Дефицит карнитинпальмитоилтрансферазы II: клинические проявления и формы.

Carnitine palmitoyltransferase II deficiency, sometimes shortened to CPT II or CPT2, is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long chain fatty acids from being transported into the mitochondria for utilization as an energy source. The disorder presents in one of three clinical forms: lethal neonatal, severe infantile hepatocardiomuscular and myopathic. First characterized in 1973 by DiMauro and DiMauro the adult myopathic form of this disease is triggered by physically strenuous activities and/or extended periods without food and leads to immense muscle fatigue and pain. It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults, primarily affecting males. CPT II deficiency is also the most frequent cause of hereditary myoglobinuria.

The three main types of carnitine palmitoyltransferase II deficiency are classified on the basis of tissue specific symptomatology and age of onset. Among the few people diagnosed with CPT2, some have unknown and/or novel mutations that place them outside these three categories while remaining positive for CPT2.

The neonatal form is the least common clinical presentation of this disorder and is almost invariably fatal in rapid fashion regardless of intervention. Symptomatic onset has been documented just hours after birth to within 4 days of life. Affected newborns typically experience respiratory failure, low blood sugar, seizures, liver enlargement, liver failure, and heart enlargement with abnormal heart rhythms leading to cardiac arrest. In most cases, elements of abnormal brain and kidney development are apparent, sometimes even at prenatal ultrasound. Infants with the lethal neonatal form usually live no longer than a few months. Neuronal migration defects have also been documented, to which the CNS pathology of the disorder is often attributed.

Symptomatic presentation usually occurs between 6 and 24 months of age, but the majority of cases have been documented in children less than 1 year of age. The infantile form involves multiple organ systems and is primarily characterized by hypoketotic hypoglycemia (recurring attacks of abnormally low levels of fat breakdown products and blood sugar) that often results in loss of consciousness and seizure activity. Acute liver failure, liver enlargement, and cardiomyopathy are also associated with the infantile presentation of this disorder. Episodes are triggered by febrile illness, infection, or fasting. Some cases of sudden infant death syndrome are attributed to infantile CPT II deficiency at autopsy.

This exclusively myopathic form is the most prevalent and least severe phenotypic presentation of this disorder. Characteristic signs and symptoms include rhabdomyolysis (breakdown of muscle fibers and subsequent release of myoglobin), myoglobinuria, recurrent muscle pain, and weakness. The myoglobin release causes the urine to be red or brown and is indicatory of damage being done to the kidneys which ultimately could result in kidney failure. Muscle weakness and pain typically resolves within hours to days, and patients appear clinically normal in the intervening periods between attacks. Symptoms are most often exercise induced, but fasting, a high fat diet, exposure to cold temperature, sleep deprivation, or infection (especially febrile illness) can also provoke this metabolic myopathy. In a minority of cases, disease severity can be exacerbated by three life threatening complications resulting from persistent rhabdomyolysis: acute kidney failure, respiratory insufficiency, and episodic abnormal heart rhythms. Severe forms may have continual pain from general life activity. The adult form has a variable age of onset. The first appearance of symptoms usually occurs between 6 and 20 years of age but has been documented in patients as young as 8 months as well as in adults over the age of 50. Roughly 80% cases reported to date have been male.

The majority of the genetic abnormalities in CPT II deficient patients affect amino acid residues somewhat removed from the active site of the enzyme. Thus, these mutations are thought to compromise the stability of the protein rather than the catalytic activity of the enzyme. Pro50His This proline is 23 residues from the active site, and is located right below the hydrophobic membrane insert in the active CPT II enzyme. have recently reported a limited correlation (lacking in statistical significance) between the genotypic array and the clinical severity of the phenotype in their patient cohorts. There is a need for further explorations of this topic in order to fully assess the biochemical ramifications of this enzymatic deficiency. The rate of long chain fatty acid oxidation in CPT II deficient patients has been proposed to be a stronger predictor of clinical severity than residual CPT II enzyme activity. For example, one study found that although the level of residual CPT II activity in adult versus infantile onset groups overlapped, a significant decrease in palmitate oxidation was noted in the infantile group when compared to the adult group. The "carnitine shuttle" is composed of three enzymes that utilize carnitine to facilitate the import of hydrophobic long chain fatty acids from the cytosol into the mitochondrial matrix for the production of energy via β oxidation. Carnitine palmitoyltransferase I (CPT I) is localized to the outer mitochondrial membrane and catalyzes the esterification reaction between carnitine and palmitoyl CoA to produce palmitoylcarnitine. Three tissue specific isoforms (liver, muscle, brain) have been identified. Carnitine acylcarnitine translocase (CACT) is an integral inner mitochondrial membrane protein that transports palmitoylcarnitine from the intermembrane space into the matrix in exchange for a molecule of free carnitine that is subsequently moved back out of the mitochondria into the cytosol. Carnitine palmitoyltransferase II (CPT II) is a peripheral inner mitochondrial membrane protein ubiquitously found as a monomeric protein in all tissues that oxidize fatty acids. It catalyzes the transesterification of palmitoylcarnitine back into palmitoyl CoA which is now an activated substrate for β oxidation inside the matrix.

CPT II deficiency has an autosomal recessive pattern of inheritance. This gene is composed of 5 exons that encode a protein 658 amino acids in length.