Defects of fatty acid metabolism

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In most cases of carnitine palmitoyl transferase 2 deficiency (CPT2) there is no Distribution weakness. Proximal weakness is seen in carnitine transporter deficiency (CT -primary carnitine deficiency) and very-long chain acyl-CoA dehydrogenase deficiency (VACD).

CPT2 and MTP may have an acute onset, whereas other forms of MTP, CT and Time course VACD produce more chronic myopathic symptoms.

Onset depends on the specific disease. Most cases of CPT2 start between 6-20 Onset/age years, CT before 7 years of age, VACD and MTP can occur in infants or adults,

There are several defects of fatty acid metabolism in the muscle including Clinical syndrome CPT2, CT, very-long chain acyl-CoA dehydrogenase deficiency (VACD), and Mitochondrial trifunctional protein deficiency (MTP).

There are at least 3 different phenotypes 1. a myopathic form with juvenile- CPT2 adult onset 2. an infantile form with hepatic, muscular, and cardiac involvement 3. a lethal neonatal form with developmental abnormalities. Adults patients develop pain, stiffness, and tightness of the muscles, although they do not get muscular cramps or second-wind phenomena. CPT2 is frequently associated with myoglobinuria. Symptoms develop after prolonged fasting, low-carbohydrate high-fat diets, exercise, infection, cold exposure, and general anesthesia. In most patients strength is normal. In general CPT2 deficiency is more common in males (6:1) with females having milder disease.

In children CT is associated with cardiomyopathy and myopathy, and in infants CT with recurrent acute episodes of hypoglycemic encephalopathy with hypoke-tonemia.

There are 3 forms: 1) Isolated skeletal muscle involvement, rhabdomyolysis, VACD and myoglobinuria worse than in CPT2 and triggered by fasting or exercise 2) A severe and often fatal childhood form with hypertrophic cardiomyopathy, recurrent episodes of hypoketotic hypoglycemia. 3) A milder childhood form with recurrent episodes of hypoketotic hypoglycemia.

The symptoms are variable ranging from a disorder resembling the severe MTP infantile form of VACD to an adult form that resembles CPT2 but with a peripheral sensorimotor neuropathy showing both demyelination and axonal degeneration not described in other disorders of fatty acid metabolism. Other features are retinitis pigmentosa and hypoparathyroidism.

Pathogenesis - CPT2: CPT2 is associated with skeletal muscle disease and the defect can be demonstrated in all tissues. The CPT2 gene is located on chromosome 1p32 and the disorder is more common in Ashkenazi Jews. There are at least 20 CPT2 gene mutations.

- CT: L-carnitine is essential for the transport of long-chain fatty acids into the Mt for P-oxidation. In primary carnitine deficiency there is increased loss of carnitine into the urine. Secondary carnitine deficiency may be due to Mt disorders, renal failure, muscular dystrophy, chronic myopathy, and liver failure. CT is usually associated with nonsense mutations of the genes encoding OCTN2, a high-affinity sodium-dependent carnitine transporter and SLC22A5, an organic cation transporter.

- VACD: VACD catalyzes most of the palmitoyl-CoA (C16) dehydrogenation in skeletal muscle, liver, and heart and is the rate-limiting enzyme in long-chain fatty acid P-oxidation. VACD is coded by ACADVL on chromosome 17p13, and is associated with at least 60 mutations.

- MTP: MTP is a heterogenous disorder and includes long-chain 3-hydroxya-cyl-CoA dehydrogenase deficiency. The following genes have been associated with this disorder: HADHA and HADHB.

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