Mitochondrial Cytopathy

Prof. Surender K YachhaDepartment of Pediatric

GastroenterologySGPGIMS, Lucknow

Mitochondria: “Powerhouse” of the cell

FAOD

RCD

Aerobicpathway

Defect

Pathogenic mitochondrial DNA mutations > 200 pathogenic point mutations, deletions,

insertions, rearrangements

Secondary enzyme deficiencies

A long and volatile list

Mitochondrial diseases

LiverBrain

Muscle

High energy dependency

Shift from one clinical phenotype to another with age

Normally: Random segregation of mitochondria during cell division between daughter cells: thus all

functionalIn disease

Mutant mitochondrial DNA >>> normal DNA and consequentially shifting

proportions

More severely affected

Mitochondria

and respiratory chain

Aerobic pathway for ATP (oxidative phosphorylation)

Balance between generation and

scavenging of reactive oxygen species

Dependence on Anaerobic pathway

(glycolysis)

Increase lactateOnly 2 ATP

38 ATP

Imbalance

Pyru

vat

e

Depletion of glycogen stores

Fatty acid ß-oxidation

(mitochondria)

80% cardiac and hepatic functions

Liver beta oxidation

Ketone bodies3 (OH) butyrateAcetoacetate

Alternative fuel supply Brain, Skeletal

cardiac

Infection, stress, fasting

80% calories (during fasting)24 hr: adults12 hr: infants Most affected

Consequences

Increased lactate Acidosis

Pyruvate not metabolised

Long chain FAOduring fasting

Ketone bodies

Try to spare glucose

Not metabolised in

FAOD

Hypoglycemia

Most affected in respiratory chain as it is last step of ATP

generation

Respiratory chain

defects

Glycolysis

1. Fatty Acid Oxidation Defects

Primary carnitine deficiencies Carnitine palmitoyltransferase deficiency (CPT) I & II Carnitine-Acylcarnitine translocase deficiency (CACT)

• Very long chain FA disorders• Long chain FA disorders• Medium chain FA disorders • Short chain FA disorders• Disorders of ketogenesis

2. Respiratory Chain Defects

Disorders in Mitochondrial Hepatopathy

1:750,000 - 2,000,000 new born screening

1:15,000 - 25,000 new born screening

“The Masquerader Of All Diseases”

Highly Deceptive !

Chameleon waiting for its prey Same chameleon changing its colour at night

Why do we struggle to identify this disease ?

Mimics other diseases

(shock, sepsis)

Wide range of symptoms(mild to severe)

(acute and chronic)

All ages affectedneonates to elderly

Presentation changes across

agesPresentation changes in same patient at different

points of time

Multisystem involvement

MitochondrialDiseases

Settings to predict this disease

Recurrent symptoms (acidosis, ketosis, high lactate)

Rapid deterioration with minor illness (URI)

Quick recovery after IV fluids

Non - response to conventional management

(e.g. good antibiotics for suspected sepsis)

Developmentally delayed child with acute symptoms

Multi-system involvement (CNS, liver, cardiac, muscle)

Settings in GI practice

Cyclical vomiting

Reyes syndrome

Unexplained liver failure (young age)

Fatty Liver on USG

Steatosis on liver biopsy

Transaminitis

with non-specific symptoms

ormulti-systemic involvement

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

Age at onset

Age at death

30% 31% 13% 16% 10%

36% 40% 8% 12% 0.01%

Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502

Consanguinity : 28%

Sib death : 43%(60% <1yr ; 25% by 2yr)

107 patients FAOD

N= 50

74%

82%

24%

8%

-

8%

3%

8%

8%

20%

5%

FAOD & RCDClinical features

Lee ,Sokol Semin Liver Dis 2007;27:259–273.

Neurological

36%

Acute attackLiver : 3-6cm

Transminases : 100-800 u/LAmmonia: 80-200 micromol/L

Mild increase in lactate

Hepatic Manifestations (73%)

Steatosis : 95% Hepatomegaly : 50% Reyes syndrome : 37% Liver failure : 11% Cholestasis : 1%

Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502

107 patients FAOD

FAOD ImportanceShort ChainDoes it really exist??

Not much of a problem Developmental delay Behavioural problems

Medium Chain (80%)(1:15,000 new born screen)

Good prognosis Maximum heterogeneity Mortality: 16-25% Intellectual delay 20-25% <6yr : decompensation >6yr : death risk reduced

Long Chain(1:85,000 new born screen)

Mainly liver manifestations Adverse prognosis

Primary Carnitine deficiency(1:750,000 - 2,000,000)

Early presentation and death

J Inherit Metab Dis (2010) 33:501–506

Long Chain Hydroxy Acyl CoA Dehydrogenase Def. (LCHADD)

Early onset: severe phenotype

Hypertrophic cardiomyopathyPericardial effusionLethality 40-80%

May have HENeonatal Cholestasis

Infantile onset: hepatic phenotype (steatosis)

Hepatomegaly, steatosisHypoglycemia

Late onset: myopathic phenotype

Exercise induced rhabdomyolysis (CK: 200,000 u/l: acute

500-5000 u/l

80% acute presentation 38% died within 3 mo of diagnosis

RecommendationFat reduced, MCT rich diet

Frequent feeding

AFLP (Acute Fatty Liver of Pregnancy)HELLP

Hemolysis, Elevated Liver enzymes, Low Platelet, Liver failure

Mother

AffectedBaby

SIDS(Sudden Infant

Death Syndrome)

Very Long and Long Chain Hydroxy Acyl CoA Dehydrogenase Def.

(VLCHADD and LCHADD)

J Inherit Metab Dis (2010) 33:501–506

Acidosis Urine ketones

Blood sugar Serum Lactate

Serum Ammonia

FAOD ++ Nil Low(non-ketotic hypoglycemia)

+ +

RCD ++ ++ Normal ++++ ±

OA +++ (persistent)

++/+++ Low/ Normal/ High

Normal ++

UCD Normal ++++

Biochemical differentiation

Non – ketotic / Hypo - ketotic hypoglycemia : Hallmark of FAOD

Screening (available in India)

Definitive (NOT available)

Tandem MS: Quantitative Fatty acid analysisC8-10 in MCAD

C14-18 in LCHADC14 in VLCAD

+ Plasma carnitine and acylcarnitine assay• Very low levels reaching zero:

primary carnitine def• 25-50% reduction: Other FAOD

Enzyme activity in cultured skin

fibroblasts or muscle biopsy

Carnitine def. also

GCMS: Urinary organic acid and acylglycine assay (available) - dicarboxyllic acids

Fatty Acid Oxidation Defects

Disorder OnsetNeonatal Liver

failureAcute

MitochondrialDNA depletion

Acute

Alpers synd Insidious

Respiratory Chain Defects involving Liver

Disorder Onset

Pearsons synd Insidious

Villous atrophy syndrome Chronic

NavajoNeurohepatopathy

Acute / chronic

Presentation Progressive liver failure Reye Syndrome Ascites Cholestasis Transaminitis

Neonate Infancy Childhood Adult

Mit-DNA depletionCataract

Nystagmus

Alpers syndRefractory seizures

Valproate Tox.

Pearsons syndPanc Insuff.

Sideroblastic anemia

Villous atrophy syndromeIDDM , Ataxia, Deafness

Retinitis pigmentosa

Respiratory Chain Defects involving Liver

Neonatal Liver failure

Navajo Neurohepatopathy

CNS + PNSAcral Mutilation

Respiratory Chain Defects

Available in India

Definitive Tests

Sample Availability in India

Ragged red fiber (Histology)

Muscle Yes

Analysis of oxygen consumption Polarographic

studies

Liver, muscles, fibroblastsfresh biopsy specimens

required (5-10gm)

No

Enzymatic activity of respiratory chain

complexes

Frozen samples (liver, kidney, myocardium)

larger tissue (open surgical in most centers)

No

Mt DNA deletions and mutations

Muscle No

All are required for confirmation?

TreatmentAcute: • 10-12.5% D• Bicarbonate, K+• Carnitine (100mg/kg)• Avoidance of fasting• Infancy – Feeding every 3-4

hourly or CNGD• Older children

– Corn starch therapy– Fat restriction: 25-30% of

total calories

MCTs:

• Rationale – MCTs do not require Carnitine cycle to cross mitochondrial membrane

• 10-20% of calories should come from MCTs

• Supplementation with essential FAs - prevents pigmentary retinopathy

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

Role of Carnitine

• Removes toxic acyl CoA intermediates & repletes intra-mitochondrial carnitine pool

• ? Risk of arrythmias in Long chain FAOD- accumulation of long chain fatty acyl carnitines

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

Life saving in Primary carnitine uptake

defect

Other FAOD - secondary carnitine deficiency

Controversial role!

Dose: 50-100mg/kg/d in divided doses