12)

Hepatocerebral syndrome 6 (09)

Maternal inherited deafness 5 (08)

Cardiomyopathy 5 (08)

Leukoencephalopathy 4 (06)

RIM with COX deficiencya 2 (03)

Barth syndromea 2 (03)

Biochemical deficiencies (114 recordednot recorded in 552 [829])

Isolated complex I 18 (27)

Isolated complex II 1 (02)

Isolated complex III 1 (02)

Isolated complex IV 14 (21)

Isolated complex V 5 (08)

Combined RCE complexes 21 (32)

CoQ10 2 (03)

TP 8 (12)

PDC 44 (66)

Molecular genetic information

mtDNA pathogenic variants 414 (622)

nDNA pathogenic variants 252 (378)

Abbreviations CoQ10 = coenzyme Q10 cPEO = chronic progressive externalophthalmoplegia KSS = Kearns-Sayre syndrome LHON = Leber hereditaryoptic neuropathy LS = Leigh syndrome MELAS = mitochondrial encepha-lomyopathy lactic acidosis and stroke-like episodes MERRF = myoclonusepilepsy with ragged red fibers MIDD = maternal inherited diabetes anddeafness also known as diabetes and deafness DAD MNGIE = mitochon-drial neurogastrointestinal encephalopathy mtDNA = mitochondrial DNANARP = neuropathy ataxia and retinitis pigmentosa nDNA = nuclear DNAPDC = pyruvate dehydrogenase complex RCE = respiratory chain enzymeRIM with COX deficiency = reversible infantile myopathy with cytochrome coxidase deficiency SANDO = sensory ataxic neuropathy with dysarthria andophthalmoparesis TP = thymidine phosphorylaseMultisystemic syndrome is defined by clinical manifestations involving atleast 3 organs Other clinical syndrome is defined as a disorder not con-forming to one of the classical syndromes or multisystemic syndromea Classical syndromes

NeurologyorgNG Neurology Genetics | Volume 6 Number 2 | April 2020 3

ResultsOf the 1533 total participants enrolled in the Registry (Jan-uary 2011ndashDecember 2018) 1410 had complete data onclinical manifestations biochemistry and genetics Geneticdiagnosis was available for 722 participants After the exclu-sion of 56 asymptomatic carriers 666 genetically diagnosedsymptomatic individuals remained for analysis (table 1)

Demographic characteristics are summarized in table 1 Age atdisease onset showed a bimodal distribution with peaks belowage 2 years and in adulthood (ge18 years) The most frequentclassical diagnoses were Leigh syndrome (LS) (97 partic-ipants) mitochondrial encephalomyopathy lactic acidosisand stroke-like episodes (MELAS) (71 participants) chronicprogressive external ophthalmoplegia (cPEO) and cPEOwithother organ-system manifestations (beside skeletal muscleinvolvement) (cPEO+) (55 participants) and Leber heredi-tary optic neuropathy (LHON) (28 participants) (table 1) Alarge proportion of participants had nonspecific disease syn-dromes (298 participants) These nonspecific disorders in-cluded multisystemic (113 participants) and other clinicalsyndromes (75 participants) (table 1) The prevalence ofnonspecific diagnoses was high in both the pediatric (lt18years) and adult population (ge18 years)

Classical mitochondrial syndromes

Leigh syndromeNinety-seven participants had LS Disease onset was seenpredominantly in infancy (lt2 years in 55 participants) (table2) The most frequent manifestations were developmentaldelay (84 participants) followed by developmental regression(42 participants) Other neurologic manifestations includedataxia (44 participants) dystonia (44 participants) and seiz-ures (38 participants) Skeletal muscle (73 participants) andthe gastrointestinal tract (26 participants) were also com-monly affected (table 2) Brain imaging showed bilateral basalganglia involvement in 55 participants andor lesions of thebrainstem (27 participants) Variants in both nuclear andmitochondrial genomes were identified 52 mtDNA and 45nDNA pathogenic variants in 21 different nuclear genes(figure 1 table 2)

Myoclonus epilepsy with ragged red fibersThirteen participants had a clinical diagnosis of myoclonusepilepsy with ragged red fibers (MERRF) Six had childhoodonset Developmental problems were reported in 5 partic-ipants (table 2) and neuropathy in 4 (table e-2 linkslwwcomNXGA226) Six participants had multiple lipomatosisAll participants had a pathogenic variant in the mitochondrialMTTK gene with the prototypical m8344AgtG pathogenicvariant (figure 1) in 9 of them

Mitochondrial encephalomyopathy lactic acidosisand stroke-like episodesSeventy-one participants (28 males 42 females and 1 un-known) had MELAS The majority had disease onset in

adulthood (table 2) Apart from key clinical findings in CNSand skeletal muscle involvement heart abnormalities wererecorded (21 participants) with cardiac arrhythmias being themost prevalent (table 2 table e-1 linkslwwcomNXGA226) Gastrointestinal tract manifestations and diabetesmellitus were also commonly reported (table 2 table e-2) Inaddition to stroke-like episodes (SLEs) the most commonCNS manifestations were seizures migraine and ataxia(tables e-1 and e-2) Thirty-nine participants had constitu-tional symptoms (short stature and low body mass index)(table 2) Genetically m3243AgtG in the mitochondrialMTTL1 gene was the most frequently observed pathogenicvariant In addition 10 of 69 participants (145) with POLGpathogenic variants manifested SLEs but only 1 was di-agnosed with MELAS

Chronic progressive external ophthalmoplegiaFifty-five participants were diagnosed with cPEOcPEO+ (18cPEO and 37 cPEO+) The majority were adults (table 2)Muscle involvement in cPEO was not confined to the ex-trinsic ocular muscles as skeletal myopathy (10 participants)and dysphagia (4 participants) were also observed Partic-ipants with cPEO+ frequently had CNS symptoms (24 par-ticipants) with ataxia and hearing loss being the mostprevalent (table e-1 linkslwwcomNXGA226) BothmtDNA and nDNA pathogenic variants have been observed(figure 1) Variants in mtDNA were more frequent thannDNA in both groups (14 cPEO participants and 23 cPEO+participants) Single large-scale mtDNA deletions werepresent in 12 participants with cPEO and 15 with cPEO+Although infrequently identified nDNA pathogenic variantswere more common in the cPEO+ (11 participants) groupthe majority had variants in POLG1 (6 cPEO+ and 2 cPEO)

Leber hereditary optic neuropathyTwenty-eight participants were diagnosed with LHON 23were males Involvement of other organ-systems was com-monly reported The most frequent extraocular affected organwas the CNS (18 participants) with a constellation of differentmanifestations including seizures (3 participants) migraineheadaches (3 participants) hearing loss (2 participants) andataxia (1 participant) (table e-1 linkslwwcomNXGA226)Of 28 participants with a genetic diagnosis only 1 hada pathogenic nDNA variant that participant was mis-diagnosed before molecular genetic testing

Biochemical diagnosisBiochemical deficiencies were recorded in 114 participants(table 1) Data on OxPhos activity were available in 666individuals of which defects were identified in 60 Combinedrespiratory enzyme deficiencies were the most common ab-normalities (21 participants) Isolated deficiencies in complexI or complex IV (cytochrome c oxidase [COX]) were themost common mono-enzymopathies Disease onset was lt2years in the majority of participants except for individualswith COX deficiency whose onset spanned the entire agespectrum (table 3) Molecular analysis revealed that isolated

4 Neurology Genetics | Volume 6 Number 2 | April 2020 NeurologyorgNG

complex I participants frequently had pathogenic variants inmtDNA (1518 participants) whereas participants with COXdeficiency commonly had nDNA pathogenic variants (914participants) (table 3) In both groups the most frequentclinical diagnosis was LS Participants with combined OxPhosdeficiencies presented with a diverse spectrum of clinical di-agnoses with LS being the most common (table 3)

PDC activity was assessed in 213 participants among whomdefects were identified in 44 (28 females and 16males) Age at

onset was lt2 years in 38 PDC deficiencyndashassociated pre-sentations were diverse and included encephalopathy (1444318) LS (944 205) encephalomyopathy (444 91)multisystemic syndrome (244 45) and cardiomyopathy(144 23) (table 3) Forty-two participants had pathogenicvariants in nDNA predominantly in PDHA1 (35 partic-ipants) CoQ10 deficiency was diagnosed in only 2 partic-ipants (of 220 tested) TP activity was reduced in 8participants of over 214 tested all had pathogenic variants inTYMP

Table 2 Demographic clinical and genetic characteristics of the 264 North AmericanMitochondrial Disease ConsortiumClinical Registry participants with canonical syndromes

LS MELAS cPEOcPEO+ LHON MERRF

N = 97 N = 71 N = 55 N = 28 N = 13

Frequency () Frequency () Frequency () Frequency () Frequency ()

Sexa

Female 48 (495) 42 (600) 37 (673) 5 (179) 7 (538)

Male 49 (505) 28 (400) 18 (327) 23 (821) 6 (462)

Missing mdash 1 mdash mdash mdash

Age at onseta

lt2 y 55 (618) 2 (31) mdash 1 (37) 4 (444)

ge2 to lt5 y 23 (258) 1 (15) 4 (91) 1 (37) mdash

ge5 to lt12 y 7 (79) 18 (277) 8 (182) 4 (148) 2 (222)

ge12 to lt18 y mdash 11 (169) 8 (182) 4 (148) mdash

ge18 y 4 (45) 33 (508) 24 (545) 17 (630) 3 (333)

Missing 8 6 11 1 4

Organ system involvement

CNS 87 (897) 68 (958) 33 (600) 18 (643) 13 (1000)

Skeletal muscle 73 (753) 60 (845) 53 (964) 6 (214) 13 (1000)

Heart 10 (103) 21 (296) 7 (127) 3 (107) 1 (77)

Developmental 91 (938) 22 (310) 2 (36) 3 (107) 5 (385)

Constitutionalb 34 (351) 39 (549) 15 (273) mdash 1 (77)

Psychiatric 10 (103) 23 (324) 19 (345) 4 (143) 4 (308)

PNS 7 (72) 11 (155) 10 (182) 2 (71) 4 (308)

Kidney 5 (52) 11 (155) 2 (36) 4 (143) mdash

Liver 1 (10) mdash mdash mdash mdash

Gastrointestinal 26 (268) 22 (310) 7 (127) 1 (36) 2 (154)

Genetic status

nDNA pathogenic variants 45 (464) 1 (14) 18 (327) 1 (36) mdash

mtDNA pathogenic variants 52 (536) 70 (986) 37 (673) 27 (964) 13 (1000)

Abbreviations cPEO = chronic progressive external ophthalmoplegia LHON = Leber hereditary optic neuropathy LS = Leigh syndrome MELAS = mito-chondrial encephalomyopathy lactic acidosis and stroke-like episodes MERRF = myoclonus epilepsy with ragged red fibers mtDNA = mitochondrial DNAnDNA = nuclear DNA PNS = peripheral nervous systema Missing values not included in the percentage denominatorb Includes cachexia chronic fatigue short stature (the patientrsquos height is below the 3rd percentile) and thinness (body mass index lt185 kgm2)

NeurologyorgNG Neurology Genetics | Volume 6 Number 2 | April 2020 5

Molecular geneticsmtDNA pathogenic variants were more frequent than nDNA(414 vs 252 participants) mtDNA variants were most prev-alent among older patients (38 of those with onset ge18 and22 of those with onset lt2) whereas nDNA variants weremost common in the youngest group (50 of those withonset lt2 [table 4]) The most common mtDNA pathogenicvariants were m3243AgtG in MT-TL1 which encodestRNALeu(UUR) (138 participants) and single deletions (67participants table e-2 linkslwwcomNXGA226) Overallthe distribution of pathogenic variants differed by age (p lt00001 table 4) The difference between the youngest andoldest groups was particularly striking Although nDNA var-iants were more than twice as frequent as mtDNA amongthose with onset lt2 (504 vs 222) the reverse is true inthe oldest-onset group (193 mtDNA vs 382 nDNA posthoc p lt 00001) Pathogenic variants in 65 different nucleargenes were reported (figure 2) Pathogenic variants in 38genes were reported uniquely in single participants (figure 2)

The early age at onset of participants with nDNA pathogenicvariants was associated with a higher frequency of de-velopmental delay (655) compared with individuals withmtDNA pathogenic variants (348 p lt 00001 (table 4) Incontrast patients with mtDNA pathogenic variants hadhigher frequencies of endocrinopathies (246 vs 91 p lt00001) overall and diabetes mellitus in particular (191 vs28 p = 00001) The overall frequencies of CNS manifes-tations were similar in participants with mtDNA and nDNApathogenic variants (829 vs 861 p = 037) Howeverparticipants with mtDNA variants had higher frequencies of

SLEs (210 vs 71 p lt 00001) migraine headaches(196 vs 99 p = 002) and dementia (92 vs 32 p =004) with lower frequencies of upper motor signs (spasticity[68 vs 151 p = 0004] and hyperactive reflexes [56 vs131 p = 0017])

Participants with m3243AgtGThe m3243AgtG pathogenic variant was reported in 138individuals who were predominantly female (89 vs 48 males)Onset of symptoms frequently occurred when participantswere age gt18 years (table e-2 linkslwwcomNXGA226)Ten different clinical syndromes were observed The mostfrequent was MELAS (56 individuals) followed by diabetesand deafness (14 participants) encephalomyopathy (9 par-ticipants) and maternally inherited diabetes (5 participants)Multisystemic syndrome was diagnosed in 33 participantsCNS was affected in 127 (table e-2) participants with seizure(55 participants) and migraine (48 participants) as the mostcommon manifestations Hearing loss was frequently recor-ded (92 participants) as well as diabetes mellitus that waspresent in 57 participants

Participants with m8344AgtGTwenty-three participants had the m8344AgtG variant (10males and 13 females) (table e-2 linkslwwcomNXGA226) Although the pathogenic variant has been classicallyassociated with MERRF 7 different phenotypes have beenidentified in the NAMDC Registry Nine participants had thediagnosis of MERRF whereas 9 individuals received otherclinical diagnoses All participants had CNS involvement withataxia (15 participants) and myoclonus (16 participants) as

Figure 1 Genes mutated in the canonical mitochondrial syndromes studied

Gene pathogenic variants in North AmericanMitochondrial Disease Consortium Registry par-ticipants with canonical syndromes cPEO =chronic progressive external ophthalmoplegiaLHON = Leber hereditary optic neuropathyMELAS = mitochondrial encephalomyopathylactic acidosis and stroke-like episodes MERRF =myoclonus epilepsy with ragged red fibersmtDNA = mitochondrial DNA

6 Neurology Genetics | Volume 6 Number 2 | April 2020 NeurologyorgNG

Table 3 Frequencies of demographic clinical and genetic features of participants with specific biochemical diagnoses

Comp I Comp II Comp III Comp IV Comp V cRCE CoQ10 TP PDC

18666 1666 1666 14666 5666 21666 2220 8214 44230

Sex

Female 9 1 1 8 3 12 1 7 28

Male 9 mdash mdash 6 2 9 1 1 16

Age at onset

lt2 y 6 1 mdash 4 3 7 mdash 1 38

ge2 to lt5 y mdash mdash mdash 6 1 5 2 mdash 2

ge5 to lt12 y 3 mdash mdash 2 mdash mdash mdash 1 3

ge12 to lt18 y 1 mdash mdash mdash mdash 1 mdash mdash mdash

ge18 y 4 mdash mdash 2 1 8 mdash 5 mdash

Clinical syndromes

Multisystemic syndrome 4 mdash 0 3 1 2 1 mdash 2

Other clinical diagnosis mdash mdash 1 1 1 1 mdash mdash 14

LS 7 1 mdash 5 2 5 1 mdash 9

Encephalomyopathy mdash mdash mdash 1 mdash 1 mdash mdash 4

MELAS 1 mdash mdash mdash mdash 2 mdash mdash mdash

Myopathy mdash mdash mdash mdash mdash 1 mdash mdash mdash

cPEO+ mdash mdash mdash 2 mdash 2 mdash mdash mdash

Encephalopathy mdash mdash mdash mdash mdash 2 mdash mdash 14

LHON 3 mdash mdash mdash mdash mdash mdash mdash mdash

CPEO mdash mdash mdash mdash mdash 1 mdash mdash mdash

KSS mdash mdash mdash mdash mdash 1 mdash mdash mdash

SANDO 1 mdash mdash 1 mdash mdash mdash mdash mdash

MIDD 1 mdash mdash mdash mdash mdash mdash mdash mdash

Alpers syndrome mdash mdash mdash 1 mdash 1 mdash mdash mdash

MNGIE mdash mdash mdash mdash mdash mdash mdash 8 mdash

Maternal inheriteddeafness

mdash mdash mdash mdash mdash mdash mdash mdash mdash

Cardiomyopathy mdash mdash mdash mdash mdash mdash mdash mdash 1

Hepatocerebral syndrome 1 mdash mdash mdash mdash 2 mdash mdash mdash

RIM with COX deficiency mdash mdash mdash mdash 1 mdash mdash mdash mdash

Genetic status

mtDNA pathogenicvariants

15 mdash 1 5 5 13 1 mdash 2

nDNA pathogenic variants 3 1 mdash 9 mdash 8 1 8 42

Abbreviations CoQ10 = coenzyme Q10 cPEO = chronic progressive external ophthalmoplegia cRCE = combined respiratory chain enzymes KSS = Kearns-Sayre syndrome LHON = Leber hereditary optic neuropathy LS = Leigh syndrome MELAS = mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes MIDD = maternal inherited diabetes and deafness MNGIE = mitochondrial neurogastrointestinal encephalopathy mtDNA = mitochondrialDNA nDNA = nuclear DNA PDC = pyruvate dehydrogenase complex RIM with COX deficiency = reversible infantile myopathy with cytochrome c oxidasedeficiency SANDO = sensory ataxic neuropathy with dysarthria and ophthalmoparesis TP = thymidine phosphorylase

NeurologyorgNG Neurology Genetics | Volume 6 Number 2 | April 2020 7

Table 4 Clinical features of participants with mtDNA pathogenic variants vs nDNA pathogenic variants

mtDNA pathogenic variants (N = 414) nDNA pathogenic variants (N = 252) p Value

Age at onset lt00001

lt2 y 78 (222) 120 (504)

ge2 and lt5 y 40 (114) 43 (181)

ge5 and lt12 y 66 (188) 10 (42)

ge12 and lt18 y 33 (94) 19 (80)

ge18 y 134 (382) 46 (193)

Missing 63 14

Sexa 037

Male 183 (443) 102 (405)

Female 230 (557) 150 (595)

Missing 1 mdash

Organ system manifestations

CNSb 343 (829) 217 (861)

Seizures 126 (304) 101 (401) 016

Ataxia 126 (304) 98 (389) 015

SLE 87 (210) 18 (71) lt00001

Migraine headaches 81 (196) 25 (99) 002

Myoclonic seizures 23 (56) 27 (107) 100

Dysarthria 68 (164) 56 (222) 036

Hearing loss 160 (386) 46 (183) lt00001

Hyperactive reflexes 23 (56) 33 (131) 0017

Other neurologic manifestation 135 (326) 99 (393) 073

Myoclonus 41 (99) 28 (111) 100

Dystonia 41 (99) 41 (163) 016

Dementia 38 (92) 8 (32) 0042

Encephalopathy 37 (89) 39 (155) 015

Chorea 15 (36) 15 (60) 073

Spasticity 28 (68) 38 (151) 00042

Parkinsonism 5 (12) 7 (28) 073

PNSb 51 (123) 59 (234)

Axonal 39 (94) 42 (167) 00078

Demyelinating 18 (43) 24 (95) 00078

Ophthalmoparesis 75 (181) 62 (246) 009

Ptosis 126 (304) 70 (278) 048

DM 79 (191) 7 (28) lt00001

Short stature 104 (251) 63 (250) 100

Myopathy 134 (324) 72 (286) 029

Developmental 144 (348) 165 (655) lt00001

Continued

8 Neurology Genetics | Volume 6 Number 2 | April 2020 NeurologyorgNG

the most common manifestations (table e-2) Skeletal muscleweakness was reported in 21 participants

Single large-scale mtDNA deletion (mtDNAD)mtDNAD was reported in 67 participants (29 males and 38females) (table e-2 linkslwwcomNXGA226) with a largespectrumof clinical syndromes (10 different diagnoses) includingKearns-Sayre syndrome (16 individuals) cPEO+ (15 individu-als) cPEO (12 individuals) and Pearson syndrome (9 individu-als) Skeletal muscle (5867 866) and CNS symptoms (44participants) were prevalent (table e-2) Ptosis (47 participants)

and ophthalmoparesis (38 participants) were frequently reported(table e-2) Hearing loss was less common (18 individuals)

Participants with POLG1 pathogenic variantsSeventy participants (25 males and 45 females) had pathogenicvariants in POLG1 (figure 2) Onset of symptoms occurredfrom infancy through late adulthood (range lt1ndash53 years)Twenty-four pathogenic variants were observed distributedalong the entire gene and with a high frequency in the linkerregion Clinical presentation encompassed 11 different syn-dromes Sensory ataxic neuropathy with dysarthria and

Table 4 Clinical features of participants with mtDNA pathogenic variants vs nDNA pathogenic variants (continued)

mtDNA pathogenic variants (N = 414) nDNA pathogenic variants (N = 252) p Value

Anxiety 67 (162) 35 (139) 073

Depression 74 (179) 32 (127) 018

Bipolar disorder 9 (22) 6 (24) 079

Gastrointestinal 97 (234) 68 (270) 031

Endocrinec 102 (246) 23 (91) lt00001

Abbreviations DM = diabetes mellitus mtDNA = mitochondrial DNA nDNA = nuclear DNA PNS = peripheral nervous system SLE = stroke-like episodea Missing values not included in the percentage denominatorb p Values are adjusted for 16 comparisons for CNS and 2 for PNS using the Holm method29c Includes diabetes mellitus hypothyroidism hypogonadotropic hypogonadism hypoparathyroidism and adrenal insufficiency

Figure 2 Nuclear gene pathogenic variant frequency in the North American Mitochondrial Disease Consortium Registry

Each square represents 1 participant

NeurologyorgNG Neurology Genetics | Volume 6 Number 2 | April 2020 9

ophthalmoparesis (SANDO) (18 participants) and Alperssyndrome (14 participants) were the most frequent Ten hadSLEs Seventeen participants had generic diagnoses of multi-systemic or other clinical syndrome Of interest phenotypevariability was observed in the 10 participants with the homo-zygous pA467T pathogenic variant (2 Alpers-Huttenlochersyndrome 4 SANDO 1 cPEO+ and 3 nonspecific clinicalsyndromes) Almost all the POLG1 participants (6670) hadCNS involvement Skeletal muscle (6170 participants) andperipheral nerve (33 participants) were often affected Themostfrequent CNS symptoms were ataxia (4570 participants) andseizures (4170 participants)

Participants with PDHA1 pathogenic variantsPDHA1 pathogenic variants were identified in 40 participants(11 males and 29 females) (figure 2) Age at onset was lt2 yearsin the majority (3340 individuals) Developmental delay wasobserved in most participants (3640) but information aboutthis manifestation was unavailable for 3 participants De-velopmental delay was absent in only 1 Encephalopathy (1340participants) and LS (740 participants) were the most com-monly diagnoses CNSwas affected in 33 individuals with seizure(2141 participants) being the most common manifestation

Participants with OPA1 pathogenic variantsOf the 13 participants with OPA1 pathogenic variants 8 hadoptic atrophy and 2 were diagnosed as optic atrophy type 1(autosomal dominant optic atrophy Kjer type) One participantwas inappropriately given a clinical diagnosis of LHON beforethe mtDNA mutation was identified Ten participants hadmanifestations outside of the optic nerve including ptosis (4)ophthalmoparesis (4) hearing loss (4) seizures (3) ataxia (3)peripheral neuropathy (2) and dilated cardiomyopathy (1)hence those patients were given non-autosomal dominant opticatrophy diagnoses (multisystemic disease cPEO plus andencephalomyopathy)

DiscussionClinical registries are essential for collecting data on rare diseasesthose data can be critical for guiding their diagnoses and care Thisstudy using data from theNAMDCRegistry is the first to depictthe spectrum of mitochondrial disorders in North America

Although participants in the Registry can be enrolled based onclinical manifestations (a genetic diagnosis is not required) thisanalysis considers only participants with a definite genetic di-agnosis Nonetheless it is worth highlighting the complexity ofthe diagnostic pathway in these patients Indeed even in the eraof next-generation sequencing13 and similarly to other largecohort studies1415 the NAMDC Registry shows a moleculardiagnostic rate of 538 (722 participants of 1341 receiveda genetic diagnosis) (table e-3 linkslwwcomNXGA226)

MtDs have diverse clinical presentations16 which our analysisconfirms with 24 different clinical entities Of interest many

participants are classified outside the classical mitochondrialphenotypes with multisystemic syndrome (113 participants)the most common diagnosis Sex stratification shows a slightpreponderance of females although the data do not includeasymptomatic carriers Also noteworthy is the skewed racialcomposition The majority of participants are Caucasian(gt85) whereas lt3 were African Americans and lt4wereAsian In contrast the 2010 US Census identified 724Caucasian 126 African American and 48 Asian Severalfactors may contribute to this disparity and although wecannot exclude a recruiting bias biological factors may playa role in disease susceptibility of some populations17

Because MtDs are typically due to defects in energy metab-olism the Registry includes data on biochemical defectsEnzyme activity assay helps to direct molecular analyses andto identify participants eligible for future therapies targetingspecific enzymatic defects1819 Among the many such defectsOxPhos deficiency has historically been considered the hall-mark of MtDs7 In the Registry the majority of the partic-ipants had an OxPhos defect followed by PDC deficiencyParticipants with OxPhos defects most frequently presentedwith multisystemic diseases This may reflect the complexgenetic control of the respiratory chain machinery2021 Re-markably few participants had complex V defects possiblydue to low frequency detection difficulty or both

To portray the features of classic mitochondrial syndromes isextremely important as new therapeutic strategies approachthe patient bedside

Participants with MELAS were prevalent in our cohort Al-though previous studies have suggested that male sex mayrepresent a risk factor for development of a full-blownMELAS syndrome we did not observe a difference by sex inour population Moreover the ratio of males was similaramong participants with the m3243AgtG variant (35) andthose with a diagnosis of MELAS (40) (table e-2 linkslwwcomNXGA226) In contrast to data obtained in otherstudies22 MELAS was the most common diagnosis in par-ticipants carrying the m3243AgtG variant The high pro-portion of participants with MELAS in the NAMDC may bedue to ascertainment bias because some of the NAMDC siteshave research projects on this disorder23

Our data also confirm the relatively low prevalence of com-plete MERRF syndrome Previous reports from the Germanand Italian registries showed that only half of the participantswith the m8344AgtG pathogenic variant have classic MERRFsyndrome24 The same proportion is observed in our cohortOf interest the age at onset in our MERRF cohort is youngerthan reported elsewhere with an age at onset before 12 yearsof age in 6 of 9 participants with available data We identifiedhearing loss in 565 of our participants with the m8344AgtGvariant and 462 with MERRF (table e-2 linkslwwcomNXGA226) This is in line with some other studies but lowerthan the German registry data2526

10 Neurology Genetics | Volume 6 Number 2 | April 2020 NeurologyorgNG

cPEOcPEO+ diagnoses are common but less frequent thanin previous reports15 This discrepancy may have arisenbecause the NAMDC Registry includes the multisystemicsyndrome category into which multiple complex cPEO+participants were classified

The Registry data highlight the vast genetic heterogeneity ofthe patients with MtDs We observed a higher frequency ofmtDNA pathogenic variants over nDNA (table 4) The com-bination of pediatric and adult clinics in the NAMDC facilitatesa comprehensive analysis across theMtD population This mayhelp explain why the proportions of mtDNA and nDNA var-iants in the Registry differ from those in other recent reports27

Other factors such as accessibility and feasibility of mtDNAtesting may also have an impact In the Registry participantswith nDNA pathogenic variants had earlier disease onset thanparticipants with mtDNA pathogenic variants with onset be-fore age 2 years in 504 individuals (table 4) We observed nodifferences in ptosis and ophthalmoparesis between the 2groups in contrast to what was observed in the Italian regis-try15 High frequencies of SLE diabetes mellitus and deafnessin mtDNA participants were present probably due to commonmtDNA pathogenic variant-associated phenotypes The higherfrequency of developmental abnormalities in the nDNA sub-group confirms previous data27 and is concordant with theyounger age at onset

The identification in our cohort of several genes mutated onlyin single individuals corroborates the ultra-rare nature ofmany MtDs genotypes

This study provides the first wide-ranging look at the MtDpopulation in North America The data also identify areas ofthe Registry that require further improvement Given theestimated prevalence of MtDs28 it is likely that only a smallproportion of North American participants has been cap-tured To address this limitation the NAMDC has developeda remote enrollment system to reach patients living in areasdistant from a NAMDC center In addition the NAMDC hascreated disease-specific natural history subregistries and otherstudies that will improve the acquisition of longitudinal dataand help to identify outcome measures for future clinicaltrials

AcknowledgmentThe authors acknowledge the contributions of theparticipants and families who have participated in theRegistry and of Amy Holbert Health Informatics InstituteRDCRN University of South Florida for administrativesupport In addition they acknowledge the efforts of thestudy coordinators

Study fundingThe project was funded by NIH U54 NS078059 The NorthAmerican Mitochondrial Disease Consortium (NAMDC) ispart of Rare Diseases Clinical Research Network (RDCRN)

an initiative of the Office of Rare Diseases Research (ORDR)National Center for Advancing Translational Sciences(NCATS) The project was funded by NIH U54 NS078059sponsored by the NINDS the Eunice Kennedy Shriver Na-tional Institute of Child Health and Development (NICHD)the Office of Dietary Supplements (ODS) and NCATS Inaddition the NAMDC has received private funding from theUnited Mitochondrial Disease Foundation (UMDF) a Pa-tient Advocacy Group (PAG) for individuals with mito-chondrial disease and their family members as well as the JWillard and Alice S Marriott Family Foundation

DisclosureDisclosures available NeurologyorgNG

Publication historyReceived by Neurology Genetics June 13 2019 Accepted in final formDecember 16 2019

Appendix Authors

Author Institution Contribution

EmanueleBarca MDPhD

Department of NeurologyColumbia UniversityMedical Center NY

Data analysis manuscriptpreparationcommunication amongcanters and study design

Yuelin LongMS

Department ofBiostatistics MailmanSchool of Public HealthColumbia University NewYork

Statistical analysis

VictoriaCooley MS

Department ofBiostatistics MailmanSchool of Public HealthColumbia University NewYork

Statistical analysis

RobertSchoenakerMD BS

Radboudumc NijmegenThe Netherlands

Manuscript preparationand data analysis

ValentinaEmmanueleMD PhD

Department of NeurologyColumbia UniversityMedical Center NY

Data analysiscommunication amongcenters and critical datareview

SalvatoreDiMauro MD

Department of NeurologyColumbia UniversityMedical Center NY

Data analysis studydesign and critical datareview

Bruce HCohen MD

Department of PediatricsNortheast Ohio MedicalUniversity and AkronChildrenrsquos Hospital

Provided participant data

Amel KaraaMD

Genetics UnitMassachusetts GeneralHospital Boston

Provided participant data

Georgirene DVladutiu PhD

Department of PediatricsState University of NewYork at Buffalo

Provided participant data

Richard HaasMBBChir

Departments ofNeurosciences andPediatrics University ofCalifornia at San Diego

Provided participant data

Continued

NeurologyorgNG Neurology Genetics | Volume 6 Number 2 | April 2020 11

Appendix (continued)

Author Institution Contribution

Johan LK VanHove MDPhD

Department of PediatricsUniversity of ColoradoSchool of MedicineAurora

Provided participant data

FernandoScaglia MD

Department of Molecularand Human GeneticsBaylor College of MedicineHouston TX TexasChildrenrsquos HospitalHouston Joint BCM-CUHKCenter of Medical GeneticsPrince of Wales HospitalShaTin New TerritoriesHong Kong

Provided participant data

Sumit ParikhMD

Department of NeurologyCleveland Clinic OH

Provided participant data

Jirair KBedoyan MDPhD

Departments of Geneticsand Genome Sciences andPediatrics and Center forHumanGenetics UniversityHospitals ClevelandMedical Center CaseWestern ReserveUniversity OH

Provided participant data

Susanne DDeBrosse MD

Departments of Geneticsand Genome Sciences andPediatrics and Center forHuman Genetics UniversityHospitals ClevelandMedicalCenter Case WesternReserve University OH

Provided participant data

Ralitza HGavrilova MD

Departments ofNeurology and ClinicalGenomics Mayo ClinicRochester MN

Provided participant data

Russell PSaneto DOPhD

Department of NeurologyUniversity of WashingtonSeattle Childrenrsquos Hospital

Provided participant data

Gregory MEnns MBChB

Department of PediatricsStanford University PaloAlto CA

Provided participant data

Peter WStacpooleMD PhD

Department of MedicineUniversity of Florida atGainesville

Provided participant data

Jaya GaneshMD

Department of PediatricsCooper UniversityHospital Camden NJ

Provided participant data

AustinLarson MD

Department of PediatricsUniversity of ColoradoSchool of MedicineAurora

Provided participant data

ZarazuelaZolkipli-CunninghamMD

Mitochondrial MedicineFrontier Program Divisionof Human Genetics TheChildrenrsquos Hospital ofPhiladelphia andUniversity of PennsylvaniaPerelman School ofMedicine University ofPennsylvania PerelmanSchool of MedicinePhiladelphia

Provided participant data

Appendix (continued)

Author Institution Contribution

Marni J FalkMD

Mitochondrial MedicineFrontier Program Divisionof Human Genetics TheChildrenrsquos Hospital ofPhiladelphia and Universityof Pennsylvania PerelmanSchool of Medicine

Provided participant data

Amy CGoldstein MD

Mitochondrial MedicineFrontier Program Divisionof Human Genetics TheChildrenrsquos Hospital ofPhiladelphia andUniversity of PennsylvaniaPerelman School ofMedicine

Provided participant data

MarkTarnopolskyMD PhD

Department of NeurologyMcMasters UniversityToronto ON Canada

Provided participant data

AndreaGropman MD

Childrenrsquos NationalMedical Center

Provided participant data

KathrynCamp MS RD

Office of DietarySupplements NationalInstitutes of HealthBethesda MD

Critical data review

DanutaKrotoski PhD

Eunice Kennedy ShriverNational Institute of ChildHealth and HumanDevelopment NationalInstitutes of HealthBethesda MD

Critical data review

KristinEngelstad MS

Department of NeurologyColumbia UniversityMedical Center NY

Provided participant data

Xiomara QRosales MD

Department of NeurologyColumbia UniversityMedical Center NY

Provided participant data

Joshua KrigerMS

Department ofBiostatistics MailmanSchool of Public HealthColumbia University NewYork

Statistical analysis

JohnstonGrier MS

Department ofBiostatistics MailmanSchool of Public HealthColumbia University NewYork

Provided participant data

RichardBuchsbaum

Department ofBiostatistics MailmanSchool of Public HealthColumbia University NewYork

Database curation anddata set preparation

John LPThompsonPhD

Department ofBiostatistics MailmanSchool of Public HealthColumbia University NewYork

Statistical analysismanuscript preparationand study design

MichioHirano MD

Department of NeurologyColumbia UniversityMedical Center NY

Data analysis manuscriptpreparationcommunication amongcenters study design andcritical data review

12 Neurology Genetics | Volume 6 Number 2 | April 2020 NeurologyorgNG

References1 DiMauro S Davidzon G Mitochondrial DNA and disease Ann Med 200537

222ndash2322 McFarland R Taylor RW Turnbull DM A neurological perspective onmitochondrial

disease Lancet Neurol 20109829ndash8403 Chinnery PF Mitochondrial disorders overview In Adam MP Ardinger HH Pagon

RA et al editors GeneReviewsreg Seattle WA University of Washington Seattle 20144 Gorman GS Schaefer AM Ng Y et al Prevalence of nuclear and mitochondrial DNA

mutations related to adult mitochondrial disease Ann Neurol 201577753ndash7595 Thompson R Robertson A Lochmuller H Natural history trial readiness and gene

discovery advances in patient registries for neuromuscular disease Adv Exp Med Biol2017103197ndash124

6 Louis ED Mayer SA Rowland LP Merrittrsquos Neurology Philadelphia PA LippincottWilliams amp Wilkins 2016

7 DiMauro S Schon EA Carelli V Hirano M The clinical maze of mitochondrialneurology Nat Rev Neurol 20139429ndash444

8 Wallace DC Zheng XX Lott MT et al Familial mitochondrial encephalomyopathy(MERRF) genetic pathophysiological and biochemical characterization of a mito-chondrial DNA disease Cell 198855601ndash610

9 Hirano M Ricci E Koenigsberger MR et al MELAS an original case and clinicalcriteria for diagnosis Neuromuscul Disord 19922125ndash135

10 Wallace DC Singh G Lott MT et al Mitochondrial DNA mutation associated withLeberrsquos hereditary optic neuropathy Science 19882421427ndash1430

11 Cohen BH Chinnery PF Copeland WC POLG-related disorders In Adam MPArdinger HH Pagon RA et al editors GeneReviewsreg Seattle WA University ofWashington Seattle 1993

12 Hirano M Mitochondrial neurogastrointestinal encephalopathy disease In AdamMP Ardinger HH Pagon RA et al editors GeneReviewsreg Seattle WA University ofWashington Seattle 1993

13 McCormick E Place E Falk MJ Molecular genetic testing for mitochondrial diseasefrom one generation to the next Neurotherapeutics 201310251ndash261

14 Pronicka E Piekutowska-Abramczuk D Ciara E et al New perspective in diagnosticsof mitochondrial disorders two yearsrsquo experience with whole-exome sequencing ata national paediatric centre J Transl Med 201614174

15 Orsucci D Angelini C Bertini E et al Revisiting mitochondrial ocular myopathiesa study from the Italian network J Neurol 20172641777ndash1784

16 Zolkipli-Cunningham Z Xiao R Stoddart A et al Mitochondrial disease patientmotivations and barriers to participate in clinical trials PLoS One 201813e0197513

17 Salvatore DiMauro CP Mitochondrial disorders due to mutations in the mitochon-drial genome In Rosenberg RN Pascual JM editors Rosenbergrsquos Molecular andGenetic Basis of Neurological and Psychiatric Disease 5th Edition San Diego CAElsevier Science Publishing Co Inc 2015271ndash281

18 Quinzii CM Emmanuele V Hirano M Clinical presentations of coenzyme q10deficiency syndrome Mol Syndromol 20145141ndash146

19 Halter JP Michael W Schupbach M et al Allogeneic haematopoietic stem celltransplantation for mitochondrial neurogastrointestinal encephalomyopathy Brain20151382847ndash2858

20 Taylor RW Pyle A Griffin H et al Use of whole-exome sequencing to determine thegenetic basis of multiple mitochondrial respiratory chain complex deficiencies JAMA201431268ndash77

21 Kemp JP Smith PM Pyle A et al Nuclear factors involved in mitochondrial trans-lation cause a subgroup of combined respiratory chain deficiency Brain 2011134183ndash195

22 Nesbitt V Pitceathly RD Turnbull DM et al TheUKMRCMitochondrial Disease PatientCohort Study clinical phenotypes associated with the m3243AgtG mutationndashimplicationsfor diagnosis and management J Neurol Neurosurg Psychiatry 201384936ndash938

23 Kaufmann P Engelstad K Wei Y et al Natural history of MELAS associated withmitochondrial DNA m3243AgtG genotype Neurology 2011771965ndash1971

24 Altmann J Buchner B Nadaj-Pakleza A et al Expanded phenotypic spectrum of them8344AgtG ldquoMERRFrdquomutation data from the German mitoNET registry J Neurol2016263961ndash972

25 Chinnery PF Howell N Lightowlers RN Turnbull DM MELAS and MERRF Therelationship between maternal mutation load and the frequency of clinically affectedoffspring Brain 19981211889ndash1894

26 Mancuso M Orsucci D Angelini C et al Phenotypic heterogeneity of the 8344AgtGmtDNA ldquoMERRFrdquo mutation Neurology 2013802049ndash2054

27 Witters P Saada A Honzik T et al Revisiting mitochondrial diagnostic criteria in thenew era of genomics Genet Med 201820444ndash451

28 Skladal D Halliday J Thorburn DR Minimum birth prevalence of mitochondrialrespiratory chain disorders in children Brain 20031261905ndash1912

29 Holm S A simple sequentially rejective multiple test procedure Scand J Statist 1979665ndash70

NeurologyorgNG Neurology Genetics | Volume 6 Number 2 | April 2020 13

DOI 101212NXG000000000000040220206 Neurol Genet

Emanuele Barca Yuelin Long Victoria Cooley et al Mitochondrial diseases in North America An analysis of the NAMDC Registry

This information is current as of March 2 2020

reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2020 The Author(s)

is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet

ServicesUpdated Information amp

httpngneurologyorgcontent62e402fullhtmlincluding high resolution figures can be found at

References httpngneurologyorgcontent62e402fullhtmlref-list-1

This article cites 24 articles 2 of which you can access for free at

Subspecialty Collections

httpngneurologyorgcgicollectionperipheral_neuropathyPeripheral neuropathy

httpngneurologyorgcgicollectionmuscle_diseaseMuscle disease

httpngneurologyorgcgicollectionmitochondrial_disordersMitochondrial disorders

httpngneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpngneurologyorgcgicollectioncohort_studiesCohort studiesfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2020 The Author(s)

is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet

ServicesUpdated Information amp

httpngneurologyorgcontent62e402fullhtmlincluding high resolution figures can be found at

References httpngneurologyorgcontent62e402fullhtmlref-list-1

This article cites 24 articles 2 of which you can access for free at

Subspecialty Collections

httpngneurologyorgcgicollectionperipheral_neuropathyPeripheral neuropathy

httpngneurologyorgcgicollectionmuscle_diseaseMuscle disease

httpngneurologyorgcgicollectionmitochondrial_disordersMitochondrial disorders

httpngneurologyorgcgicollectiondevelopmental_disordersDevelopmental disorders

httpngneurologyorgcgicollectioncohort_studiesCohort studiesfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpngneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpngneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

reserved Online ISSN 2376-7839Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology All rightsan open-access online-only continuous publication journal Copyright Copyright copy 2020 The Author(s)

is an official journal of the American Academy of Neurology Published since April 2015 it isNeurol Genet