Primary systemic carnitine deficiency is a genetic disease caused by a violation of the metabolism of this substance, leading to an increase in its loss by the body with urine. Manifestations depend on the form of pathology – patients may have appetite disorders, hepatomegaly, lesions of the central nervous system and heart. Diagnosis is performed by biochemical studies of blood plasma, medical imaging methods (radiography, ultrasound), molecular genetic analyses. Treatment of this disease is carried out by prescribing oral administration of carnitine to make up for its deficiency (substitution therapy).
Primary systemic carnitine deficiency (carnitine transporter deficiency) is a hereditary pathology characterized by pronounced metabolic disorders due to impaired processes of carnitine assimilation coming from food. This disease was first described in 1975 by Karpaty, who managed to prove the relationship of the symptoms observed in an 11-year-old boy (muscle weakness, liver and brain damage) with a lack of carnitine. It was only in 1998 that geneticists were able to identify a gene whose defects lead to the development of this disease. The mechanism of inheritance of the disease is autosomal recessive, the sexual distribution does not have any features, pathology affects both men and women with the same frequency. A feature of the primary systemic carnitine deficiency is the unequal occurrence in different ethnic groups – if Europeans have it at 1:100,000, then, for example, the Japanese have it at 1:4,000, and the inhabitants of the Faroe Islands have it at 1:500.
Primary systemic carnitine deficiency is caused by mutations of the SLC22A5 gene, which is located on the 5th chromosome. It encodes a sequence of a protein called sodium-dependent carnitine transporter (OCTN2), which is secreted mainly in skeletal muscle tissue, the myocardium and partly in the kidneys. Most varieties of defects in the SLC22A5 gene cause the above protein to cease to be released at all (nonsense mutations), sometimes the formation of this factor is produced, but its structure does not allow carnitine to be attached. In recent years, mutations have been identified that lead to disruption of the formation of the sodium-dependent carnitine transporter only in the heart – this is the reason for one of the clinical forms of primary systemic carnitine deficiency. In total, over a hundred different defects of this gene have been described to date, all of them are inherited by an autosomal recessive mechanism.
The result of mutations of the SLC22A5 gene is the absence or impaired structure of the OCTN2 protein. For this reason, carnitine entering the body with food is not absorbed properly, and its deficiency occurs. This compound plays a central role in the intracellular transport of fatty acids (the so–called carnitine shuttle), delivering them to the place of oxidation – mitochondria. In conditions of its lack, the transport of fatty acids, which serve as an important source of nutrition for most tissues, is disrupted, which dramatically slows down the processes of their oxidation. Almost the entire pathogenesis of primary systemic carnitine deficiency is reduced to energy starvation of tissues and organs, especially those in which rapid biochemical processes occur. First of all, these are the liver, kidneys, skeletal muscles and myocardium. In the absence of fat oxidation, the consumption of carbohydrates (glucose) sharply increases to compensate for energy deficiency, therefore, in most cases, pathology is accompanied by hypoglycemia, muscle weakness, liver and heart damage. Neurological symptoms of the disease are due to the fact that glucose is also the only source of energy for neurons.
Symptoms and classification
There are two main clinical forms – metabolic and cardiomyopathic. In the metabolic variety, the first symptoms of the disease appear very early – usually during the first two years of a child’s life, up to this point, an increased frequency of infectious lesions of the upper respiratory tract is recorded. Then the patient suffering from primary systemic carnitine deficiency loses appetite, becomes apathetic, lags behind his peers in physical development. Vomiting and shortness of breath are often observed during physical exertion (due to both cardiomyopathy and muscle weakness), over time, the patient develops phobias and other psychological disorders. In the absence of treatment of the metabolic form of primary systemic carnitine deficiency, hypoglycemic coma and death eventually develop. Viral or bacterial infections, starvation, and psychoemotional stresses can provoke a sudden fatal outcome.
The cardiomyopathic form of primary systemic carnitine deficiency is characterized by a more benign course, more often develops in people over 50 years of age. With this type of disease, only the heart is affected, cardiomegaly occurs, which can develop into dilated cardiomyopathy. Patients complain of increased fatigue, shortness of breath during exercise, pressing pains in the heart (cardialgia). In the absence of treatment of this form of primary systemic carnitine deficiency, signs of heart failure gradually increase, which usually becomes the cause of death of patients. However, its development takes place over many years, and in the first 3-6 years there are no symptoms of the disease, so this type of pathology allows you to maintain a satisfactory quality of life.
The primary systemic carnitine deficiency is determined by studying the patient’s hereditary history, biochemical blood and urine tests, radiography, ultrasound, as well as molecular genetic analysis. Signs of the metabolic form of the disease are childhood, low glucose (hypoglycemia), plasma carnitine and ketone bodies of the blood against the background of hyperammonemia and a slight increase in creatine phosphokinase. There is also a lag in psychophysical development, memory disorders, muscle weakness, parents of patients indicate frequent vomiting attacks and colds in the child. X-ray or ultrasound examinations of internal organs in patients with a metabolic form of primary systemic carnitine deficiency often reveal hepatomegaly and cardiomyopathy.
In the cardiomyopathic form of the disease, there are only signs of myocardial damage – cardiomegaly or dilated cardiomyopathy. In addition, with this type of primary systemic carnitine deficiency, a reduced level of this compound in blood plasma is determined. The methods of modern genetics allow direct automatic sequencing of the SLC22A5 gene sequence, which determines the presence or absence of mutations. The presence of such a disease in close relatives gives grounds for carrying out a genetic determination of the heterozygous carrier of the defective gene. If both parents are carriers of SLC22A5 mutations, it makes sense to conduct a prenatal diagnosis of primary systemic carnitine deficiency in their unborn child.
The need for early diagnosis of this disease is due to the fact that the earlier treatment begins, the more favorable the prognosis becomes. In cases where the presence of primary systemic carnitine deficiency was detected even before the birth of the child, timely prescription of medications allowed to avoid almost all severe symptoms of the disease. Therapy is reduced to oral administration of carnitine preparations to make up for its deficiency.
With various complications of the disease or with its late diagnosis, symptomatic treatment is also indicated. Drip infusion of glucose solutions for hypoglycemia is carried out, hepatoprotectors and means for improving appetite are prescribed. Similarly, the cardiomyopathic form of primary systemic carnitine deficiency is treated.
Prognosis and prevention
The prognosis of this disease depends on many factors: the clinical form, the timeliness of treatment, compliance with the doctor’s recommendations. The metabolic form of primary systemic carnitine deficiency is more severe – quite often it is detected only in the presence of pronounced and largely irreversible lesions of the heart, liver and nervous system, which significantly worsens the prognosis. Even with early or prenatal diagnosis of this type of pathology, sick children should undergo regular examination by a gastroenterologist and a cardiologist. The cardiomyopathic form is characterized by nonspecific symptoms, therefore, traditional drugs are often prescribed to improve myocardial trophism, which in this case have only a partial effect. Prevention of primary systemic carnitine deficiency is possible only within the framework of prenatal diagnosis of this condition.