Cardiomyopathies in

mitochondrial disorders

Anu Suomalainen Wartiovaara MD PhD, Professor

FinMIT

Research Program of Molecular Neurology Biomedicum-Helsinki University of Helsinki

http://research.med.helsinki.fi/neuro/Wartiovaara/default.htm

Mitochondrial disorders Progressive encephalopathy Neurodegeneration Strokes, demyelination Epilepsy, ataxia, parkinsonism, migraines cognitive decline, hemiparesis, psychiatric symptoms Cardiomyopathy, conduction defects Kidney dysfunction Diabetes Intestinal dysfunction: malabsorption, diarrhea Infertility, premature menopause Sideroblastic anemia Immunological defects

Deafness, hearing deficit Retinitis pigmentosa Optic neuropathy Cataracts Defects of vision, blindness Acute liver damage Hepatopathy Muscle weakness Cramps Tiredness in exercise Sensory or motor neuropathies Tingling, pain and numbness of extremities

Cardiac  energy  metabolism    

➲  Over  90%  of  ATP  synthesis  from  mitochondrial  respira=on    ➲Flexible  use  of  all  nutrients  –  glucose,  fat,  ketones    ➲Despite  large  fluctua=ons  in  work  load,  amazingly  stable  metabolism  -­‐    “stability  paradox”  

Data analysis. The position of each pixel relative to the cellmust be identical for all three separately obtained images. Toavoid error arising from slight movement of the cell duringimage acquisitions, we aligned the three cell images, ifnecessary, before calculation of SMb as follows. First, we chosefive to seven marker points in a small region of interest (ROI)that were peculiar with respect to light absorption, and theabsolute positions of these points were recorded. Thesemarker points appeared to correspond to locations ofmitochon-dria according to the results of rhodamine-123 staining (datanot shown). We then checked whether these marker pointswere in fact found at the same absolute coordinates in theremaining two images. If not, the deflections of the markersfrom the expected coordinates were calculated. Finally, theaffine transform (linear mapping of an image including shiftsand rotation) was conducted over the remaining two cellimages so that the square errors of the deflections could beminimized. Also, the images were low-pass filtered threetimes.

After the alignment and low-pass filtering, the calculationdepicted in Eq. 4 was conducted for all the pixels. Wedetermined the local SMb as follows. First, we arbitrarilyselected, in the SMb image, �12 ⇥ 4-µm rectangular ROIswithin a cell parallel to the long axis of the cell (see Fig. 3).AnSMb distribution histogram was then calculated for each ROI.The histogram was subsequently fitted to a normal distribu-tion using IgorPro data analysis software (WaveMetrics,Lake Oswego, OR). In cases in which the histogram wassignificantly skewed or the standard deviation of the SMbhistogram was ⌃0.5, we discarded the data. Finally, wecalculated the mean of the histogram and regarded it torepresent the local SMb.

Calibration. We conducted a calibration that relates localSMb to local PO2. We added 2 mM NaCN to the suspensionmedium and conducted SMb measurements for superfusiongas containing either 0.25, 0.51, 0.96, 2.09, or 3.14% oxygen.We assumed that NaCN abolishes the consumption of oxygenby the cell, thereby abolishing PO2 gradients from the extra-cellular medium to the intracellular space. Hence, intracellu-lar PO2 is in equilibrium with gas PO2. The relationshipbetween PO2 of the superfusion gas and measured SMb wasfitted to the Hill equation.

V̇O2 measurement. Because the magnitude of intracellularPO2 gradients would be proportional to flux of oxygen to thecell (10), we used 1 µM CCCP (an uncoupler of oxidative

phosphorylation) to amplify the intracellular PO2 gradients.Therefore, we needed to determine V̇O2 of the cell in thepresence of 1 µM CCCP. Five milliliters of the cell suspensionwere placed in the airtight measuring cuvette, in which anoxygen electrode (model 17026, Instrumentation Laboratory)was inserted. The cell suspension was vigorously stirredusing a magnetic stirrer. The time-dependent decrease in PO2of the suspension medium was recorded, and the rate of fall ofPO2 (�PO2/�t in Torr/min) was converted to the rate of oxygenconsumption (nmol O2 ·min⇤1 ·106 cells⇤1) using the followingequation

V̇O2 ⌅ ⇧w· (�PO2 /�t)/N ⇥ 106

where N is the number of cells per milliliter and ⇧w is thesolubility of oxygen in water (1.62 µmol · l⇤1 ·Torr⇤1 at 27°C).

RESULTS

We attempted a visualization of intracellular oxygenwith a subcellular spatial resolution in the presence ofan uncoupler of oxidative phosphorylation, 1 µM CCCP.When the cell suspension was superfused with 2.09(15.2 Torr) or 3.14% (22.8 Torr) O2 gas, intracellular SMbaveraged over the cell was �0.4–0.7 (corresponding to�1.9–8.7 Torr; see the results of calibration below)(Fig. 1, solid curve). These results indicate the presenceof large PO2 gradients in the extracellular medium,presumably resulting from the absence of the specificoxygen carrier myoglobin and the unstirred layer sur-rounding the cell surface (18). It should be noted thatintracellular oxygenation in this condition appearscomparable to the volume-averaged SMb reported in theworking cardiac cell in vivo (3, 5).

Figure 2 shows the representative data demonstrat-ing the visualization of intracellular oxygenation in asingle individual cardiomyocyte. For PO2 of the superfu-sion gas of 15.2 Torr, significant gradients of SMb fromthe sarcolemma toward the center of the cell weredemonstrated (indicated in pseudo colors). To quantita-tively analyze these radial heterogeneities of SMb, wecalculated SMb in small rectangular ROIs within a cell

Fig. 2. Representative data demon-strating reconstruction of SMb. Trans-mitted images of a single cardiomyo-cyte (left) were converted to an SMbimage (right) using Eq. 4. SMb is repre-sented in pseudo colors. The cell wasincubated with 1 µM CCCP to augmentintracellular PO2 gradients. PO2 of su-perfusion gas was 15.2 Torr. Cell bound-aries were manually traced.

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Takahashi  et  al.,  Am  J  Physiol  Heart  Circ  Physiol.  1998;275:225-­‐233.  

Why  are  not  all  mitochondrial  disorders  involving  the  heart?  

 Typical  manifesta=on:    

hypertrophic  cardiomyopathy  Early  onset  

 Specific  adult  disorders  -­‐  mtDNA  

     

Molecular mechanisms of cardiomyopathies Novel tools for diagnosis

Case report: Infantile hypertrophic

cardiomyopathy Clinical First child of healthy parents Normal pregnancy, neonatal period 4 months:

hypertrophic cardiomyopathy, muscle weakness lactate levels 2-7mmol/l Brain MRI normal, EEG slightly slow

Rapidly progressive disease 10 months: death due to cardiac arrest

Respiratory  chain  Complex  I,  III  and  IV  deficiency  

 in  heart    

Götz, Tyynismaa et al. Am J Hum Genet 2011

 

•  Children  and  adults  with  verified  or  suspected  mitochondrial  disorder  of  unknown  cause  (n>50)  

•  Children  with  cardiomyopathies  (n>150)  

à 50-60 million short sequence fragments à  1.5% of the whole genome =exome (18,000 genes) Comparison to control genome: - Known variants vs mutations

Whole-exome sequencing

Sequence of all coding gene regions of the patient’s genome

Results of whole-exome sequencing in the patient

P2 All variants 65849 Unknown 6323 Map to gene 1549

Homozygous 43

Damaging 7 Mitochondrial 1

True disease causing mutation?

Presence in population Absent in over 3000 control subjects

Presence in other cardiomyopathy families Functional consequnces

Family 2: prenatal hypertrophic cardiomyopathy

o  Prenatal: extrasystolia o  At birth: poor condition,

cardiomyopathy, hyperlactacidemia, death at postnatal day 3

o  Brother died in utero at week 40 o  Compound heterozygosity for two

AARS2 mutations

AARS2 gene: infantile cardiomyopathy gene AARS2 – targets to mitochondria

Aminoacyl-tRNA synthetases - important for mitochondrial translation

Charges a tRNA with aminoacid Specific synthetases for each tRNA-aa pair; mitochondrial and cytoplasmic tRNA structure specific; recognition often based on anticodon; amino acid specificity lower

L155R affects architecture of the catalytic domain R592W predicted to affect tRNA binding at editing

domain

Liliya Euro

Acceptor stem of tRNA, minor groove contacts with positively charged recidues R592 at level of tRNA G2:U71

Amino acyl formation affected at catalytic site

Amino acylation defect

Reduced alanine incorporation to polypeptides

L155R

Editing defect

Misincorporation of amino acids (serine, glycine) into polypeptides

R592W

impaired    mitochondrial  protein  synthesis  

P1   P2  

Clinical  history  (family  II)  •  II/IV  child,  girl  •  normal  pregnancy  and  birth  •  at  6  months  of  age  aeer  infec=on  

(o==s)  =red,  cough  •  sudden  death  at  emergency  room  

at  age  7  months  •  autopsy:  severe  cardiac  

enlargement,  hypertrophic  cardiomyopathy  

•  III/IV  child,  girl  •  normal  pregnancy  and  birth  •  4  months:  liver  fagy  

degenera=on    –  e=ology  unknown  

•  9  months:  cardiomyopathy  

•  now  13  years:    –  cardiomyopathy,  no  extreme  

physical  stress  –  selec=ve  mu=sm  –  normal  school,  learning  

difficul=es  

Carroll  et  al.  Hum  Mutat  2013  

CI + IV deficiency in heart

Sk.Muscle Heart

C P1 C P1

Sk.Muscle Heart

C P1 C P1

CI_39kDa

CII_70kDa

CIII_45kDa

CIV_COXI

CIV_COXII

CV_ATP_alpha

COMPLEX III

COMPLEX II

COMPLEX IV

COMPLEX I

C1 P1 C2

BN-PAGE SDS-PAGE

Exome  sequencing  results:  mitochondrial  ribosome  mutated  

Hetero-­‐  zygote    carriers  

Homo-­‐  zygote  muta=on  

wt  

Ø A  muta=on  in  MRPL44,  in  exon  2  Ø c.  467  T>G,  L156R  Ø nuclear  encoded  component  of  a  large  subunit  of  the  mitochondrial  ribosome      

Figures  by  Pirjo  Isohanni  G/T                        G/G                          G/G                  T/T  

G/T     G/T    

Conclusions: children

Mitochondrial translation defects may manifest primarily as early cardiomyopathy Our experience and literature: mostly fatal, but if the patient survives the critical phase, cardiomyopathy may stabilize after school age Exome analysis reveals new syndromes with variable clinical manifestations – not previously recognized as single-gene disorders Our experience: most children’s mitochondrial disorders are caused by rare variants in single or few families – even in genetic isolates

Gene search possible from a single patient Major progress in DNA diagnosis & research Confirms diagnosis & inheritance pattern Provides means for genetic counseling & research of pathogenic mechanism

MELAS Mitochondrial brain disease, muscle symptoms,

lactate acidosis, stroke-like episodes

In Finland carriers ~1:5000 – 1:10.000 Australia cohort ~ 1:200

Symptoms:

Maternal-inherited diabetes + hearing loss (MIDD)

Severe children’s encephalopathy Early brain infarcts Muscle weakness Cardiomyopathy

MELAS: tRNALeu(UUR) mutation m.3243A>G

Adult onset MELAS

The most common form of MELAS in Finland Diabetes (adult-onset, insulin-dependent) + Hearing loss + Hypertrophic cardiomyopathy

[page 32] [Cardiogenetics 2013; 3:e6]

Family 1 The proband (II:2) is a 39-year old male,

who presented at the age of 35 years with exer-cise-induced muscle pain, proximal leg weak-ness, dyspnea and sinus tachycardia 106/minand S3 in cardiac auscultation. He had beenprescribed diuretics due to swelling of theankles. Figure 2A shows the electrocardiogram(ECG). Serum pro-B-type natriuretic peptide(pro-BNP) concentration was elevated but tho-rax X-ray did not show pulmonary congestion.The main echocardiographic finding was non-obstructive left-ventricular hypertrophy (LVH;Figure 2A, Table 2). Doppler examination sug-gested elevated filling pressures. Magneticresonance spectroscopy of the brain showedlactate increase in the thalamus, but no neuro-logical signs or symptoms. Skeletal musclesample showed that 20% of muscle fibers werecytochrome-c-oxidase (COX)-negative, succi-nate dehydrogenase positive, strongly support-ing the diagnosis of mitochondrial dysfunctionalso underlying his cardiomyopathy. Familyhistory was negative for mitochondrial dis-eases or cardiomyopathy. During clinical fol-low-up, his cardiologic condition has remainedstable, without arrhythmias or dyspnea. Leftventricular walls have remained thickened, butthe early peak diastolic LV/mitral annularvelocity (E/Em) ratios have nearly normalized.

Family 2The proband (III:6) is a woman with dia-

betes mellitus, sensorineural hearing impair-ment and depression. At the age of 51 yearsshe developed acute pulmonary edema, hyper-tension and lactacidemia. Despite regularpulse and normal sized heart, serum troponinT and creatinine kinase-MB isoenzyme mass(CK-Mbm) levels were elevated (Table 1). ECGand echocardiography demonstrated LVH, withdiminished systolic function and restrictivehemodynamics (Figure 2B, Table 2). Coronaryangiography demonstrated 70% stenosis in theproximal left anterior descending coronaryartery (LAD), a total occlusion of middle LADwith collaterals from the right coronary artery,and 50% and 80% stenosis in first diagonalbranch of LAD (D1) and second diagonalbranch of LAD (D2), respectively. LV end dias-tolic pressure was 18 mmHg. Medical treat-ment of coronary artery disease was chosen.The diagnosis of mitochondrial contribution inhypertrophic CMP was strongly supported byhistological results of skeletal muscle biopsysamples, showing over 30% of COX-negativemuscle fibers, many of them also showing theragged-red fiber appearance, typical and diag-nostic for mitochondrial myopathy. In follow-up she developed episodes of cardiac decom-pensation induced by atrial flutter (ventricularresponse of 90/min) or fibrillation (~ 110/min)alternating with sinusbradycardia. Theseepisodes were accompanied with metabolic

Article

Figure 1. The family pedigrees. The index patients are marked with a black arrow. Blacksymbols indicate cardiac hypertrophy and signs or symptoms of heart failure; gray indi-cates subjects with increased relative wall thickness in echocardiography. MtDNA muta-tions were as followed: Family 1 – MELAS T3258C tRNA Leu(UUR); Family 2 and 3 –MELAS A3243G tRNA Leu (UUR); % indicates the people whose mutant mtDNA het-eroplasmy levels were studied, and the amount of mutant mtDNA in different tissues.

Figure 2. A) Patient II:2, family 1. Electrocardiogram (ECG) shows lateral t-inversions(left panel) and echocardiography (right panel) increased left ventricular wall thickness inparasternal long axis view (arrows); B) Patient III:6, family 2. ECG shows lateral q-wavesand abnormal r-peaks in the lateral chest leads (left panel), echocardiography (rightpanel) left ventricular hypertrophy (arrows). Apical view.

MELAS-­‐muta=on  and  cardiomyopathy  

Lee  ventricular  hypertrophy  -­‐  leading  sign  of  disease  

-­‐  thickening  of  heart  walls  upon  acute  decompensa=on,  especially  septum    

 

[page 32] [Cardiogenetics 2013; 3:e6]

Family 1 The proband (II:2) is a 39-year old male,

who presented at the age of 35 years with exer-cise-induced muscle pain, proximal leg weak-ness, dyspnea and sinus tachycardia 106/minand S3 in cardiac auscultation. He had beenprescribed diuretics due to swelling of theankles. Figure 2A shows the electrocardiogram(ECG). Serum pro-B-type natriuretic peptide(pro-BNP) concentration was elevated but tho-rax X-ray did not show pulmonary congestion.The main echocardiographic finding was non-obstructive left-ventricular hypertrophy (LVH;Figure 2A, Table 2). Doppler examination sug-gested elevated filling pressures. Magneticresonance spectroscopy of the brain showedlactate increase in the thalamus, but no neuro-logical signs or symptoms. Skeletal musclesample showed that 20% of muscle fibers werecytochrome-c-oxidase (COX)-negative, succi-nate dehydrogenase positive, strongly support-ing the diagnosis of mitochondrial dysfunctionalso underlying his cardiomyopathy. Familyhistory was negative for mitochondrial dis-eases or cardiomyopathy. During clinical fol-low-up, his cardiologic condition has remainedstable, without arrhythmias or dyspnea. Leftventricular walls have remained thickened, butthe early peak diastolic LV/mitral annularvelocity (E/Em) ratios have nearly normalized.

Family 2The proband (III:6) is a woman with dia-

betes mellitus, sensorineural hearing impair-ment and depression. At the age of 51 yearsshe developed acute pulmonary edema, hyper-tension and lactacidemia. Despite regularpulse and normal sized heart, serum troponinT and creatinine kinase-MB isoenzyme mass(CK-Mbm) levels were elevated (Table 1). ECGand echocardiography demonstrated LVH, withdiminished systolic function and restrictivehemodynamics (Figure 2B, Table 2). Coronaryangiography demonstrated 70% stenosis in theproximal left anterior descending coronaryartery (LAD), a total occlusion of middle LADwith collaterals from the right coronary artery,and 50% and 80% stenosis in first diagonalbranch of LAD (D1) and second diagonalbranch of LAD (D2), respectively. LV end dias-tolic pressure was 18 mmHg. Medical treat-ment of coronary artery disease was chosen.The diagnosis of mitochondrial contribution inhypertrophic CMP was strongly supported byhistological results of skeletal muscle biopsysamples, showing over 30% of COX-negativemuscle fibers, many of them also showing theragged-red fiber appearance, typical and diag-nostic for mitochondrial myopathy. In follow-up she developed episodes of cardiac decom-pensation induced by atrial flutter (ventricularresponse of 90/min) or fibrillation (~ 110/min)alternating with sinusbradycardia. Theseepisodes were accompanied with metabolic

Article

Figure 1. The family pedigrees. The index patients are marked with a black arrow. Blacksymbols indicate cardiac hypertrophy and signs or symptoms of heart failure; gray indi-cates subjects with increased relative wall thickness in echocardiography. MtDNA muta-tions were as followed: Family 1 – MELAS T3258C tRNA Leu(UUR); Family 2 and 3 –MELAS A3243G tRNA Leu (UUR); % indicates the people whose mutant mtDNA het-eroplasmy levels were studied, and the amount of mutant mtDNA in different tissues.

Figure 2. A) Patient II:2, family 1. Electrocardiogram (ECG) shows lateral t-inversions(left panel) and echocardiography (right panel) increased left ventricular wall thickness inparasternal long axis view (arrows); B) Patient III:6, family 2. ECG shows lateral q-wavesand abnormal r-peaks in the lateral chest leads (left panel), echocardiography (rightpanel) left ventricular hypertrophy (arrows). Apical view.

Conclusions:    MELAS-­‐  m.3243A>G  

 cardiomyopathy  a  common  manifesta=on    

May  be  provoked  by  physical  stress  May  be  asymptoma=c  May  manifest  as  acute  arrhythmia  with  rapid  progressive  disease  course  May  stabilize  

à  All  MELAS-­‐carriers:  cardiology  consulta=on  recommended    

Thanks  to  all  the  pa=ents  and  their  families  who  contributed  to  our  studies  and  helped  to  increase  understanding  of  mechanisms  of  mitochondrial  disease  

From  Euromit  to  Horizon  2020:  how  to  reinforce  mito  interna=onal  networks  

     

We  start  to  be  good  in  diagnosis    

Progress  in  understanding  mechanism        

à  Emphasis  on  therapy  

Mitochondrial disorders: variability is a challenge for therapy trials

Progressive encephalopathy Neurodegeneration Strokes, demyelination Epilepsy, ataxia, parkinsonism, migraines cognitive decline, hemiparesis, psychiatric symptoms Cardiomyopathy, conduction defects Kidney dysfunction Diabetes Intestinal dysfunction: malabsorption, diarrhea Infertility, premature menopause Sideroblastic anemia Immunological defects

Deafness, hearing deficit Retinitis pigmentosa Optic neuropathy Cataracts Defects of vision, blindness Acute liver damage Hepatopathy Muscle weakness Cramps Tiredness in exercise Sensory or motor neuropathies Tingling, pain and numbness of extremities

Emphasis  on  therapy:    Op=mal  treatment  trial  with  pa=ents  who  are/have  

   •  Age  &  gender  matched  

•  Similar  manifesta=ons  •  Similar  gene=c  background  •  Similar  amount  of  mutant  mtDNA  •  Similar  stage  of  severity  

•  Placebo-­‐controlled  double-­‐blind  studies    à Small  pa=ent  groups,  significance  compromised  à Interna=onal  collabora=on  

Knowledge  -­‐  Coordina=on  -­‐  Applica=on  

Na=onal  registries  à Informa=on  of  natural  history  of  disease  à Standardized  data  collec=on  à Enrollment  to  therapy  trials  with  large  enough  study  groups  

Priori=za=on  of  therapy  trials  based  on  preclinical  evidence  à  “interna=onal  coordina=on  group”  for  mitochondrial  disease  and  treatment  –  Europe,  USA,  Japan,  Australia;  Bethesda  2012  

Horizon  2020  

•  Horizon  2020:      The  biggest  EU  research  and  innova=on  programme  ever:    €80  billion  of  funding  available  over  7  years  (2014  to  2020)  

•  “The  goal  is  to  ensure  Europe  produces  world-­‐class  science,  removes  barriers  to  innova=on  and  makes  it  easier  for  the  public  and  private  sectors  to  work  together  in  delivering  innova=on.”  

Horizon  2020  aims  /  health  •  Research  of  mechanisms:  

improve  understanding  of  the  causes  and  mechanisms  underlying  health,  healthy  ageing  and  disease  

•  Diagnos=cs  and  treatment:  improve  our  ability  to  monitor  health  and  to  prevent,  detect,  treat  and  manage  disease  

•  models  and  tools  for  health  and  care  delivery.  

•  support  older  persons  to  remain  ac=ve  and  healthy  

Rare  disorders    are  a  major  health  problem  

Affec=ng  fewer  than  1:2000  of  popula=on    In  EU:  6000-­‐8000  dis=nct  rare  diseases  affect  6-­‐8%  of  the  popula=on  –  between  27  and  36  million  people  à  Most  are  lacking  therapy  

 

Special  issues  for  rare  diseases  

•  small  and  dispersed  pa=ent  popula=ons    •  nature  of  the  therapies  oeen  highly  specialized  and  novel  

•  Academia  and  company  collabora=on  thin  •  limited  market  for  such  therapies    à  low  commercial  return  à   Low  interest  of  pharma  companies  for  development  

   

Rare  diseases  Interna=onal  Rare  Diseases  Research  

Consor=um  (IRDiRC)    

•  Launched  2011  to  strengthen  interna=onal  collabora=on    

•  Aims  to  deliver  200  new  therapies  for  rare  diseases  and  means  to  diagnose  most  of  them  by  the  year  2020  

•  Co-­‐funded  by  member  states  •  aims  at  understanding  of  

disease  mechanisms  and  natural  history  of  rare  diseases    

•  objec=ve  to  develop  new  diagnos=c  tools  and  treatments  (preclinical,  animal  models,  cell-­‐  gene  therapy)    

•  Transna=onal      •  5-­‐6.000.000  €  per  grant    •  Total  budget  60.000.000    

Rare  diseases  Interna=onal  Rare  Diseases  Research  

Consor=um  (IRDiRC)    •  Co-­‐funded  by  member  states:  state  commitment  •  aims  at  understanding  of  disease  mechanisms  and  

natural  history  of  rare  diseases    •  objec=ve  to  develop  new  diagnos=c  tools  and  

treatments  (preclinical,  animal  models,  cell-­‐  gene  therapy)    

•  Transna=onal      •  5-­‐6.000.000  €  per  grant    •  Total  budget  60.000.000    

Mitochondrial  disease  consor=a  poten=al  for:    

Animal  models    Coordina=on  of  trials  for  promising  therapeu=c  strategies    

– MtDNA  maintenance  diseases  –  Respiratory  chain  diseases  of  childhood  –  Transla=on  disorders                

 Deadline  for  applica=ons    2014-­‐10-­‐14  17:00:00  (Brussels  local  =me)      

Registries  Pa=ent  trials  àCollabora=on  with  industry  

Pa=ent  organiza=ons  –  strong  and  important  impact  

•  Different  countries  –  very  different  levels  of  organiza=on  in  different  countries  

•  Raising  awareness  -­‐  lobbying  •  Facilita=ng  funding  •  Spreading  informa=on  –  collec=ng  pa=ents  together  with  a  common  voice  

•  Contacts  to  both  research  and  pharma  •  Peer  support  

EUROMIT  2014  –  Tampere,  Finland  

Mitochondrial  medicine  from  1990  

 First  parallel  conference  of  scien=sts  with  pa=ents  and  their  families  and  carers    Aim  to  -­‐  Generate  pa=ent  support  –  issues  vary  in  different  countries  

-­‐  Raise  awareness  -­‐  Enhance  contact  between  pa=ent  organiza=ons  in  Europe  

-­‐  Train  medical  personnel