Carn Def Group6

8/2/2019 Carn Def Group6

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Systemic Carnitine

Deficiency



CLINICAL CASE

Patient Y

- 3 ½ yrs.old boy

- From Chihuahua, Mexico- Non consaguineous Parents



6 MONTHS OLD

CHF after URTI

Hepatomegaly Hypotonia

3rd of admission:

LethargicGeneral Seizure

Cardiac Arrest

Noted afterrecovery:Proximal Muscle Weakness

Growth Retardation



20, 24 and 33 MONTHS OLD

Cardiorespi arrest after URTI

Hepatomegaly

11th admission:

Fatty changes in Liver

Lack of ketone bodies after 24 hours

Final Diagnosis:

SYSTEMIC CARNITINE DEFICIENCY



Carnitine Synthesis



L lysine 3-hydroxy-trimethyl-L-lysin

4-trimethylammoniobutanal

Glycine

Y-ButyrobetaineL-carnitine

Succinate CoA O2 2-oxoglutarate

N-trimethyllysineHydroxylase

H20 NAD+

2 H+ NADH



Carnitine Shuttle



Acyl-CoA Synthetase CPT I

CPT II Translocase

Carnitine AcylcarnitineFAC

FAC

Acylcarnitine

FFA + AcCYTOSOL

OUTER MITOCHONDRIAL

MEMBRANE

INNER

MTOCHONDRIAL

MEMBRANE

B-Oxidation

Carnitine

FAC



Carnitine 75% provided in diet; 25% synthesized in liver

- meat, poultry, fish & dairy products

- 70 ± 80% of dietary intake is absorbed

Carnitine is used to regulate levels of acyl-CoA inside cells

- CoA pools are limited and CoA is needed in other processes

(GNG, CAC, Urea cycle, F-ox)

- Transfer acyl to carnitine to restore CoA pools so the

acyl-carnitine serve as a reservoir of activated acyl groups.

N+

CH3

CH3

CH3CH2 CH CH2

C O-

O

OH



Adapted from http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.htmlTo CAC

excreted in

urine

Urea Cycle

regulated step

*emphasis on

green text added



carbamoyl phosphate synthetase-I

acetyl-Co

A+

glutamateN

-acetylglutamate+

Co

A

activates

N-acetylglutamate synthetase

Without restoration of CoA pools,

Acetyl-CoA levels drop N-acetylglutamate (NAG) will not be made

CPS I will not be activated and so urea cycle will not proceed

NH4+ builds up



also called

Systemic primary carnitine deficiency (CDSP) Deficiency of plasma-membrane carnitine transporter

Carnitine transporter deficiency or carnitine uptake defect (CUD)

autosomal recessive metabolic disorder prevents the body from using fats for energy, particularly during

periods without food. Carnitine, a natural substance acquired mostly through diet, is used by cells

to process fats and produce energy.

People with primary carnitine deficiency have:

defective proteins called carnitine transporters, which bring carnitine

into cells and prevent its escape from the body.

Primary Carnitine Deficiency



aka Plasmalemmal Carnitine Transporter Defect

cardiomyopathy (disease of heart muscle)

Late infancy or early childhood (1 ~ 7 years)

hypoglycemic, hypoketotic encephalopathy (disorder of brain)

1 month ~ 5 years of age

responds to carnitine supplementation

suspected compensation by other transporters




Defect in active transport of carnitine across the cell

membrane

from blood into cell

by OCTN2 a member of the SLC22 family of

transporters

(1) renal reabsorption is impaired

(2) tissues are unable to concentrate carnitine(heart, muscle, fibroblasts)

reason limited improvement seen if plasma

carnitine supplemented to normal (must be

higher)




1) Electrogenic

2)Na+ indep

3) reversible

1)OC uniport

2)H+/OC antiport*3) Na+/Carn cotrans

1) R eversible

2) Cotransport

3)Divalent OC

SLC22 Transporter FamilyEur J Physiol (2004) 447:666-676



Quinidineanti-malarial / antiarrhymic

Cephaloridineb-lactam antibiotic

VerapamilCa2+ flux inhibitor

antiangina / antiarrhymic

Pharmacological Inhibitors of OCTN2



N+

CH2

CH2

CH2

CH2

CH3

CH3CH3

CH3

CH2CH

CH2

CH2CH3

CH2CH3

C O-

O

TEA Valproate

N+

CH3

CH3

CH3

CH2

CH CH2

C O-

O

OH

CarnitineZwitterion

Organic Cation (OC) Organic Anion (OA)

Competitive Inhibitors of OCTN2



J. Pharm. Exp. Ther., (2002), 302, 3, 1286



J. Pharm. Exp. Ther., (2002), 302, 3, 1286

Binding Site Speculation Based on Competition Expts

OCTN2



Cell (2003), 111, 113-122



Systemic Carnitine

Deficiencyy Attributed to impaired hepatic biosynthesis and/or

excessive renal excretion of carnitine.

yPlasma, liver, and muscle carnitine levels arereduced.

y Usually manifests in infancy or childhood as

progressive muscle weakness or episodes of hepatic

and cerebral dysfunction precipitated by sustainedexercise or fasting.



Systemic Carnitine

Deficiencyy Symptoms include hypoglycemia, hyperammonemia,

and elevated levels of liver and muscle enzymes in

serumy Cardiomyopathy and congestive heart failure are

common and may be the direct cause of death.

y Pathologically, the muscle shows marked increase in

the number of lipid droplets, mainly in type I musclefibers.



Myopathic Carnitine Deficiencyy Manifests during childhood or early adult life as

progressive proximal muscle weakness, exertional

myalgias, cardiomyopathyy Muscle shows an increased number of lipid droplets,

especially in type I muscle fibers.



Carnitine DeficienciesMyopathic Systemic

Tissue Involved Muscle Several tissues and plasma

Carnitine Levels Reduced only in

muscle

Reduced in several tissues

Plasma Carnitine

Levels

Normal Normal/decreased

Ser um Enzymes Elevated in muscle Elevated in muscle and liver

Fatty Infiltration Muscle Muscle, liver, and other

tissues

Ketone Bodies

Production

Present Absent

Dysf unctions Muscle Hepatic, Central nervous

system

Carnitine Therapy Less responsive Responsive



Carnitine Transport System



Fatty Acid Oxidation in the Liver



Lipid Accumulation in

Tissuesy Carnitine deficiency or abnormalities in carnitine

transferases blocks fatty acid oxidation

y

Acyl-CoA, without carnitine and carnitinetransferases, will not be transported and oxidized in

the mitochondria

y Impaired fatty acid oxidation results to lipid

accumulation in tissues such as the muscle and liver



Acyl-CoA synthase

Carnitinepalmitoyl

transferase I

Caritinepalmitoyl

transferase II

Carnitineacylcarnitin

etranslocase

OUTER

MITCHONDRIAL

MEMBRANE

INNER

MITCHONDRIAL

MEMBRANE

FFA

ATP

+ CoA

AMP

+ PPi

Acyl-

CoA

Acyl-

CoA Carnitine

AcylcarnitineCoA

Acylcarnitin

e

CoA

Acylcarnitine

Acyl-CoA

Carnitine

F-

Oxidation



Acyl-CoA F-hydroxyacylCoA

F-KetoacylCoA

Acyl-CoA +

Acetyl-CoA

Trans-Enoyl-CoA

FAD NADH

+ H

NADH2O

FADH

2

CoA-

SH

Acyl CoA dehydrogenase

F-hydroxylCoA

dehydrogenase

Enoyl CoA hydaratase

Ketothiolase

Citric AcidCycle Ketogene

sis



Acetyl-CoA +

Acetyl-CoA

Acetoacetyl

CoA

3-Hydroxy-3-

methyl CoA

Acetoacetic

acid

F-

Hydroxybutyrate

DH

(exhaled thru

lungs) Acetone

Acetyl-

CoA

Acetyl-CoA

NAD NADH +

H

H2

O

Thiolase

HMG-CoA Synthase

HMG-CoA Lyase

F-hydroxybutyrate

DH

Citric AcidCycle

Acetyl-CoA

F-

Oxidatio

n



pyruva

te

AcetylCoA

oxaloacet

ate

Pyruvate

carboxylasePyruvate

DH

(-)

Gluconeogenisis

(+

)

Citric AcidCycle

ADP +

Pi

CO2 +

ATP



y Fatty acid alone can¶t penetrate into the inner

mitochondria membrane

y

The primary function of carnitine is to transfer long-chain fatty acids from the cytosol into the

mitochondria.

y Acyl-CoA that enters the mitochondria undergoes

beta oxidation which yields Acetyl-CoA as endproduct



` Thus the inhibits the

transport of Fatty acid into the mitochondria

` Ketone bodies are derived from Acetyl- CoA from

oxidation of fatty acid in the liver.leads to the

inhibition of pyruvate dehydrogenase, resulting in

activation of Pyruvate carboxylase which

catalyzes oxaloacetate(which is need ingluconeogenesis pathway)

Carn Def Group6

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