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Mitochondrial Cytopathy




        Prof. Surender K Yachha
 Department of Pediatric Gastroenterology
          SGPGIMS, Lucknow
Mitochondria: “Powerhouse” of the cell




                                 FAOD




                                  RCD
Defect
Mitochondrial diseases

           High energy
           dependency




               In disease
 Mutant mitochondrial DNA >>> normal DNA
  and consequentially shifting proportions
    Shift from one clinical phenotype to
             another with age
Mitochondria
                   and
            respiratory chain




                                 Dependence on
 Aerobic pathway for ATP        Anaerobic pathway
(oxidative phosphorylation)        (glycolysis)




                                Increase lactate
       38 ATP
                                  Only 2 ATP
80% calories (during fasting)
       24 hr: adults
       12 hr: infants           Most affected
Consequences
Glycolysis




                                      Hypoglycemia




    Not metabolised    Respiratory    Try to spare
       in FAOD        chain defects     glucose
Disorders in
Mitochondrial Hepatopathy
1. Fatty Acid Oxidation Defects




  2. Respiratory Chain Defects
“The Masquerader Of All Diseases”

        Highly Deceptive !
Why do we struggle
to identify this disease ?




        Mitochondrial
          Diseases
Settings to predict this disease
Settings in GI practice
107 patients
              FAOD
                                  74%
 30%      31%            13%            16%         10%


<1mo   1mo – 1yr     1yr – 2 yr         >2yr       unknown



 36%      40%            8%             12%         0.01%
                                  82%


        N= 50
       Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
24%



8%    FAOD & RCD
 -    Clinical features
8%


3%


8%

8%


20%


      Lee ,Sokol Semin Liver Dis
5%
           2007;27:259–273.
Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
FAOD                           Importance
Short Chain                     Not much of a problem
Does it really exist??          Developmental delay
                                Behavioural problems
Medium Chain (80%)              Good prognosis
(1:15,000 new born screen)      Maximum heterogeneity
                                Mortality: 16-25%
                                Intellectual delay 20-25%
                                <6yr : decompensation
                                >6yr : death risk reduced

Long Chain                      Mainly liver manifestations
(1:85,000 new born screen)      Adverse prognosis
Primary Carnitine deficiency    Early presentation and death
(1:750,000 - 2,000,000)
                                J Inherit Metab Dis (2010) 33:501–506
Long Chain Hydroxy Acyl CoA Dehydrogenase Def.
                  (LCHADD)
 Early onset: severe         Hypertrophic cardiomyopathy
     phenotype                    Pericardial effusion
                                   Lethality 40-80%
                                     May have HE
                                Neonatal Cholestasis
Infantile onset: hepatic      Hepatomegaly, steatosis
 phenotype (steatosis)              Hypoglycemia
Late onset: myopathic      Exercise induced rhabdomyolysis
       phenotype               (CK: 200,000 u/l: acute
                                      500-5000 u/l
Very Long and Long Chain
Hydroxy Acyl CoA Dehydrogenase Def.
      (VLCHADD and LCHADD)




           J Inherit Metab Dis (2010) 33:501–506
Biochemical differentiation
        Acidosis         Urine      Blood sugar Serum Serum
                        ketones                 Lactate Ammonia
FAOD        ++            Nil              Low        +       +
                       (non-ketotic hypoglycemia)
RCD         ++             ++           Normal      ++++      ±

OA          +++          ++/+++    Low/ Normal/     Normal   ++
        (persistent)                   High
UCD                               Normal                     ++++
Fatty Acid Oxidation Defects
                  Screening                            Definitive
              (available in India)                   (NOT available)
 Tandem MS: Quantitative Fatty acid analysis
              C8-10 in MCAD
             C14-18 in LCHAD
                                                     Enzyme activity in
              C14 in VLCAD
                                                        cultured skin
                                                   fibroblasts or muscle
   + Plasma carnitine and acylcarnitine assay
                                                           biopsy
         •Very low levels reaching zero:
                                                     Carnitine def. also
              primary carnitine def
        •25-50% reduction: Other FAOD

GCMS: Urinary organic acid and acylglycine assay
       (available) - dicarboxyllic acids
Respiratory Chain Defects
               involving Liver
  Disorder        Onset             Disorder             Onset
Neonatal Liver    Acute           Pearsons synd         Insidious
    failure
                             Villous atrophy syndrome   Chronic
Mitochondrial     Acute
DNA depletion                        Navajo             Acute /
 Alpers synd     Insidious      Neurohepatopathy        chronic
Respiratory Chain Defects involving Liver




Neonate   Infancy   Childhood    Adult
Respiratory Chain Defects
Definitive                       Sample                 Availability
     Tests                                                   in India
    Ragged red fiber                  Muscle                    Yes
      (Histology)

    Analysis of oxygen       Liver, muscles, fibroblasts        No
consumption Polarographic     fresh biopsy specimens
         studies                 required (5-10gm)

   Enzymatic activity of             Frozen samples             No
    respiratory chain         (liver, kidney, myocardium)
       complexes            larger tissue (open surgical
                                    in most centers)
  Mt DNA deletions and                    Muscle                No
       mutations
Treatment




  Lee ,Sokol Semin Liver Dis 2007;27:259–273
Role of Carnitine




    Lee ,Sokol Semin Liver Dis 2007;27:259–273
14 mitochondrial hepatopathy ahmedabad-july-2012

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14 mitochondrial hepatopathy ahmedabad-july-2012

  • 1. Mitochondrial Cytopathy Prof. Surender K Yachha Department of Pediatric Gastroenterology SGPGIMS, Lucknow
  • 4. Mitochondrial diseases High energy dependency In disease Mutant mitochondrial DNA >>> normal DNA and consequentially shifting proportions Shift from one clinical phenotype to another with age
  • 5. Mitochondria and respiratory chain Dependence on Aerobic pathway for ATP Anaerobic pathway (oxidative phosphorylation) (glycolysis) Increase lactate 38 ATP Only 2 ATP
  • 6. 80% calories (during fasting) 24 hr: adults 12 hr: infants Most affected
  • 7. Consequences Glycolysis Hypoglycemia Not metabolised Respiratory Try to spare in FAOD chain defects glucose
  • 8. Disorders in Mitochondrial Hepatopathy 1. Fatty Acid Oxidation Defects 2. Respiratory Chain Defects
  • 9. “The Masquerader Of All Diseases” Highly Deceptive !
  • 10. Why do we struggle to identify this disease ? Mitochondrial Diseases
  • 11. Settings to predict this disease
  • 12. Settings in GI practice
  • 13. 107 patients FAOD 74% 30% 31% 13% 16% 10% <1mo 1mo – 1yr 1yr – 2 yr >2yr unknown 36% 40% 8% 12% 0.01% 82% N= 50 Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
  • 14. 24% 8% FAOD & RCD - Clinical features 8% 3% 8% 8% 20% Lee ,Sokol Semin Liver Dis 5% 2007;27:259–273.
  • 15. Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
  • 16. FAOD Importance Short Chain  Not much of a problem Does it really exist??  Developmental delay  Behavioural problems Medium Chain (80%)  Good prognosis (1:15,000 new born screen)  Maximum heterogeneity  Mortality: 16-25%  Intellectual delay 20-25%  <6yr : decompensation  >6yr : death risk reduced Long Chain  Mainly liver manifestations (1:85,000 new born screen)  Adverse prognosis Primary Carnitine deficiency  Early presentation and death (1:750,000 - 2,000,000) J Inherit Metab Dis (2010) 33:501–506
  • 17. Long Chain Hydroxy Acyl CoA Dehydrogenase Def. (LCHADD) Early onset: severe Hypertrophic cardiomyopathy phenotype Pericardial effusion Lethality 40-80% May have HE Neonatal Cholestasis Infantile onset: hepatic Hepatomegaly, steatosis phenotype (steatosis) Hypoglycemia Late onset: myopathic Exercise induced rhabdomyolysis phenotype (CK: 200,000 u/l: acute 500-5000 u/l
  • 18. Very Long and Long Chain Hydroxy Acyl CoA Dehydrogenase Def. (VLCHADD and LCHADD) J Inherit Metab Dis (2010) 33:501–506
  • 19.
  • 20. Biochemical differentiation Acidosis Urine Blood sugar Serum Serum ketones Lactate Ammonia FAOD ++ Nil Low + + (non-ketotic hypoglycemia) RCD ++ ++ Normal ++++ ± OA +++ ++/+++ Low/ Normal/ Normal ++ (persistent) High UCD Normal ++++
  • 21. Fatty Acid Oxidation Defects Screening Definitive (available in India) (NOT available) Tandem MS: Quantitative Fatty acid analysis C8-10 in MCAD C14-18 in LCHAD Enzyme activity in C14 in VLCAD cultured skin fibroblasts or muscle + Plasma carnitine and acylcarnitine assay biopsy •Very low levels reaching zero: Carnitine def. also primary carnitine def •25-50% reduction: Other FAOD GCMS: Urinary organic acid and acylglycine assay (available) - dicarboxyllic acids
  • 22. Respiratory Chain Defects involving Liver Disorder Onset Disorder Onset Neonatal Liver Acute Pearsons synd Insidious failure Villous atrophy syndrome Chronic Mitochondrial Acute DNA depletion Navajo Acute / Alpers synd Insidious Neurohepatopathy chronic
  • 23. Respiratory Chain Defects involving Liver Neonate Infancy Childhood Adult
  • 25. Definitive Sample Availability Tests in India Ragged red fiber Muscle Yes (Histology) Analysis of oxygen Liver, muscles, fibroblasts No consumption Polarographic fresh biopsy specimens studies required (5-10gm) Enzymatic activity of Frozen samples No respiratory chain (liver, kidney, myocardium) complexes larger tissue (open surgical in most centers) Mt DNA deletions and Muscle No mutations
  • 26. Treatment Lee ,Sokol Semin Liver Dis 2007;27:259–273
  • 27. Role of Carnitine Lee ,Sokol Semin Liver Dis 2007;27:259–273