Transcript L-Carnitine in Primary Systemic Carnitine

L-Carnitine in Primary Systemic
Carnitine Deficiency
L-Carnitine is a natural substance!
25% L-carnitine is synthesized from amino acid lysine and
methionine mostly in our liver and kidney.
75% L-carnitine comes from our diet.
2
L-Carnitine is present all-over our body!
Tissue /
Body Fluids
L-Carnitine
Content
nmol/g
Muscle
1.100 – 3.900
Heart
600 – 1.200
Liver
600 – 1.000
Kidney
300 – 600
Brain
500 – 1.000
Blood
40 – 60
Carnitine/Acylcarnitines in our fluids
Plasma free carnitine (FC) is in
dynamic balance with acylcarnitines
(AC) with the acyl to free Carnitine
ratio of ≤ 0.4 being considered
normal.
Carnitine deficiency
 FC< 20 micromol/L
 AC/FC > 0,4
L-carnitine Deficiency Types
Primary L-Carnitine Deficiency
Is a rare genetic defect of the Carnitine
transporter OCTN2 in the cell
membrane
Secondary L-Carnitine Deficiency
As a consequence of mitochondrial
enzymes genetic defects, or
pathologies or drugs treatment
Primary Carnitine Deficiency
Primary Sistemic Carnitine Deficiency may occur from infancy to adolescence.
Early recognition and treatment with high dose oral L-Carnitine is life –saving.
L-Carnitine Clinical Pharmacology (I)
• L-Carnitine is a natural substance essential for our energy metabolism.
• L-Carnitine brings long-chain fatty acids into mitochondria for oxidation and
energy production.
• Fatty acids are the energy substrates for all tissues except the brain.
• In cardiac and skeletal muscle, fatty acids provide the main energy production.
SPC L-Carnitine Oral Solution China
Growth Velocity & Basal Metabolic Rate
Dynamics
Son’kin and Tambovtseva (2012). Energy Metabolism in Children and Adolescents, Bioenergetics, Dr Kevin Clark (Ed.),
ml/kg/min
Fatty acid oxidation is higher in children than
adults
hours
Oxygen consumption and carbon dioxide production for each group during the background hood day.
Symbols (Triangle = child VO2, Diamond = child VCO2,
Square = adult VO2, Circle = adult VCO2).
Values are means ± SE
Kostyak JC et al (2007) Nutrition Journal, 6:19
Carnitine transport across the plasma and
mitochondrial membranes
Saini-Chohan et al, Journal of Lipid Research 2012. 53: 4–27
OCTNs in Carnitine Kinetic and Pharmacology
Tamai Biopharm. Drug Dispos. 34: 29–44 (2013)
A
30
25
Control
20
Patient
15
Mather
Father
10
Control
5
0
0
20
40
60
80
Carnitine, µM)
A)
B)
B
45
100
Carnitine Uptake nmlo/ml cell water/h
Carnitine Uptake nmlo/ml cell water/h
Carnitine Transport in Primary Carnitine
Deficiency
40
35
30
25
20
15
10
5
0
0
10
20
30
Time (hours)
Kinetic analysis of carnitine transport in fibroblast from the patient and his parents
Time course of Carnitine (0,5 µM)
Scaglia F et al, Genetics Medicine. 1998 ; 1(1): 34–39
40
50
Carnitine Transport
Rose EC et al, Hum Mutat. 2012 January ; 33(1): 118–123
Plasma Carnitine After Single IV or Oral Dose
▲
Plasma Carnitine nmol/ml
1000
500
▲
●
●
100
●
▲
▲
●
●
●
20
▲
●
●
10
●
2
1/4
1
2
3
4
6
24
Time, hours
Plasma carnitine values after single 900 mg iv carnitine in healthy adult (blue) or child with SPCD (green) or 1.5 oral in
the same child
Chapoy PR et al, N Engl J Med., 1980; 303(24): 1389-94
Oral Carnitine Withdrawal in Patient with Systemic Primary
Carnitine Deficiency
80
6000
Urine carnitine (µmol/g creatinine
Plasma carnitine (µmol/L)
70
60
50
40
30
20
10
0
-18
-12
0
12
24
36
48
60
72
84
Time (hours)
Plasma and urinary free
and total carnitine
Stanley CA et al, Pediatr Res., 1993; 34(1): 89-97
96
5000
4000
3000
2000
1000
0
-18
-6
6
18
30
42
54
66
78
Time (hours)
values after discontinuation of carnitine 50-100 mg/kg/d tid at 0 h.
90
Carnitine Deficiency & Fatty Acid Toxicity
Longo N at al, Am J Med Genet C Semin Med Genet 142C(2) (2006) 77–85
L-carnitine plays a key role in metabolism
• L-Carnitine
is
crucial
metabolism/oxidation
and
exclusive
for
fatty
acid
• Fatty acid oxidation is fundamental part of metabolic pathways
• The metabolic pathways link the main vital organs and tissues
• L-Carnitine is strictly linked to the metabolic pathways of main
vital organ and tissues
• Carnitine deficiency induces derangement of the metabolic
pathways with impairment of the vital organs and tissues
Systemic Primary Carnitine Deficiency CDSP:
Childhood myopathic (cardiac) presentation
Chest radiographs
A) 4 years with a heart size upper
limits of normal.
B) 6.5 years severe cardiomegaly,
and low plasma total carnitine
(1.0 nmol/mL)
C) the cardiac size decreased to
normal by six months of oral LC
treatment (100 mg/Kg/day)
D) 10.5 years the cardiac size
remained normal for more than 5
years with LC therapy.
Pierpont 2000
Systemic Primary Carnitine Deficiency CDSP:
Childhood myopathic (cardiac) presentation
HEART ECHOCARDIOGRAM
Pre-treatment
Kinali 2004
Post-treatment
Systemic Primary Carnitine Deficiency CDSP:
Childhood myopathic (cardiac) presentation
4-months old
male infant:
at presentation
10 days
L-Carnitine
treatment
Zales 1995
6 months
L-Carnitine
treatment
Primary Carnitine Deficiency
Two-dimensional transthoracic echocardiogram (short-axis view) at the level of the papillary
muscles shows normal left ventricular size and function with mildly increased left ventricular wall
thickness, most prominent in the lateral and inferolateral walls
Ascunce et al., Tex Heart Inst J. 2013; 40(1): 104–105.
Primary Carnitine Deficiency
Cardiac magnetic resonance image (basal short-axis view) shows normal left ventricular size and
function and focal increased wall thickness involving the lateral wall (arrow).
Ascunce et al., Tex Heart Inst J. 2013; 40(1): 104–105.
Primary Carnitine Deficiency
Cardiac magnetic resonance image (basal short-axis view) shows focal increased wall thickness
with delayed gadolinium enhancement involving the inferolateral wall (arrow).
Ascunce et al., Tex Heart Inst J. 2013; 40(1): 104–105.
Primary Carnitine Deficiency
ECG at presentation demonstrating:
•
Ventricular Fibrillation ( A )
•
ventricular ectopy occurring at a fixed coupling
interval ( B )
•
sinus
rhythm
with
inferolateral
repolarization ( C ; arrows)
Mazzini M at al, Cardiology 120 (2011) 52–58
early
Primary Carnitine Deficiency
ECGs obtained during the initial hospitalization ( left )
and after 6 months of treatment with carnitine ( right).
The initial findings of inferolateral early repolarization
and increased voltage resolved
Mazzini M at al, Cardiology 120 (2011) 52–58
Primary Carnitine Deficiency
Electrocardiogram in carnitine deficiency before carnitine treatment with high peaked T waves
(left)and 3 months after treatment with a normal pattern
Gilbert-Barness, American Journal of Medical Genetics 140, Issue 19, 1993-2006
Myocardial histology and immunohistochemistry in
Primary Carnitine Deficiency
Myocardial biopsy shows boxcar nuclei and vacuoles (A; arrows), positive Oil Red O staining for intramyocardial lipid accumulation (B; arrow) and enlarged,
swollen mitochondria seen with electron microscopy (C, D; arrows). Immunohistochemistry with antibodies directed against aldehyde 4-hydroxy-2-nonenal 4HNE (E , F) and sarcoendoplasmic reticulum calcium ATPase SERCA-SO 3 shows increased staining (F, H) compared to normal controls ( E, G)
Mazzini M at al, Cardiology 120 (2011) 52–58
Primary Carnitine Deficiency
Electronmicrograph of the myocarditis showing increased number and size of the mitochondria
Gilbert-Barness, American Journal of Medical Genetics 140, Issue 19, 1993-2006
Primary Carnitine Deficiency
Microscopic section of skeletal muscle showing lipid within Type I myocytes. Oil red O stain.
Gilbert-Barness, American Journal of Medical Genetics 140, Issue 19, 1993-2006
Fatty Liver Caused by Carnitine Deficiency
Limketkai BN at al, J Gen Intern Med Med. 2007; 23(2): 210-13
Hyperammonemic Encephalopathy Caused by
Carnitine Deficiency
Limketkai BN at al, J Gen Intern Med Med. 2007; 23(2): 210-13
Nine patients had FAO disorders, PCD was the most common (8/9, 89%).
Convulsions were the most obvious symptom, and one presented with cardiomyopathy.
Cardiac and neurological symptoms disappeared rapidly after oral L-carnitine.
One 26-months old girl with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,
had febrile convulsions.
She developed normally after treatment with oral carnitine and standard diet
recommendation.
Primary Systemic Carnitine Deficiency
6-year-old girl - clinical features:
neonatal metabolic acidosis, epilepsy,
recurrent infections, acute
encephalopathy, and dilated
cardiomyopathy with heart failure
before 4 years of age.
Other features such as hepatomegaly,
hypoglycemia, or hyperammonemia
were noted around 5 years of age.
Her health improved with resolving
cardiomyopathy after the use of Lcarnitine (50-100 mg/kg/day).
Hou JW Chang Gung Med J 2002;25:832-7
Treatment of Primary Carnitine Deficiency
 Primary Carnitine Deficiency is fatal/letal, unless promptly diagnosed and
immediately treated with L-Carnitine.
 All life treatment with high strength L-carnitine supplement is essential
and resolve critical clinical situations:(eg. Normalization of cardiac function).
L-Carnitine oral solution will need to be continued for all life!
Oral L-Carnitine Indications
Chronic treatment of primary (and secondary) carnitine deficiency.
Main clinical presentations:
•
•
•
•
•
•
cardio - myopathy
hypotonia
muscle weakness
hypoketotic hypoglycemia
failure to thrive
recurrent episodes of Reye-like encephalopathy
The recommended dosage of Levocarnitine Oral Solution is:
• 50 to 100 mg/kg/day equivalent to 0.5 to 1mL/kg/day T.I.D (three times
a day)
• to be increased to a maximum of 3g/day (30 mL/day)
SPC L-Carnitine Oral Solution China