SlideShare a Scribd company logo
1 of 57
Download to read offline
Practical Approaches to
   a Mito Diagnosis
 Richard H. Haas M.B., B.Chir., M.R.C.P.
 Director UCSD Mitochondrial Disease Laboratory
       Co-Director UCSD Mitochondrial and
            Metabolic Disease Center
Overview of Mitochondrial Diagnosis
Basic Mito Facts and Background, including what mitochondria do
Types of problems that can be caused by Mito dysfunction
Genetics, in brief
Mito Diseases - what are they and how are they classified
(OXPHOS, Leigh's, MELAS, etc.)
Inherent problems in diagnosis/diagnostic approaches of both
OXPHOS and mtDNA disease - Heteroplasmy
Testing, in brief, including advantages and limitations of new
nDNA gene sequencing
Clues to the diagnosis of mitochondrial disease for clinicians (and
families)
How does one arrive at a diagnosis of Mito disease? Combination of
clinical testing, biochemical testing, personal and family history, and
symptoms/clinical presentation
Why are more invasive tests (i.e. muscle biopsy) sometimes
necessary?
How is the field of mitochondrial medicine changing? Are there new
types of mitochondrial disease? What may the future look like for
this field and for patients/families?
Haas diagnosis 2012
Haas diagnosis 2012
Haas diagnosis 2012
Haas diagnosis 2012
Basic Mito Facts
Prokaryote (Bacterial) origin of
mitochondria & mtDNA – symbiotic
relationship
1500 nuclear mitochondrial genes
2-10 mtDNA molecules per mitochondrion
100 – 10,000 mitochondria per nucleated
cell
mtDNA is maternally inherited
Kirkman MA, Yu-Wai P, Chinnery PF
Clin Med. 2008 Dec;8(6):601-6.
Haas diagnosis 2012
Major Mitochondrial Functions
Make ATP for cellular energy –
oxidative phosphorylation
Metabolize
– fats
– carbohydrates
– amino acids
Interconvert carbohydrates, fats and amino acids
Synthesize some proteins
Reproduce themselves (replicate), fusion/fission
Participate in apoptosis
Make free radicals
Innate Immunity
Human mtDNA 16569 bp
Patient photos
removed for
privacy purposes.
Oxphos Disease
A disease of energy metabolism resulting in
  impairment of oxidative phosphorylation

Nuclear Gene Defects (80% of Child disease)
  mtDNA Defects (60% of Adult disease)
Leigh Syndrome—
  Cytochrome Oxidase Deficiency
  Experimental Treatment with TAU and DCA




         patient photo removed for
         privacy purposes.




                                         Age 16
Age 5              Age 8             Graduating from HS
                                        In June 2011
Leigh Syndrome: Subacute Necrotizing
        Encephalomyelopathy
Haas diagnosis 2012
Leigh
Syndrome
                 15%




   30%     25%
MELAS

Mitochondrial Encephalomyopathy with
Lactic Acidosis and Stroke-like Episodes
Severe Pediatric MELAS—
   90% Heteroplasmy

     Age 19: prepubertal,
     short stature, ataxia,
     dementia, seizures
     Multiple occipital
     infarcts cortical
     blindness
     Deafness, myopathy,
     cardiomyopathy
     Plasma lactate 3.5 mM,
     CSF lactate 5.5 mM
     Calcified Basal Ganglia


                         Skoglund RR.
                         Neurology. 1979 May;29(5):717-20
Haas diagnosis 2012
Haas diagnosis 2012
Heteroplasmy




Wild Type       Mutant
Heteroplasmy in Fibroblasts
          Cox I 488      Porin 594      merge




Control




MELAS
 3243
How Does Genetic Mitochondrial
      Disease Present ?
Acute/ Subacute                 Chronic
–   Severe Metabolic Crisis     –   Growth Retardation
–   Encephalopathy              –   Developmental Delay
–   Arrhythmia, Heart block     –   ‘Strabismus’
–   Opthalmoplegia, Blindness   –   Diabetes
–   Stroke                      –   Irritable Bowel Syndrome
                                –   Cardiomyopathy
                                –   Neuropathy, Ataxia
                                –   Hypotonia and Weakness
                                –   Exercise Intolerance
                                –   Dementia
Severity of Disease Affects Onset

                           MITOCHONDRIAL DISEASE




      SEVERE                      MODERATE                   MILD




                                   CHILDHOOD
      INFANCY                       TEENAGE
                                                             ADULT




Severe Lactic Acidosis   Leigh's Syndrome      MELAS   Parkinson's Disease
Haas diagnosis 2012
Haas diagnosis 2012
Diagnosis of Mitochondrial Disease

                           Clinical Symptoms

           Physical Exam
                                               Family History




Metabolic Tests              Diagnosis             Organ Evaluation
Blood, Urine, CSF                                     (MRI/MRS,
                                                      EKG/Echo)


                                               Molecular Genetics
       Tissue Biopsy
       (Skin, Muscle,
        Liver, Heart)       Biochemistry
                            Oxphos Studies
                             ETC analysis
Metabolic & Other Tests
Blood, Urine & CSF

       CPK
       Lactate and Pyruvate
       Ammonia
       Plasma Amino Acids
       Plasma Acyl-carnitine profile
       Plasma Carnitine
       Urine Organic Acids
       DNA Studies
Available Mito Tests
 Test                         Tissue
   Histology/EM                 Muscle, Liver, Heart
            Carnitine, CoQ
   Nuclear DNA                  Blood, All Tissues
   mtDNA                        All Tissues, Muscle Best

   Electron Transport           Muscle Fresh/Frozen,
    Assays                        Fibroblasts, Liver, Heart
   Polarographic Assay          Fresh muscle, Liver, Heart
                                  or Mitochondria

   Enzyme Assay          All Tissues, Mitochondria,
                           Fibroblasts
   Protein Immunoassay  Mitochondria (Blue Native)
    Immunocytochemistry    Tissue (Clear Native)
    Immunohistochemistry   Fibroblasts/ Muscle Tissue
Tissue Diagnosis
 Available Tissues
     Blood
     Saliva (Buccal Epithelial Cells)
     Urine Sediment
     Muscle
     Skin Fibroblasts
     Other Tissues
       Liver
       Heart
Heteroplasmy




     Wild Type   Mutant
The Basics of Tissue Testing for
Mitochondrial Disease


    Tissues for mtDNA Testing –
     The Heteroplasmy Problem


    Blood    Saliva    Urine           Muscle


                               % of Mutation
Saliva Collection (Oragene)
Muscle Biopsy Problems
 Histochemistry
   Often normal in Pediatric cases
 Electron Microscopy (EM)
   May help but often difficult to get
 ETC Assays
   Lab to lab variation
   Very susceptible to sample handling
Haas diagnosis 2012
Leigh
Syndrome
                 15%




   30%     25%
Figure 3. Residual activity of complex I CS ratios in the 66 skeletal muscle biopsies
                            analyzed in this patient series




                                            Bernier, F.P. et al. Neurology 2002;59:1406-1411
Ragged Red Fiber Myopathy
Neurometabolic Evaluation

                       Referred age 16 months with
                         Global delay & hypotonia
                         Plasma lactate 4.1 mM
                         CPK 155 U/L
                         Urine organic acids – mild
                           increase in 3-OH isovalerate
                           and glutamate.
                         Plasma acylcarnitines
                           C5OH, C3 and C2.
                         Biotinidase normal
                         Leukocyte carboxylases
   SS Age 23 months        normal
Haas diagnosis 2012
Muscle PCR Msp-I Digest

                                NARP 8993 T>C or G
           SS     PC       WT
                                     60-70%




338
                                   169
Summary
 Tissue sampling for mitochondrial disease is
  dictated by the tests required. Nuclear DNA
  testing requires only blood
 Blood, saliva and urine for mtDNA testing
  are all feasible but heteroplasmy presents a
  problem
 Muscle biopsy remains the ‘Gold Standard’
  for electron transport chain assay and for
  mtDNA testing
 Fresh muscle offers the opportunity to
  perform functional polarography and to
  isolate mitochondria for electron transport
  and protein study
Probability of Mitochondrial
               Disease
Clinical + Biochemical Criteria
   Definite
   Probable
   Possible
   Unlikely
Wolf N., Smeitink J.A.
Neurology. 2002 Nov 12;59(9):1402-5
Haas diagnosis 2012
Epidemiology
>1:200 Children are Born with Potentially
      Pathogenic mtDNA Mutations




The American Journal of Human Genetics 83, 254–260, August 8, 2008

Screened for just 10 (5%) of >200 known pathogenic mtDNA mutations.
mtDNA Disease
                             (<50% of Total)
                          9.2 per 100,000 Retired Adults
                               16.5 per 100,000
                           Working Adults and Children

                         Total Prevalence = 25.7 per 100,000
                                = 1 in 4,000 (3,891)


                        mtDNA + nDNA Disease
                           Birth Incidence

                          1 in 2,000 will Develop Disease
                              1 in 4,000 Before Age 10
                               1 in 4,000 After Age 10



Epidemiology of Mitochondrial DNA Disease
Expanding the Phenotype

   A never-ending process
The Dynamic Nature of Mitochondrial Networks

 Control Fibroblast                 Severe Complex I Deficiency




From Nhu-an Pham et al. Microsc.Microanal. 10, 247-260, 2004
David Chan
Caltech
Mitochondrial fusion and fission
Mitochondrial fusion GTPases
 – Mitofusin 2
     (MF2) Charcot-Marie-Tooth disease CMT2A
     HMSN VI
 – Optic atrophy 1 (OPA1)
     Autosomal Dominant Optic Atrophy
Fission proteins
 – Dynamin Related Protein 1 (DRP1)
     Infantile mitochondrial cytopathy with lactic
     acidemia VLCFA, optic atrophy and hypotonia
Autism:
tRNA Lys G8363A mtDNA Point Mutation


              Four year-old boy with history of normal pre-,
                 peri- and postnatal courses
                Normal development until 18 months of age
                Progressive loss of expressive language and
                 language comprehension
                Gradual increase in disruptive behavior,
                 hyperkinesis, and self injurious behavior
                Mild motor clumsiness but no ataxia
                Normal plasma lactate
                Sister with Leigh Disease




     Graf W.D. et al. J Child Neurol. 2000 Jun;15(6):357-61
Autism and Mitochondria
 Autism
Spectrum
   1:110




           Classical
            Autism
                            Definite
                            Mito Disease
                            >1:5000
   5 - 8%
                       Probable
                       Mito Disease
  Possible Mito
     Disease
(Mito Dysfunction)
Haas diagnosis 2012
Haas diagnosis 2012

More Related Content

What's hot

Genetics of Mitochondrial disorders
Genetics of Mitochondrial disordersGenetics of Mitochondrial disorders
Genetics of Mitochondrial disordersPramod Krishnan
 
Mitochondria related diseases
Mitochondria related diseasesMitochondria related diseases
Mitochondria related diseasesSanman samova
 
Mitochondrial disorders
Mitochondrial disordersMitochondrial disorders
Mitochondrial disordersAmr Saeed
 
MITOCHONDRIAL DISORDER
MITOCHONDRIAL DISORDERMITOCHONDRIAL DISORDER
MITOCHONDRIAL DISORDERLovely Sinha
 
Mitochondrial Diseases
Mitochondrial DiseasesMitochondrial Diseases
Mitochondrial DiseasesTayyab Chishti
 
Mitochondrial Myopathy
Mitochondrial MyopathyMitochondrial Myopathy
Mitochondrial MyopathyDeathscife1
 
Congenital myasthenic syndrome
Congenital myasthenic syndromeCongenital myasthenic syndrome
Congenital myasthenic syndromeNeurologyKota
 
Mitochondial disorders
Mitochondial disordersMitochondial disorders
Mitochondial disordersaqsa ayoub
 
Neurological Aspects of Tuberous Sclerosis
Neurological Aspects of Tuberous Sclerosis Neurological Aspects of Tuberous Sclerosis
Neurological Aspects of Tuberous Sclerosis Ade Wijaya
 
genetic diseases of mitochondrial origin genetic diseases
genetic diseases  of mitochondrial origin genetic diseases genetic diseases  of mitochondrial origin genetic diseases
genetic diseases of mitochondrial origin genetic diseases Nisha Sunny
 
Enzyme replacement therapy in neurological disorders
Enzyme replacement therapy in neurological disordersEnzyme replacement therapy in neurological disorders
Enzyme replacement therapy in neurological disordersNeurologyKota
 
Dr. Boles MitoAction Presentation 9/13/13
Dr. Boles MitoAction Presentation 9/13/13Dr. Boles MitoAction Presentation 9/13/13
Dr. Boles MitoAction Presentation 9/13/13mitoaction
 
MBG*3050 Progeria Presentation
MBG*3050 Progeria PresentationMBG*3050 Progeria Presentation
MBG*3050 Progeria Presentationguest4050de
 
Antinuclear Antibodies by Bio-Plex 2200
Antinuclear Antibodies by Bio-Plex 2200Antinuclear Antibodies by Bio-Plex 2200
Antinuclear Antibodies by Bio-Plex 2200Marta Talise
 
Congenital myasthenic syndromes
Congenital myasthenic syndromesCongenital myasthenic syndromes
Congenital myasthenic syndromesnikhilprerana
 
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathyNeurology Residency
 
Congenital myasthenic syndrome
Congenital myasthenic syndromeCongenital myasthenic syndrome
Congenital myasthenic syndromePrashant Makhija
 

What's hot (20)

Genetics of Mitochondrial disorders
Genetics of Mitochondrial disordersGenetics of Mitochondrial disorders
Genetics of Mitochondrial disorders
 
Mitochondria related diseases
Mitochondria related diseasesMitochondria related diseases
Mitochondria related diseases
 
Mitochondrial disorders
Mitochondrial disordersMitochondrial disorders
Mitochondrial disorders
 
MITOCHONDRIAL DISORDER
MITOCHONDRIAL DISORDERMITOCHONDRIAL DISORDER
MITOCHONDRIAL DISORDER
 
Mitochondrial diseases
Mitochondrial diseasesMitochondrial diseases
Mitochondrial diseases
 
Basics
BasicsBasics
Basics
 
Mitochondrial Diseases
Mitochondrial DiseasesMitochondrial Diseases
Mitochondrial Diseases
 
Mitochondrial Myopathy
Mitochondrial MyopathyMitochondrial Myopathy
Mitochondrial Myopathy
 
Mitochondrial Disorder
Mitochondrial DisorderMitochondrial Disorder
Mitochondrial Disorder
 
Congenital myasthenic syndrome
Congenital myasthenic syndromeCongenital myasthenic syndrome
Congenital myasthenic syndrome
 
Mitochondial disorders
Mitochondial disordersMitochondial disorders
Mitochondial disorders
 
Neurological Aspects of Tuberous Sclerosis
Neurological Aspects of Tuberous Sclerosis Neurological Aspects of Tuberous Sclerosis
Neurological Aspects of Tuberous Sclerosis
 
genetic diseases of mitochondrial origin genetic diseases
genetic diseases  of mitochondrial origin genetic diseases genetic diseases  of mitochondrial origin genetic diseases
genetic diseases of mitochondrial origin genetic diseases
 
Enzyme replacement therapy in neurological disorders
Enzyme replacement therapy in neurological disordersEnzyme replacement therapy in neurological disorders
Enzyme replacement therapy in neurological disorders
 
Dr. Boles MitoAction Presentation 9/13/13
Dr. Boles MitoAction Presentation 9/13/13Dr. Boles MitoAction Presentation 9/13/13
Dr. Boles MitoAction Presentation 9/13/13
 
MBG*3050 Progeria Presentation
MBG*3050 Progeria PresentationMBG*3050 Progeria Presentation
MBG*3050 Progeria Presentation
 
Antinuclear Antibodies by Bio-Plex 2200
Antinuclear Antibodies by Bio-Plex 2200Antinuclear Antibodies by Bio-Plex 2200
Antinuclear Antibodies by Bio-Plex 2200
 
Congenital myasthenic syndromes
Congenital myasthenic syndromesCongenital myasthenic syndromes
Congenital myasthenic syndromes
 
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
 
Congenital myasthenic syndrome
Congenital myasthenic syndromeCongenital myasthenic syndrome
Congenital myasthenic syndrome
 

Viewers also liked

одо
одоодо
одоltuya
 
GETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and Humor
GETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and HumorGETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and Humor
GETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and Humormitoaction
 
NC PCI Progress Report, February 2012
NC PCI Progress Report, February 2012NC PCI Progress Report, February 2012
NC PCI Progress Report, February 2012ncAIDSfund
 
Silicon Valley Marketo User Group Meeting August 23, 2012
Silicon Valley Marketo User Group Meeting August 23, 2012Silicon Valley Marketo User Group Meeting August 23, 2012
Silicon Valley Marketo User Group Meeting August 23, 2012ryanvong
 
LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)
LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)
LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)Percy Lopez
 
TUBE FEEDING FOR DYSMOTILITY CONSUMERS
TUBE FEEDING FOR  DYSMOTILITY CONSUMERSTUBE FEEDING FOR  DYSMOTILITY CONSUMERS
TUBE FEEDING FOR DYSMOTILITY CONSUMERSmitoaction
 
11th Annual Biosimilars Uk (2012)
11th Annual Biosimilars Uk (2012)11th Annual Biosimilars Uk (2012)
11th Annual Biosimilars Uk (2012)shad121
 
Commercial areas design_guidelines
Commercial areas design_guidelinesCommercial areas design_guidelines
Commercial areas design_guidelinesPalak Acharya
 
Emerging therapies for FAODs
Emerging therapies for FAODsEmerging therapies for FAODs
Emerging therapies for FAODsmitoaction
 
Ihoteak eta gure apainketa
Ihoteak eta gure apainketaIhoteak eta gure apainketa
Ihoteak eta gure apainketaELIZALDE
 
New Media II slideshow
New Media II slideshowNew Media II slideshow
New Media II slideshowCollegeStartup
 
INSTALACJA Zielonka
INSTALACJA ZielonkaINSTALACJA Zielonka
INSTALACJA ZielonkasalonyVi
 
Kejohanan sukan sk perwira 2012.ppt
Kejohanan sukan sk perwira 2012.pptKejohanan sukan sk perwira 2012.ppt
Kejohanan sukan sk perwira 2012.pptHaslinda Md Pee
 
Plan and create assessments in sa
Plan and create assessments in saPlan and create assessments in sa
Plan and create assessments in saAdam Caplan
 
[Tieu luan] tham do thi phan cua heineken
[Tieu luan] tham do thi phan cua heineken[Tieu luan] tham do thi phan cua heineken
[Tieu luan] tham do thi phan cua heineken3272
 
MitoAction Pyruvate Disorders Presentation 11-07-2014
MitoAction Pyruvate Disorders Presentation 11-07-2014MitoAction Pyruvate Disorders Presentation 11-07-2014
MitoAction Pyruvate Disorders Presentation 11-07-2014mitoaction
 
Content Marketing, Content Creation and Content Curation presentation
Content Marketing, Content Creation and Content Curation presentationContent Marketing, Content Creation and Content Curation presentation
Content Marketing, Content Creation and Content Curation presentationSue Duris, MBA
 

Viewers also liked (20)

одо
одоодо
одо
 
Mps
MpsMps
Mps
 
GETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and Humor
GETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and HumorGETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and Humor
GETTING THROUGH THE DAY WITH MITO: Treatments, Supplements and Humor
 
Functions
FunctionsFunctions
Functions
 
NC PCI Progress Report, February 2012
NC PCI Progress Report, February 2012NC PCI Progress Report, February 2012
NC PCI Progress Report, February 2012
 
Silicon Valley Marketo User Group Meeting August 23, 2012
Silicon Valley Marketo User Group Meeting August 23, 2012Silicon Valley Marketo User Group Meeting August 23, 2012
Silicon Valley Marketo User Group Meeting August 23, 2012
 
LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)
LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)
LEY FUNDAMENTAL DE LA EDUCACIÓN (Honduras 2012)
 
TUBE FEEDING FOR DYSMOTILITY CONSUMERS
TUBE FEEDING FOR  DYSMOTILITY CONSUMERSTUBE FEEDING FOR  DYSMOTILITY CONSUMERS
TUBE FEEDING FOR DYSMOTILITY CONSUMERS
 
11th Annual Biosimilars Uk (2012)
11th Annual Biosimilars Uk (2012)11th Annual Biosimilars Uk (2012)
11th Annual Biosimilars Uk (2012)
 
Commercial areas design_guidelines
Commercial areas design_guidelinesCommercial areas design_guidelines
Commercial areas design_guidelines
 
Emerging therapies for FAODs
Emerging therapies for FAODsEmerging therapies for FAODs
Emerging therapies for FAODs
 
Ihoteak eta gure apainketa
Ihoteak eta gure apainketaIhoteak eta gure apainketa
Ihoteak eta gure apainketa
 
New Media II slideshow
New Media II slideshowNew Media II slideshow
New Media II slideshow
 
Mapping palestine
Mapping palestineMapping palestine
Mapping palestine
 
INSTALACJA Zielonka
INSTALACJA ZielonkaINSTALACJA Zielonka
INSTALACJA Zielonka
 
Kejohanan sukan sk perwira 2012.ppt
Kejohanan sukan sk perwira 2012.pptKejohanan sukan sk perwira 2012.ppt
Kejohanan sukan sk perwira 2012.ppt
 
Plan and create assessments in sa
Plan and create assessments in saPlan and create assessments in sa
Plan and create assessments in sa
 
[Tieu luan] tham do thi phan cua heineken
[Tieu luan] tham do thi phan cua heineken[Tieu luan] tham do thi phan cua heineken
[Tieu luan] tham do thi phan cua heineken
 
MitoAction Pyruvate Disorders Presentation 11-07-2014
MitoAction Pyruvate Disorders Presentation 11-07-2014MitoAction Pyruvate Disorders Presentation 11-07-2014
MitoAction Pyruvate Disorders Presentation 11-07-2014
 
Content Marketing, Content Creation and Content Curation presentation
Content Marketing, Content Creation and Content Curation presentationContent Marketing, Content Creation and Content Curation presentation
Content Marketing, Content Creation and Content Curation presentation
 

Similar to Haas diagnosis 2012

Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...
Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...
Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...mitoaction
 
Mitochondrial dna and dysfunctions
Mitochondrial dna and dysfunctionsMitochondrial dna and dysfunctions
Mitochondrial dna and dysfunctionsNandhini Elango
 
複製 Mitalipov
複製  Mitalipov複製  Mitalipov
複製 Mitalipovt7260678
 
Mitochondrial disorders overview
Mitochondrial disorders overviewMitochondrial disorders overview
Mitochondrial disorders overviewsabiiiiii
 
Mitochondrial Medicine - Mosul project
Mitochondrial Medicine - Mosul projectMitochondrial Medicine - Mosul project
Mitochondrial Medicine - Mosul projectMohammad Alkataan
 
Stephan Zuckner - 'Neuropatías periféricas hereditarias'
Stephan Zuckner - 'Neuropatías periféricas hereditarias'Stephan Zuckner - 'Neuropatías periféricas hereditarias'
Stephan Zuckner - 'Neuropatías periféricas hereditarias'Fundación Ramón Areces
 
Bmb 411 presentation open
Bmb 411 presentation  openBmb 411 presentation  open
Bmb 411 presentation openbuk11
 
Bmb 411 presentation open
Bmb 411 presentation  openBmb 411 presentation  open
Bmb 411 presentation openbuk11
 
Acute myeloid leukemia
Acute myeloid leukemiaAcute myeloid leukemia
Acute myeloid leukemiaPradip Katwal
 
Elementary genetics by momen
Elementary genetics by momenElementary genetics by momen
Elementary genetics by momenMomen Ali Khan
 
Judith Campisi at Health Extension Salon #3
Judith Campisi at Health Extension Salon #3Judith Campisi at Health Extension Salon #3
Judith Campisi at Health Extension Salon #3Health_Extension
 
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...dkNET
 
Neuroblastoma urology rotation
Neuroblastoma urology rotation Neuroblastoma urology rotation
Neuroblastoma urology rotation Stav Debi
 
Highyieldtopics
HighyieldtopicsHighyieldtopics
HighyieldtopicsHULK136
 
14 mitochondrial hepatopathy ahmedabad-july-2012
14 mitochondrial hepatopathy ahmedabad-july-201214 mitochondrial hepatopathy ahmedabad-july-2012
14 mitochondrial hepatopathy ahmedabad-july-2012Atit Ghoda
 
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...KineMed, Inc.
 

Similar to Haas diagnosis 2012 (20)

Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...
Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...
Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Dis...
 
Mitochondrial dna and dysfunctions
Mitochondrial dna and dysfunctionsMitochondrial dna and dysfunctions
Mitochondrial dna and dysfunctions
 
複製 Mitalipov
複製  Mitalipov複製  Mitalipov
複製 Mitalipov
 
Mitalipov
MitalipovMitalipov
Mitalipov
 
Mitochondrial disorders overview
Mitochondrial disorders overviewMitochondrial disorders overview
Mitochondrial disorders overview
 
Mitochondrial Medicine - Mosul project
Mitochondrial Medicine - Mosul projectMitochondrial Medicine - Mosul project
Mitochondrial Medicine - Mosul project
 
Stephan Zuckner - 'Neuropatías periféricas hereditarias'
Stephan Zuckner - 'Neuropatías periféricas hereditarias'Stephan Zuckner - 'Neuropatías periféricas hereditarias'
Stephan Zuckner - 'Neuropatías periféricas hereditarias'
 
Bmb 411 presentation open
Bmb 411 presentation  openBmb 411 presentation  open
Bmb 411 presentation open
 
Bmb 411 presentation open
Bmb 411 presentation  openBmb 411 presentation  open
Bmb 411 presentation open
 
Mitochondrial diseases overview!
Mitochondrial diseases overview!Mitochondrial diseases overview!
Mitochondrial diseases overview!
 
Prion diseases
Prion diseasesPrion diseases
Prion diseases
 
Acute myeloid leukemia
Acute myeloid leukemiaAcute myeloid leukemia
Acute myeloid leukemia
 
Elementary genetics by momen
Elementary genetics by momenElementary genetics by momen
Elementary genetics by momen
 
Judith Campisi at Health Extension Salon #3
Judith Campisi at Health Extension Salon #3Judith Campisi at Health Extension Salon #3
Judith Campisi at Health Extension Salon #3
 
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...
 
Neuroblastoma urology rotation
Neuroblastoma urology rotation Neuroblastoma urology rotation
Neuroblastoma urology rotation
 
Highyieldtopics
HighyieldtopicsHighyieldtopics
Highyieldtopics
 
14 mitochondrial hepatopathy ahmedabad-july-2012
14 mitochondrial hepatopathy ahmedabad-july-201214 mitochondrial hepatopathy ahmedabad-july-2012
14 mitochondrial hepatopathy ahmedabad-july-2012
 
101111 als
101111 als101111 als
101111 als
 
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...
 

More from mitoaction

Slides faod - the other mitochondrial energy diseases - vockley
Slides   faod - the other mitochondrial energy diseases - vockleySlides   faod - the other mitochondrial energy diseases - vockley
Slides faod - the other mitochondrial energy diseases - vockleymitoaction
 
Help is on the Way
Help is on the WayHelp is on the Way
Help is on the Waymitoaction
 
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction
 Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunctionmitoaction
 
Mito Cocktail final
Mito Cocktail finalMito Cocktail final
Mito Cocktail finalmitoaction
 
McGuire - Immune Systems
McGuire - Immune SystemsMcGuire - Immune Systems
McGuire - Immune Systemsmitoaction
 
Mitochondrial Disease & Immune Systems
Mitochondrial Disease & Immune SystemsMitochondrial Disease & Immune Systems
Mitochondrial Disease & Immune Systemsmitoaction
 
App overview video
App overview videoApp overview video
App overview videomitoaction
 
Dr. Karaa - MMS Standards of Care
Dr. Karaa - MMS Standards of CareDr. Karaa - MMS Standards of Care
Dr. Karaa - MMS Standards of Caremitoaction
 
Leigh Syndrome - Mary Kay Koenig, MD
Leigh Syndrome - Mary Kay Koenig, MDLeigh Syndrome - Mary Kay Koenig, MD
Leigh Syndrome - Mary Kay Koenig, MDmitoaction
 
"Is it Really Mito"
"Is it Really Mito""Is it Really Mito"
"Is it Really Mito"mitoaction
 
What you should know about genetic testing for mitochondrial disorders
What you should know about genetic testing for mitochondrial disordersWhat you should know about genetic testing for mitochondrial disorders
What you should know about genetic testing for mitochondrial disordersmitoaction
 
Microbiome and Mitochondria
Microbiome and MitochondriaMicrobiome and Mitochondria
Microbiome and Mitochondriamitoaction
 
Mitochondrial Replacement Therapy
Mitochondrial Replacement TherapyMitochondrial Replacement Therapy
Mitochondrial Replacement Therapymitoaction
 
Mitochondria and MitoQ – A research update
Mitochondria and MitoQ – A research updateMitochondria and MitoQ – A research update
Mitochondria and MitoQ – A research updatemitoaction
 
Day-to-Day Management of Mitochondrial Disease
Day-to-Day Management of Mitochondrial DiseaseDay-to-Day Management of Mitochondrial Disease
Day-to-Day Management of Mitochondrial Diseasemitoaction
 
Exercise and nutrition in Mitochondrial Disease
Exercise and nutrition in Mitochondrial DiseaseExercise and nutrition in Mitochondrial Disease
Exercise and nutrition in Mitochondrial Diseasemitoaction
 
Diagnostic Testing for Mitochondrial Disease
Diagnostic Testing for Mitochondrial DiseaseDiagnostic Testing for Mitochondrial Disease
Diagnostic Testing for Mitochondrial Diseasemitoaction
 
How to Build Your Mitochondrial Medical Home
How to Build Your Mitochondrial Medical HomeHow to Build Your Mitochondrial Medical Home
How to Build Your Mitochondrial Medical Homemitoaction
 
Extended Year Services 2016
Extended Year Services 2016Extended Year Services 2016
Extended Year Services 2016mitoaction
 

More from mitoaction (20)

Slides faod - the other mitochondrial energy diseases - vockley
Slides   faod - the other mitochondrial energy diseases - vockleySlides   faod - the other mitochondrial energy diseases - vockley
Slides faod - the other mitochondrial energy diseases - vockley
 
Help is on the Way
Help is on the WayHelp is on the Way
Help is on the Way
 
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction
 Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction
Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction
 
DTC Testing
DTC TestingDTC Testing
DTC Testing
 
Mito Cocktail final
Mito Cocktail finalMito Cocktail final
Mito Cocktail final
 
McGuire - Immune Systems
McGuire - Immune SystemsMcGuire - Immune Systems
McGuire - Immune Systems
 
Mitochondrial Disease & Immune Systems
Mitochondrial Disease & Immune SystemsMitochondrial Disease & Immune Systems
Mitochondrial Disease & Immune Systems
 
App overview video
App overview videoApp overview video
App overview video
 
Dr. Karaa - MMS Standards of Care
Dr. Karaa - MMS Standards of CareDr. Karaa - MMS Standards of Care
Dr. Karaa - MMS Standards of Care
 
Leigh Syndrome - Mary Kay Koenig, MD
Leigh Syndrome - Mary Kay Koenig, MDLeigh Syndrome - Mary Kay Koenig, MD
Leigh Syndrome - Mary Kay Koenig, MD
 
"Is it Really Mito"
"Is it Really Mito""Is it Really Mito"
"Is it Really Mito"
 
What you should know about genetic testing for mitochondrial disorders
What you should know about genetic testing for mitochondrial disordersWhat you should know about genetic testing for mitochondrial disorders
What you should know about genetic testing for mitochondrial disorders
 
Microbiome and Mitochondria
Microbiome and MitochondriaMicrobiome and Mitochondria
Microbiome and Mitochondria
 
Mitochondrial Replacement Therapy
Mitochondrial Replacement TherapyMitochondrial Replacement Therapy
Mitochondrial Replacement Therapy
 
Mitochondria and MitoQ – A research update
Mitochondria and MitoQ – A research updateMitochondria and MitoQ – A research update
Mitochondria and MitoQ – A research update
 
Day-to-Day Management of Mitochondrial Disease
Day-to-Day Management of Mitochondrial DiseaseDay-to-Day Management of Mitochondrial Disease
Day-to-Day Management of Mitochondrial Disease
 
Exercise and nutrition in Mitochondrial Disease
Exercise and nutrition in Mitochondrial DiseaseExercise and nutrition in Mitochondrial Disease
Exercise and nutrition in Mitochondrial Disease
 
Diagnostic Testing for Mitochondrial Disease
Diagnostic Testing for Mitochondrial DiseaseDiagnostic Testing for Mitochondrial Disease
Diagnostic Testing for Mitochondrial Disease
 
How to Build Your Mitochondrial Medical Home
How to Build Your Mitochondrial Medical HomeHow to Build Your Mitochondrial Medical Home
How to Build Your Mitochondrial Medical Home
 
Extended Year Services 2016
Extended Year Services 2016Extended Year Services 2016
Extended Year Services 2016
 

Recently uploaded

"Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio..."Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio...Sujoy Dasgupta
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu Medical University
 
AORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectionAORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectiondrhanifmohdali
 
Mental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil ThirusanguMental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil Thirusangu Medical University
 
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaMale Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaSujoy Dasgupta
 
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfSGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfHongBiThi1
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...Shubhanshu Gaurav
 
Neurological history taking (2024) .
Neurological  history  taking  (2024)  .Neurological  history  taking  (2024)  .
Neurological history taking (2024) .Mohamed Rizk Khodair
 
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D.  Bawankar.pptPharmacokinetic Models by Dr. Ram D.  Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D. Bawankar.pptRamDBawankar1
 
EXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionEXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionkrishnareddy157915
 
Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024EwoutSteyerberg1
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyZurück zum Ursprung
 
SGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA .pdf
SGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA    .pdfSGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA    .pdf
SGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA .pdfHongBiThi1
 
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdfCONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdfDolisha Warbi
 
blood bank management system project report
blood bank management system project reportblood bank management system project report
blood bank management system project reportNARMADAPETROLEUMGAS
 
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfSGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfHongBiThi1
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdfHongBiThi1
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets barmohitRahangdale
 

Recently uploaded (20)

"Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio..."Radical excision of DIE in subferile women with deep infiltrating endometrio...
"Radical excision of DIE in subferile women with deep infiltrating endometrio...
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu
 
AORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectionAORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissection
 
Mental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil ThirusanguMental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil Thirusangu
 
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaMale Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
 
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdfSGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
SGK RỐI LOẠN KALI MÁU CỰC KỲ QUAN TRỌNG.pdf
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
 
Neurological history taking (2024) .
Neurological  history  taking  (2024)  .Neurological  history  taking  (2024)  .
Neurological history taking (2024) .
 
How to master Steroid (glucocorticoids) prescription, different scenarios, ca...
How to master Steroid (glucocorticoids) prescription, different scenarios, ca...How to master Steroid (glucocorticoids) prescription, different scenarios, ca...
How to master Steroid (glucocorticoids) prescription, different scenarios, ca...
 
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D.  Bawankar.pptPharmacokinetic Models by Dr. Ram D.  Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
 
EXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung functionEXERCISE PERFORMANCE.pptx, Lung function
EXERCISE PERFORMANCE.pptx, Lung function
 
Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024
 
How to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturallyHow to cure cirrhosis and chronic hepatitis naturally
How to cure cirrhosis and chronic hepatitis naturally
 
SGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA .pdf
SGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA    .pdfSGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA    .pdf
SGK NGẠT NƯỚC ĐHYHN RẤT LÀ HAY NHA .pdf
 
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdfCONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
CONNECTIVE TISSUE (ANATOMY AND PHYSIOLOGY).pdf
 
Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...
Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...
Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel,...
 
blood bank management system project report
blood bank management system project reportblood bank management system project report
blood bank management system project report
 
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdfSGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
SGK RỐI LOẠN TOAN KIỀM ĐHYHN RẤT HAY VÀ ĐẶC SẮC.pdf
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets bar
 

Haas diagnosis 2012

  • 1. Practical Approaches to a Mito Diagnosis Richard H. Haas M.B., B.Chir., M.R.C.P. Director UCSD Mitochondrial Disease Laboratory Co-Director UCSD Mitochondrial and Metabolic Disease Center
  • 2. Overview of Mitochondrial Diagnosis Basic Mito Facts and Background, including what mitochondria do Types of problems that can be caused by Mito dysfunction Genetics, in brief Mito Diseases - what are they and how are they classified (OXPHOS, Leigh's, MELAS, etc.) Inherent problems in diagnosis/diagnostic approaches of both OXPHOS and mtDNA disease - Heteroplasmy Testing, in brief, including advantages and limitations of new nDNA gene sequencing Clues to the diagnosis of mitochondrial disease for clinicians (and families) How does one arrive at a diagnosis of Mito disease? Combination of clinical testing, biochemical testing, personal and family history, and symptoms/clinical presentation Why are more invasive tests (i.e. muscle biopsy) sometimes necessary? How is the field of mitochondrial medicine changing? Are there new types of mitochondrial disease? What may the future look like for this field and for patients/families?
  • 7. Basic Mito Facts Prokaryote (Bacterial) origin of mitochondria & mtDNA – symbiotic relationship 1500 nuclear mitochondrial genes 2-10 mtDNA molecules per mitochondrion 100 – 10,000 mitochondria per nucleated cell mtDNA is maternally inherited
  • 8. Kirkman MA, Yu-Wai P, Chinnery PF Clin Med. 2008 Dec;8(6):601-6.
  • 10. Major Mitochondrial Functions Make ATP for cellular energy – oxidative phosphorylation Metabolize – fats – carbohydrates – amino acids Interconvert carbohydrates, fats and amino acids Synthesize some proteins Reproduce themselves (replicate), fusion/fission Participate in apoptosis Make free radicals Innate Immunity
  • 13. Oxphos Disease A disease of energy metabolism resulting in impairment of oxidative phosphorylation Nuclear Gene Defects (80% of Child disease) mtDNA Defects (60% of Adult disease)
  • 14. Leigh Syndrome— Cytochrome Oxidase Deficiency Experimental Treatment with TAU and DCA patient photo removed for privacy purposes. Age 16 Age 5 Age 8 Graduating from HS In June 2011
  • 15. Leigh Syndrome: Subacute Necrotizing Encephalomyelopathy
  • 17. Leigh Syndrome 15% 30% 25%
  • 18. MELAS Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes
  • 19. Severe Pediatric MELAS— 90% Heteroplasmy Age 19: prepubertal, short stature, ataxia, dementia, seizures Multiple occipital infarcts cortical blindness Deafness, myopathy, cardiomyopathy Plasma lactate 3.5 mM, CSF lactate 5.5 mM Calcified Basal Ganglia Skoglund RR. Neurology. 1979 May;29(5):717-20
  • 23. Heteroplasmy in Fibroblasts Cox I 488 Porin 594 merge Control MELAS 3243
  • 24. How Does Genetic Mitochondrial Disease Present ? Acute/ Subacute Chronic – Severe Metabolic Crisis – Growth Retardation – Encephalopathy – Developmental Delay – Arrhythmia, Heart block – ‘Strabismus’ – Opthalmoplegia, Blindness – Diabetes – Stroke – Irritable Bowel Syndrome – Cardiomyopathy – Neuropathy, Ataxia – Hypotonia and Weakness – Exercise Intolerance – Dementia
  • 25. Severity of Disease Affects Onset MITOCHONDRIAL DISEASE SEVERE MODERATE MILD CHILDHOOD INFANCY TEENAGE ADULT Severe Lactic Acidosis Leigh's Syndrome MELAS Parkinson's Disease
  • 28. Diagnosis of Mitochondrial Disease Clinical Symptoms Physical Exam Family History Metabolic Tests Diagnosis Organ Evaluation Blood, Urine, CSF (MRI/MRS, EKG/Echo) Molecular Genetics Tissue Biopsy (Skin, Muscle, Liver, Heart) Biochemistry Oxphos Studies ETC analysis
  • 29. Metabolic & Other Tests Blood, Urine & CSF  CPK  Lactate and Pyruvate  Ammonia  Plasma Amino Acids  Plasma Acyl-carnitine profile  Plasma Carnitine  Urine Organic Acids  DNA Studies
  • 30. Available Mito Tests  Test  Tissue  Histology/EM  Muscle, Liver, Heart  Carnitine, CoQ  Nuclear DNA  Blood, All Tissues  mtDNA  All Tissues, Muscle Best  Electron Transport  Muscle Fresh/Frozen, Assays Fibroblasts, Liver, Heart  Polarographic Assay  Fresh muscle, Liver, Heart or Mitochondria  Enzyme Assay  All Tissues, Mitochondria, Fibroblasts  Protein Immunoassay  Mitochondria (Blue Native) Immunocytochemistry Tissue (Clear Native) Immunohistochemistry Fibroblasts/ Muscle Tissue
  • 31. Tissue Diagnosis  Available Tissues  Blood  Saliva (Buccal Epithelial Cells)  Urine Sediment  Muscle  Skin Fibroblasts  Other Tissues  Liver  Heart
  • 32. Heteroplasmy Wild Type Mutant
  • 33. The Basics of Tissue Testing for Mitochondrial Disease  Tissues for mtDNA Testing – The Heteroplasmy Problem Blood Saliva Urine Muscle % of Mutation
  • 35. Muscle Biopsy Problems  Histochemistry  Often normal in Pediatric cases  Electron Microscopy (EM)  May help but often difficult to get  ETC Assays  Lab to lab variation  Very susceptible to sample handling
  • 37. Leigh Syndrome 15% 30% 25%
  • 38. Figure 3. Residual activity of complex I CS ratios in the 66 skeletal muscle biopsies analyzed in this patient series Bernier, F.P. et al. Neurology 2002;59:1406-1411
  • 39. Ragged Red Fiber Myopathy
  • 40. Neurometabolic Evaluation  Referred age 16 months with  Global delay & hypotonia  Plasma lactate 4.1 mM  CPK 155 U/L  Urine organic acids – mild increase in 3-OH isovalerate and glutamate.  Plasma acylcarnitines C5OH, C3 and C2.  Biotinidase normal  Leukocyte carboxylases SS Age 23 months normal
  • 42. Muscle PCR Msp-I Digest NARP 8993 T>C or G SS PC WT 60-70% 338 169
  • 43. Summary  Tissue sampling for mitochondrial disease is dictated by the tests required. Nuclear DNA testing requires only blood  Blood, saliva and urine for mtDNA testing are all feasible but heteroplasmy presents a problem  Muscle biopsy remains the ‘Gold Standard’ for electron transport chain assay and for mtDNA testing  Fresh muscle offers the opportunity to perform functional polarography and to isolate mitochondria for electron transport and protein study
  • 44. Probability of Mitochondrial Disease Clinical + Biochemical Criteria Definite Probable Possible Unlikely
  • 45. Wolf N., Smeitink J.A. Neurology. 2002 Nov 12;59(9):1402-5
  • 48. >1:200 Children are Born with Potentially Pathogenic mtDNA Mutations The American Journal of Human Genetics 83, 254–260, August 8, 2008 Screened for just 10 (5%) of >200 known pathogenic mtDNA mutations.
  • 49. mtDNA Disease (<50% of Total) 9.2 per 100,000 Retired Adults 16.5 per 100,000 Working Adults and Children Total Prevalence = 25.7 per 100,000 = 1 in 4,000 (3,891) mtDNA + nDNA Disease Birth Incidence 1 in 2,000 will Develop Disease 1 in 4,000 Before Age 10 1 in 4,000 After Age 10 Epidemiology of Mitochondrial DNA Disease
  • 50. Expanding the Phenotype A never-ending process
  • 51. The Dynamic Nature of Mitochondrial Networks Control Fibroblast Severe Complex I Deficiency From Nhu-an Pham et al. Microsc.Microanal. 10, 247-260, 2004
  • 53. Mitochondrial fusion and fission Mitochondrial fusion GTPases – Mitofusin 2 (MF2) Charcot-Marie-Tooth disease CMT2A HMSN VI – Optic atrophy 1 (OPA1) Autosomal Dominant Optic Atrophy Fission proteins – Dynamin Related Protein 1 (DRP1) Infantile mitochondrial cytopathy with lactic acidemia VLCFA, optic atrophy and hypotonia
  • 54. Autism: tRNA Lys G8363A mtDNA Point Mutation  Four year-old boy with history of normal pre-, peri- and postnatal courses  Normal development until 18 months of age  Progressive loss of expressive language and language comprehension  Gradual increase in disruptive behavior, hyperkinesis, and self injurious behavior  Mild motor clumsiness but no ataxia  Normal plasma lactate  Sister with Leigh Disease Graf W.D. et al. J Child Neurol. 2000 Jun;15(6):357-61
  • 55. Autism and Mitochondria Autism Spectrum 1:110 Classical Autism Definite Mito Disease >1:5000 5 - 8% Probable Mito Disease Possible Mito Disease (Mito Dysfunction)