Case 1 Description
ID/CC
A newborn, 2 days old. Admitted to the clinic listless and poorly perfused with hepatomegaly and nonsinus cardiac rhythm.
HPI
Uncomplicated pregnancy, normal body weight. Both parents are asymptomatic carriers for the defect.
Labs/Findings
Sodium, potassium, bicarbonate, calcium, magnesium, lactate, ammonia, creatine, pH, all normalized after hydration.
EKG: multiple arrythmias
Total Carnitine: 156.7 nmol/mg (normal)
Free Carnitine: 0.6 nmol/mg (significantly low)
Questions
1. This patient is diagnosed as having CPT II deficiency. What is the role of CPT II in long-chain fatty acid metabolism?
2. Why is the metabolism of short-chain fatty acids unaffected in this disorder?
3. Would a defect in the carnitine acylcarnitine translocase have the same effect as CPT II deficiency? Why or why not?
4. Why do patients with CPT II deficiency present with hypoketosis (low serum concentration of ketone bodies) ?
5. Would increased dietary intake of carnitine help this patient?
Answers/Discussion for Case 1
1. What is the role of CPT II in long-chain fatty acid metabolism?
Carnitine palmitoyltransferase (CPT) is required for transport of long-chain fatty acids into the mitochondrial matrix, the site of beta oxidation. CPT consists of two enzymes, CPT-I and CPT-II. CPT-I is located in the outer membrane of the mitochondrion and converts palmitoyl-CoA to palmitoylcarnitine inside the mitochondrial matrix. CPT-II then reconverts palmitoylcarnitine and Coenzyme A into carnitine and palmitoyl-CoA, which undergoes beta oxidation.
2. Why is the metabolism of short and medium-chain fatty acids unaffected in this disorder?
Short and medium-chain fatty acids are able to cross the mitochondrial membrane by diffusion.
3. Would a defect in the carnitine acylcarnitine translocase have the same effect as CPT II deficiency? Why or why not?
Yes it would. Carnitine acylcarnitine translocase is required for the transport of acylcarnitine across the inner mitochondrial membrane where CPT II is located. A defect in either of these two enzymes would inhibit beta oxidation of fatty acids.
4. Why do patients with CPT II deficiency present with hypoketosis?
Patients with hypoketosis have a low serum concentration of ketone bodies. A patient with CPT II deficiency would present with hypoketosis because a product of beta-oxidation, acetyl-CoA, is a precursor for ketone body synthesis.
5. Would increased dietary intake of carnitine help this patient?
No. Although the patient's level of free carnitine would rise, a functional CPT II is still required to cleave acyl-CoA from the acylcarnitine complex.
Quick review of fatty acid breakdown
Back to Intro to carnitine deficiency
Case 2 Description
ID/CC
11 year-old male with muscle weakness and episodes of hypoglycemia.
HPI
Patient is always weak and clumsy. Acute episodes of coma and confusion at 3 1/2 and 9 years of age. Progressive muscle weakness.
Labs/Findings
Lipid excess in the muscles
Increased glucose utilization
Impaired oxidation of long-chain fatty acids
Serum carnitine levels normal after carnitine therapy
Muscle carnitine levels unchanged
Questions
1. Which type of primary carnitine deficiency does this patient appear to have?
2. Suggest a plausible mechanism for the hypoglycemia?
3. Why would this patient have episodes of coma and confusion?
4. Was carnitine therapy beneficial to the patient in this situation? What is the significance of the serum and muscle carnitine levels in this patient after the carnitine therapy?
Answers/Discussion for Case 2
1. Which type of primary carnitine deficiency does this patient appear to have?
This patient is suffering from systemic carnitine deficiency which affects many organ systems, including the brain. Muscle carnitine deficiency affects only the muscles.
2. Suggest a plausible mechanism for the hypoglycemia?
During periods of fasting increased utilization of fatty acids are required as the energy source by the muscles. Because this patient cannot metabolize long chain fatty acids, glucose is used by the muscles as the energy source thus depleting the body's glycogen stores.
3. Why would this patient have episodes of coma and confusion?
The coma and confusion is caused by the decreased amount of glucose available to the brain. The brain utilizes glucose as its main energy source.
4. Was carnitine therapy beneficial to the patient in this situation? What is the significance of the serum and muscle carnitine levels in this patient after the carnitine therapy?
Although carnitine supplements can be helpful in primary carnitine deficiencies, it does not always work. It did not help this patient improve because although his serum levels of carnitine has risen, the carnitine levels in his muscles did not increase. Low levels of carnitine in the muscles indicates that carnitine cannot get into the cells where it is needed, despite the fact that serum concentration of carnitine is normal.
Quick review of fatty acid breakdown
Back to Intro to carnitine deficiency