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© Copyright 2018 Mark Korson, MD. All rights reserved
Mitochondrial Dysfunction in the Organic Acidemias:
Mark S. Korson, MD
VMP Genetics
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© Copyright 2018 Mark Korson, MD. All rights reserved
CARBOHYDRATE
FAT
PROTEIN ENERGY
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© Copyright 2018 Mark Korson, MD. All rights reserved
A case of methylmalonic acidemia
A 22 year old woman delivers a male at 37 weeks gestation following an unremarkable pregnancy, labor, and delivery. The baby was alert upon delivery. Weight measured 6-1/2 lb. Breast-fed well on day 1, then circumcised; afterwards, felt cold. By day 2, began to feed poorly, became hypoglycemic, transferred to the nursery. IV glucose given. Blood pH=7.27. Electrolytes showed a bicarbonate of 7, repeat 5. Intubated for transport, and given IV bicarbonate.
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Upon arrival in the NICU, poorly responsive, jaundiced, with a deep labored breathing.
Labs:- Bicarbonate 8, anion gap 32- BUN 41, creatinine 1.9- Ammonia 96 µmol/L (NL<95), repeat 212- Urine ketones positive (3+)
© Copyright 2018 Mark Korson, MD. All rights reserved
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The baby underwent dialysis. After placement of dialysis lines, repeat ammonia measured 1480 µmol/L. After two cycles - ammonia 586.
Urine organic acids - marked elevation of methylmalonic acid
Diagnosis – methylmalonic acidemia
© Copyright 2018 Mark Korson, MD. All rights reserved
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
PROPIONATE FROM GUT BACTERIA
ILE
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ILE
PROPIONYL CoA CARBOXYLASE
PROPIONATE FROM GUT BACTERIA
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ILE
METHYLMALONYL CoA MUTASE
PROPIONATE FROM GUT BACTERIA
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ACETYL CoA
ILE TIGLYL CoA
2-Me-3-OH-BUTYRYL CoA
2-Me-ACETOACETYL CoA
ACETOACETATE
3-OH-BUTYRATE
KETONES
PROPIONATE FROM GUT BACTERIA
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Normal urine organic acid profile (GC/MS TIC)
(GC/MS TIC analysis)
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ACETYL CoA
ILE TIGLYL CoA
2-Me-3-OH-BUTYRYL CoA
2-Me-ACETOACETYL CoA
ACETOACETATE
3-OH-BUTYRATE
KETONES
PROPIONATE FROM GUT BACTERIA
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Urine organic acids (propionic acidemia)
Courtesy Dr. Piero Rinaldo
Lab session 1
Propionate precursors
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ACETYL CoA
ILE TIGLYL CoA
2-Me-3-OH-BUTYRYL CoA
2-Me-ACETOACETYL CoA
ACETOACETATE
3-OH-BUTYRATE
KETONES
PROPIONATE FROM GUT BACTERIA
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Urine organic acids (propionic acidemia)
Courtesy Dr. Piero Rinaldo
Lab session 1
Ketones
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
3-OH-PROPIONATE
CARNITINE
METHYLCITRATE
ILE
PROPIONYL-CARNITINE
GLYCINE
PROPIONYL-GLYCINE
OXALO-ACETATE
3-OH-ISOVALERATE
ACETYL CoA
PROPIONATE FROM GUT BACTERIA
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Urine organic acids (propionic acidemia)
Courtesy Dr. Piero Rinaldo
Lab session 1
Propionate metabolites
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ILE
METHYLMALONYL CoA MUTASE
PROPIONATE FROM GUT BACTERIA
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Urine organic acids (methylmalonic acidemia)
Courtesy Dr. Piero Rinaldo
Lab session 1
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ILE
LOTS OF KETONES
LOW WBCs LOW PLATELETS
HIGH BLOOD ACID LEVEL
HIGH AMMONIA
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Poor feeding, vomiting àdehydrationLethargy, altered consciousness à comaLooks “septic”Rapid breathing
• Metabolic acidosis• High ammonia
Possible symptoms
© Copyright 2017 Mark Korson, MD. All rights reserved
METABOLIC CRISIS
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Advanced crisis symptoms
© Copyright 2017 Mark Korson, MD. All rights reserved
ACUTE COMPLICATIONS
ApneaSlowing heart rateSeizuresHypothermiaGeneralized/non-specific organ dysfunctionStroke-like episodeSudden death
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Anorexia, vomitingFailure to thriveProtein intoleranceDevelopmental delays/regressionHypotoniaDystonia/movement disordersSkin rash (Candida)Cardiomyopathy
Chronic symptoms
© Copyright 2017 Mark Korson, MD. All rights reserved
LATE-ONSET PRESENTATIONS
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Long term
© Copyright 2017 Mark Korson, MD. All rights reserved
CHRONIC COMPLICATIONS I
Growth retardationDevelopmental delays, seizuresDystonia/movement disorders Basal ganglia stroke
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METHYLMALONIC ACIDEMIA
© Copyright 2018 Mark Korson, MD. All rights reserved
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METHYLMALONIC ACIDEMIA
BASAL GANGLIA
THALAMUS
© Copyright 2018 Mark Korson, MD. All rights reserved
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METHYLMALONIC ACIDEMIA
BASAL GANGLIA
BASAL GANGLIA:CaudatePutamen
Globus pallidus
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Long term
© Copyright 2018 Mark Korson, MD. All rights reserved
CHRONIC COMPLICATIONS I
Growth retardationDevelopmental delays, seizuresDystonia/movement disorders Basal ganglia stroke Kidney failurePancreatitis
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© Copyright 2018 Mark Korson, MD. All rights reserved
CASE – Propionic acidemia
“Casey” presented in the neonatal period. Had problems with global developmental delays, autistic features, hypotonia, seizures. Fed mostly by gastrostomy. Developed progressive retinal disease at age 18 years, died of acute cardiac decompensation at age 20 years.
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© Copyright 2018 Mark Korson, MD. All rights reserved
CASE – Propionic acidemia
“Iris” presented in the neonatal period. Had problems with global developmental delays, hypotonia, seizures. Fed mostly by gastrostomy. Cardiomyopathy identified at age 16 years, progressive à died from cardiac failure at age 21
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Long term
© Copyright 2018 Mark Korson, MD. All rights reserved
CHRONIC COMPLICATIONS II
CardiomyopathyOptic nerve atrophy à blindnessHearing loss (sensorineural)Diabetes
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Components
© Copyright 2018 Mark Korson, MD. All rights reserved
High acid / high ammonia / low glucoseToxic accumulation(s)Significant deficiency(ies))Overall energy deficiencyImpact from the triggering event (infection)Iatrogenic worsening
PATHOGENESIS OF ORGANIC ACIDEMIAS
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GLUCOSE
FATPROTEIN
ENERGYENERGY
ENERGY
© Copyright 2018 Mark Korson, MD. All rights reserved
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GLUCOSE
PROTEIN PYRUVATE LACTATE
AEROBIC METABOLISM
FAT
ATP© Copyright 2018 Mark Korson, MD. All rights reserved
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GLUCOSE
FATPROTEIN PYRUVATE LACTATE
KREBS CYCLE
ELECTRON TRANSPORT CHAIN ATP© Copyright 2018 Mark Korson, MD. All rights reserved
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GLUCOSE
FATPROTEIN PYRUVATE LACTATE
KREBS CYCLE
CYTO
SOL
MIT
OCH
OND
RIO
N
ELECTRON TRANSPORT CHAIN ATP© Copyright 2018 Mark Korson, MD. All rights reserved
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KREBS CYCLE
ANY DEFECT IN ENERGY METABOLISM WITHIN THE MITOCHONDRION =
MITOCHONDRIAL DISORDER
ELECTRON TRANSPORT CHAIN ATP© Copyright 2018 Mark Korson, MD. All rights reserved
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ELECTRON TRANSPORT CHAIN© Copyright 2018 Mark Korson, MD. All rights reserved
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RESPIRATORY CHAIN© Copyright 2018 Mark Korson, MD. All rights reserved
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
e-e-
e-e-
H+H+H+H+
Cyt Ce-e-
H+H+O2H+H+
ADP ATP
Cyt C
e- Q
H+`H+NAD+
H+H+ H+
H+H+H+
Cyt C
H+`
e-e-e-
IN
OUT
2OH- OH-
Respiratory chain
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Complex V: ATP synthase
Oster G and Wang H. BBA 2000;1458:482
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Characteristics
© Copyright 2018 Mark Korson, MD. All rights reserved
100s of MITOCHONDRIAL DISEASES
Multi-systemicOnset at any ageProgressive
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Neurologic
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Developmental delaysDevelopmental regressionHypotoniaDystonia/movement disordersAtaxia (unsteadiness)MigraineStroke-like episodes
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MITOCHONDRIAL DISEASE Leigh variant
© Copyright 2018 Mark Korson, MD. All rights reserved
METHYLMALONIC ACIDEMIA
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METHYLMALONIC ACIDEMIA MITOCHONDRIAL DISEASE Leigh variant
Isikay, Ped Neuro, 2014
© Copyright 2017 Mark Korson, MD. All rights reserved© Copyright 2018 Mark Korson, MD. All rights reserved
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PROPIONIC ACIDEMIA MITOCHONDRIAL DISEASE Leigh variant
Johnson, Ped Neuro, 2009
© Copyright 2017 Mark Korson, MD. All rights reserved© Copyright 2818 Mark Korson, MD. All rights reserved
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Muscle
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
WeaknessFatiguePain, crampingMuscle injury
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Hearing
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Neurosensory impairment
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Eyes/vision
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Blurriness, double visionPtosis (droopy eyelids)Problems with night visionRetinal pigmentation, optic atrophy
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Heart
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
CardiomyopathyArrhythmia (heart rhythm problems)
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Kidney
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Tubular dysfunction (problems with reabsorption)
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Gut
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Dysmotility:• Uncoordinated swallowing• GE reflux, sticking, vomiting• Gastroparesis with pain, distention,
early satiety or anorexia• Pseudo-obstruction• Constipation
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Bladder
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Neurogenic bladder with weakness and loss of control
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Endocrine
© Copyright 2018 Mark Korson, MD. All rights reserved
MITOCHONDRIAL DISEASE - SYMPTOMS/SIGNS
Diabetes mellitusHypothyroidism (low thyroid)Adrenal dysfunction (low adrenal)Parathyroid dysfunction (low parathyroid)
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Characteristics
© Copyright 2018 Mark Korson, MD. All rights reserved
100s of MITOCHONDRIAL DISEASES
Multi-systemicOnset at any ageProgressiveSome symptoms can vary in intensity, like fatigue
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Weakness
Fatigue
© Copyright 2018 Mark Korson, MD. All rights reserved
FATIGUE and WEAKNESS ARE NOT THE SAME
When tested, muscles are weak
Muscle strength varies over the dayAfter resting, patients may have normal strengthAfter exercise, patients may be weak, but can recover with rest“Like a battery that discharges too rapidly”
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Characteristics
© Copyright 2018 Mark Korson, MD. All rights reserved
100s of MITOCHONDRIAL DISEASES
Multi-systemicOnset at any ageProgressiveSome symptoms can vary in intensity, like fatigueInfections à long recovery time; if very prolonged, recovery may not be completeAutonomic dysfunction
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC FUNCTIONS
GUT & BLADDER FUNCTION
HEART RATE
BLOOD PRESSURE
SKIN COLOR
SWEATING
TEMPERATURE
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
TEMPERATURE
SWEATING
SKIN COLOR
BLOOD PRESSURE
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC FUNCTIONS
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
TEMPERATURE
BLOOD PRESSURE
SKIN COLOR
SWEATING
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
BLOOD PRESSURE
SKIN COLOR
SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC FUNCTIONS
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
BLOOD PRESSURE
SKIN COLOR
SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
BLOOD PRESSURE
SKIN COLOR
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC FUNCTIONS
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
BLOOD PRESSURE
SKIN COLOR
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
BLOOD PRESSURE
SPONTANEOUSLY PALE, FLUSHED,
MOTTLED
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC FUNCTIONS
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
BLOOD PRESSURE
SPONTANEOUSLY PALE,FLUSHED,
MOTTLED
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
DIZZINESS, FATIGUE,
IRRITABILITY
SPONTANEOUSLY PALE,FLUSHED,
MOTTLED
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC FUNCTIONS
GUT & BLADDER FUNCTION
FAST OR SLOW HEART RATE
DIZZINESS, FATIGUE,
IRRITABILITY
SPONTANEOUSLY PALE,FLUSHED,
MOTTLED
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
PROBLEMS WITH GUT & BLADDER
FUNCTION
FAST OR SLOW HEART RATE
DIZZINESS, FATIGUE,
IRRITABILITY
SPONTANEOUSLY PALE,FLUSHED,
MOTTLED
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
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© Copyright 2018 Mark Korson, MD. All rights reserved
AUTONOMIC DYSREGULATION
PROBLEMS WITH GUT & BLADDER
FUNCTION
FAST OR SLOW HEART RATE
DIZZINESS, FATIGUE,
IRRITABILITY
SPONTANEOUSLY PALE,FLUSHED,
MOTTLED
INAPPROPRIATE SWEATING
HIGH / LOW / UNSTABLE TEMP
Autonomic symptoms run together
for bad
and for good
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© Copyright 2018 Mark Korson, MD. All rights reserved
Why are organic acidemias like mitochondrial disorders?
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Components
PATHOGENESIS OF ORGANIC ACIDEMIAS
© Copyright 2018 Mark Korson, MD. All rights reserved
High acid / high ammonia / low glucoseToxic accumulation(s)Significant deficiency(ies)Overall energy deficiencyImpact from the triggering event (infection)Iatrogenic worsening
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GLUCOSE
FATPROTEIN PYRUVATE LACTATE
KREBS CYCLE
ELECTRON TRANSPORT CHAIN ATP© Copyright 2018 Mark Korson, MD. All rights reserved
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ILE GUT BACTERIAL PROPIONATE
ANAPLEUROSIS
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LEU 2-KETOISOCAPROIC ACID
ISOVALERYL CoA
KREBS CYCLE
3-METHYLCROTONYL CoA
3-METHYLGLUTACONYL CoA
3-OH-3-METHYLGLUTARYL CoA
ACETOACETATE+
ACETYL CoA© Copyright 2018 Mark Korson, MD. All rights reserved
ANAPLEUROSIS
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CHOLESTEROL SIDE CHAINS
VAL MET THR
© Copyright 2018 Mark Korson, MD. All rights reserved
ODD CHAIN FATS
PROPIONYL CoA
METHYLMALONYL CoA
KREBS CYCLE
SUCCINYL CoA
ILE GUT BACTERIAL PROPIONATE
CATAPLEUROSIS
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LEU 2-KETOISOCAPROIC ACID
ISOVALERYL CoA
KREBS CYCLE
3-METHYLCROTONYL CoA
3-METHYLGLUTACONYL CoA
3-OH-3-METHYLGLUTARYL CoA
ACETOACETATE+
ACETYL CoA© Copyright 2018 Mark Korson, MD. All rights reserved
CATAPLEUROSIS
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Causes of low energy
© Copyright 2018 Mark Korson, MD. All rights reserved
ORGANIC ACIDEMIAS
Inadequate supply of substrate to the Krebs cycle à inadequate ATP supply
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Components
PATHOGENESIS OF ORGANIC ACIDEMIAS
© Copyright 2017 Mark Korson, MD. All rights reserved
High acid / high ammonia / low glucoseToxic accumulation(s)Significant deficiency(ies)Overall energy deficiencyImpact from the triggering event (infection)Iatrogenic worsening
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GLUCOSE
FATPROTEIN PYRUVATE LACTATE
KREBS CYCLE
CYTO
SOL
MIT
OCH
OND
RIO
N
ELECTRON TRANSPORT CHAIN ATP© Copyright 2018 Mark Korson, MD. All rights reserved
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Causes of low energy
© Copyright 2018 Mark Korson, MD. All rights reserved
ORGANIC ACIDEMIAS
Inadequate supply of substrate to the Krebs cycle à inadequate ATP supply
Poisoning of the energy production system à inadequate ATP supply
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© 2008-2017 Society for Inherited Metabolic Disorders www.simd.org
Urine organic acids (propionic acidemia)
Courtesy Dr. Piero Rinaldo
Lab session 1
Evidence of mitochondrial dysfunction
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© Copyright 2018 Mark Korson, MD. All rights reserved
Organic acidemias are not PRIMARY MITOCHONDRIAL DISORDERS
The have SECONDARY MITOCHONDRIAL DYSFUNCTION, and can behave like
mitochondrial disorders
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© Copyright 2018 Mark Korson, MD. All rights reserved
A case of methylmalonic acidemia
A 22 year old woman delivers a male at 37 weeks gestation following an unremarkable pregnancy, labor, and delivery. The baby was alert upon delivery. Weight measured 6-1/2 lb. Breast-fed well on day 1, then circumcised; afterwards, felt cold. By day 2, began to feed poorly, became hypoglycemic, transferred to the nursery. IV glucose given. Blood pH=7.27. Electrolytes showed a bicarbonate of 7, repeat 5. Intubated for transport, and given IV bicarbonate.
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Upon arrival in the NICU, poorly responsive, jaundiced, with a deep labored breathing.
Labs:- Bicarbonate 8, anion gap 32- BUN 41, creatinine 1.9- Ammonia 96 µmol/L (NL<95), repeat 212- Urine ketones positive (3+)
© Copyright 2018 Mark Korson, MD. All rights reserved
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The baby underwent dialysis. After placement of dialysis lines, repeat ammonia measured 1480 µmol/L. After two cycles - ammonia 586.
Urine organic acids - marked elevation of methylmalonic acid
Diagnosis – methylmalonic acidemia
© Copyright 2018 Mark Korson, MD. All rights reserved
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EPILOGUE:• Showed developmental delays (cognitive>motor) by 1-2
years of age• Gastrostomy tube placed at 9 months to ensure adequate
nutrition and taking of medications• Relatively few metabolic crises, mild severity• By 4 years, was not tolerating feeds consistently; slow
gastric emptying and gastroesophageal reflux noted, so jejunostomy tube placed
• Central line placed at 4 years for IV blood draws and access
© Copyright 2018 Mark Korson, MD. All rights reserved
DISEASE COURSE OVER TIME
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EPILOGUE (continued):• By 5 years – liver and/or kidney transplantation
considered à combined liver-kidney transplant. Good recovery without complications
• Improvement of fatigue and gut motility for 6-12 months, then progression
• Developed temperature (heat>cold) intolerance, random pallor/flushing, high heart rate/low blood pressure requiring higher fluid intake
• Relatively few metabolic crises, mild severity
© Copyright 2018 Mark Korson, MD. All rights reserved
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EPILOGUE (continued):• By 8 years, parenteral (IV) nutrition added because of
unreliability of GI tract• By 11 years, on total parenteral nutrition due to gut failure• At 13 years – cerebral atrophy, basal ganglia changes (MRI)
• At 16 years – diagnosed with diabetes mellitus
© Copyright 2018 Mark Korson, MD. All rights reserved
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COMPARISON – MITO + PA/MMA
© Copyright 2018 Mark Korson, MD. All rights reserved
Organic acidemias Mitochondrial disease
Abnormal biochemistry
Lactate, Krebs cycle intermediates,
3-methylglutaconic acid
Lactate, Krebs cycle intermediates,
3-methylglutaconic acid
MRI findings Basal ganglia lesions Basal ganglia lesions
Cellular energetics Reduced energy expenditureDecreased oxygen extraction
Reduced energy expenditureDecreased oxygen extraction
Histopathology+ +
Respiratory chain dysfunction + +
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MMA KIDNEY – ABNL MITOCHONDRIA
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ABNL MITOCHONDRIAL FUNCTION IN OAS
• Reduced cytochrome oxidase activity in liver in propionic and methylmalonic acidemia (Hayasaka et al, 1982)
• Reduced energy expenditure in patients with propionic and methylmalonic acidemia (Feillet et al, 2000)
• Inhibition of mitochondrial electron transport chain activities in rat brain by methymalonic acid (Brusque et al, 2002)
• Decreased OXPHOS activity in liver, kidney, heart, muscle in PA and MMA (de Keiser KY et al, 2009)
© Copyright 2018 Mark Korson, MD. All rights reserved
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ABNL MITOCHONDRIAL FUNCTION IN OAS
• Propionate metabolites may inhibit pyruvate and 2-ketoglutarate dehydrogenase and deplete key compounds in the Krebs cycle (acetyl CoA, oxaloacetate, succinyl CoA) (Schreiber et al, 2012)
• Decreased electron transport enzyme activity in MMA mouse model (mut-/-) (Chandler RJ et al, 2009)
• Cardiac muscle in PA – OXPHOS dysfunction, decreased coenzyme Q10 (Fragaki K et al, 2011)
• In PA, documented mitochondrial dysfunction, increased reactive oxygen species and oxidative damage. Oral treatment with MitoQ or resveratrol shows benefit (Rivera et al, 2017)
© Copyright 2018 Mark Korson, MD. All rights reserved
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Components
PATHOGENESIS OF ORGANIC ACIDEMIAS
© Copyright 2017 Mark Korson, MD. All rights reserved
High acid / high ammonia / low glucoseToxic accumulation(s)Significant deficiency(ies)Overall energy deficiencyImpact from the triggering event (infection)Iatrogenic worsening
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Mitochondrial disease
Symptomatic therapy for…
Supplements
APPROACH TO TREATMENT
© Copyright 2017 Mark Korson, MD. All rights reserved
No treatment at present, but it is coming…
Organ-specific diseaseAutonomic dysfunction
Coenzyme Q10N-acetylcysteineOthers
CARDIOMYOPATHY HEARING LOSS
DIABETES
HYPOTHYROIDISM
OTHER
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Thank You!
Mark S. Korson, MD
www.vmpgenetics.com
404.793.7800 voice | 866.744.5665 fax