1. Mitochondrial Cytopathy
Prof. Surender K Yachha
Department of Pediatric Gastroenterology
SGPGIMS, Lucknow

2. Mitochondria: “Powerhouse” of the cell
FAOD
RCD

3. Defect

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

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

24. Respiratory Chain Defects

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