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 long-chain 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 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 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 · Cardiomyopathy, Dilated · Heart Failure, Congestive · Hyperammonemia · Hypoglycemia · Myoglobinuria · 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

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