Transcript PPS Lecture

In the name of GOD
carnitine transporter deficiency
Dr.mohammad raza alaei
Pediatric Endocrinologist
Shahid beheshty university
carnitine transporter deficiency
• also known as:
• Systemic primary carnitine
deficiency (SPCD)
• carnitine uptake defect
• systemic carnitine deficiency
• Primary carnitine deficiency
carnitine transporter deficiency
• Carnitine is an important amino acid for
fatty acid metabolism
• produced in the kidneys and liver
• derived from meat and dairy products in
the diet
• essential role in the transfer of longchain fatty acids into the mitochondria
for beta-oxidation.
carnitine transporter deficiency
• Biologic effects of low carnitine levels
may not be clinically significant until
they reach less than 10-20% of normal
(1-2% of normal)
• carnitine transporter that is present in
heart, muscle, and kidney
• intracellular carnitine concentrations
20- to 50-fold higher than plasma
concentration
Pathophysiology
• Carnitine deficiency may be primary or
secondary
• Primary carnitine deficiency:
• is the only genetic defect
• Mutations in the organic cation/carnitine
transporter (OCTN2)
• In defective carnitine transporter renal
tubular cells unable to reabsorption
carnitine prior to its excretion in urine
Pathophysiology
• massively increased urine carnitine
levels and significantly decreased
plasma carnitine & Intracellular
• carnitine impairs the entry of long-chain
fatty acids into the mitochondrial matrix
• impairs beta-oxidation and energy
production, and the production of
ketone bodies
Pathophysiology
• The 3 areas of involvement include
• 1)the cardiac muscle, (progressive
cardiomyopathy) the most common
form of presentation
• 2) the CNS, which is affected by
encephalopathy caused by hypoketotic
hypoglycemia
• 3) the skeletal muscle, which is affected
by myopathy.
Pathophysiology
• Muscle carnitine deficiency (restricted
to muscle) is characterized by depletion
of carnitine levels in muscle with normal
serum concentrations
• Evidence indicates that the causal
factor is a defect in the muscle carnitine
transporter.
Pathophysiology
• secondary carnitine deficiency :
• metabolic disorders eg,urea cycle
disease, organic acidemias
• Preterm newborns
• Valproic acid
Epidemiology
• Frequency:
• In Japanese study, 1 per 40,000 births
• In Australia 1:37,000-1:100,000
newborns
• Low levels of free carnitine can be
identified in newborn screening
• may reflect maternal primary carnitine
deficiency
Epidemiology
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Mortality/Morbidity
Sudden death
Heart failure
Hypoglycemic Hypoketotic
encephalopathy
• Race:
• Overall, this disorder is panethnic
• Sex: No sex predilection
Epidemiology
• Age:
• onset ranging from 1 month to 7 years
• Infants typically present with
hypoketotic hypoglycemia
• older children present with
cardiomyopathy or skeletal myopathy
Signs and symptoms
• Primary carnitine deficiency
• Muscle carnitine deficiency
• Secondary carnitine deficiency
Signs and symptoms
• Primary carnitine deficiency
• One classic initial presentation of is
hypoketotic hypoglycemic
encephalopathy, accompanied by
hepatomegaly, elevated liver
transaminases, and hyperammonemia
• in the 1st yr of life
• often preceded by metabolic stress
such as extended fasting, infections or
vomiting
Signs and symptoms
• Cardiomyopathy ,most common
presentation ,beginning at 1-4 yr
• may occur with rapidly progressive
heart failure
• Pericardial effusion has also been
observed in association with primary
carnitine deficiency
• Muscle weakness may accompany the
heart failure or present by itself.
Signs and symptoms
• Carnitine deficiency may be a cause of
GI dysmotility, with recurrent episodes
of abdominal pain and diarrhea
• Hypochromic anemia
• recurrent infections
• Mild developmental delay can be the
only manifestation in rare cases
Signs and symptoms
• Maternal cases of SPCD have been
identified at a higher than expected
rate, often in women who are
asymptomatic
• Some mothers have also been
identified through newborn screening
with cardiomyopathy that had not been
previously diagnosed
Signs and symptoms
• Although SPCD is an autosomal
recessive condition
• heterozygotes have been shown to be
at an increased risk for developing
benign cardiomyopathy
Signs and symptoms
• Muscle carnitine deficiency
• Severe reduction in muscle carnitine
levels and normal serum carnitine
concentrations characterize muscle
carnitine deficiency
• restricted to muscle
• no renal leak of carnitine or signs of
liver involvement
Signs and symptoms
• Symptoms can appear in the first years
• may occur later during the second or
third decade
• proximal muscular weakness of varying
degree
• exercise intolerance
• myalgia
Signs and symptoms
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Secondary carnitine deficiency
Patients with organic acidemias
mitochondrial disorders
urea cycle defects
Renal Fanconi Tubulopathy
valproic acid
AIDS who are being treated with
zidovudine
Diagnosis
• In non-specific presentation : extremely
low plasma carnitine level combined
with an increased concentration of
carnitine in urine the
• newborn screening
• confirmed by:
• 1)molecular testing
• 2)functional studies assessing the
uptake of carnitine in cultured
fibroblasts
treatment
• oral carnitine (100-200 mg/kg/day)
• is highly effective
• correcting the cardiomyopathy and
muscle weakness
• As well as any impairment in fasting
ketogenesis
• Treatment continued for life
treatment
• very good outcomes for early treatment
• Mothers who are identified after a
positive newborn screen but are
asymptomatic are typically offered
carnitine supplementation as well
• identification and treatment may
prevent adult onset manifestations
Differential Diagnoses
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Cardiomyopathy, Dilated
Heart Failure, Congestive
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Hyperammonemia
Hypoglycemia
Myoglobinuria
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Sudden Infant Death Syndrome
History
• Carnitine deficiency most commonly as
a secondary finding to other metabolic
conditions
• The first case of SPCD was reported in
the 1980, in a child with fasting
hypoketotic hypoglycemia
• Later cases were reported with
cardiomyopathy and muscle weakness
• Newborn screening
Take home message
• hypoketotic hypoglycemic
encephalopathy
• Cardiomyopathy ,most common
presentation ,beginning at 1-4 yr
• Sudden Infant Death Syndrome
• muscular weakness
• valproic acid , zidovudine , RTA ,
premature
Thank you