Andersen syndrome is a rare hereditary pathology characterized by an extended QT interval and high–amplitude U teeth on the ECG, ventricular arrhythmia, attacks of muscle paralysis, the presence of external signs of dysmorphic genesis. Patients have low-set ears, a wide forehead, an abnormally enlarged jaw, a stable deformation of the fingers with fusion and webbing, an increased distance between the eyes, low growth, scoliosis. The diagnosis is established on the basis of clinical data, the results of a genetic study and an ECG. Treatment is symptomatic, includes taking calcium antagonists and beta-blockers, limiting physical activity.
In 1971 , the Danish doctor E. Andersen described the symptoms of dysmorphogenesis, ventricular arrhythmia and paralysis attacks in an 8-year-old boy. In 1994, neurologist R. Tavil investigated the clinical picture of the disease in more detail, differentiated transient paralysis in this disease from other forms of periodic paralysis. In his works, he first used the term “Andersen syndrome”. Currently, another name is also common – Andersen-Tavil syndrome. Epidemiology is extremely low: 1 case of the disease per 1 million newborns is diagnosed. The incidence is the same among girls and boys, as well as among different races and ethnic groups. Andersen syndrome should be distinguished from Andersen’s disease – a hereditary disease of glycogen accumulation in organs and tissues.
In 2001, the genetic basis of Andersen syndrome was determined: when studying clinical cases in a family of 15 people, scientists found a link between the inheritance of the disease and the presence of heterozygous mutations in the KCNJ2 gene located at the 17q locus of chromosome 23. This gene is responsible for the synthesis of the alpha subunit of the Kir2.1 protein in the incoming potassium channels of the cardiac and skeletal muscles.
Hereditary transmission of the syndrome occurs by an autosomal dominant mechanism, while isolated sporadic cases have been identified – a spontaneous primary mutational change in the gene during conception. With autosomal dominant inheritance, the probability of having a sick child in a couple where one of the parents has a defective gene is 50%. The penetrance of the disease is widely variable, so not all patients have detailed symptoms. The severity of the pathology varies within the family: in some patients it is manifested by pronounced cardiological and myopathic disorders, in others it is asymptomatic.
The pathogenetic basis of Andersen syndrome is the insufficiency of the production of protein molecules Kir2.1. They are part of the structure of potassium channels of cells capable of excitability – cardiomyocytes, brain neurons, striated muscle cells. Potassium channels regulate the resting membrane potential of skeletal muscles and cardiac muscle. With their dysfunction, the excitability of tissues pathologically changes: the output of K+ ions from cells with a hyperpolarized membrane is disrupted in the final phase of potential repolarization.
Transcriptions of the KCNJ2 gene containing a large amount of Kir2.1 are found in the tissues of the heart (especially in the atria and ventricles), brain, placenta, skeletal muscles, lungs. α-subunits of Kir2.1 form a tetramer inside the cell walls, form a potassium channel. In Andersen syndrome, an insufficient number of these subunits are synthesized. As a result, depolarization and destabilization of the resting membrane potential occurs, ventricular arrhythmias, muscle contractions, and paralysis appear.
The complete clinical picture of Andersen syndrome is represented by a triad of symptoms, including potassium-dependent periodic paralysis, ventricular arrhythmias, anomalies of the structure of the skull and limbs. In mild forms of the disease, transient muscle paralysis is felt as short-term bouts of weakness in the legs and arms. Moderate and severe course of the syndrome is accompanied by complete or partial paralysis of the limbs, generalized paresis with loss of sensitivity, the possibility of arbitrary movements. These episodes often occur after intense physical activity or waking up in the morning, suddenly in a state of relaxation and rest. Triggers of paralysis include walking on an empty stomach, an abundant meal, physical exertion after a period of sitting, colds, inhalation of toxic gases.
Arrhythmias are the most common symptom of the disease. In some patients, they are detected only with an ECG. Subjectively, there may be a feeling of palpitations and heart rate interruptions, increased heart rate, discomfort and chest pain, dizziness, loss of consciousness and sensations close to fainting. Signs of dysmorphic genesis are represented by low growth; macrocephaly – an increase in the size of the skull by 10% or more from the normal age; dolichocephaly – elongation of the skull in the anteroposterior direction due to premature ossification of the arrowhead suture. Hypertelorism is also observed – a wide arrangement of paired organs, for example, the eyes. Ears set low and rotated back. In some patients, an epicanthus is formed – a fold at the inner corner of the eye. The hard and soft palate often remain uninfected, the upper jaw has small dimensions (micrognathia), the fingers are abnormally shortened (brachydactyly), the fifth fingers are laterally and medially curved (clinodactyly). Sometimes there is a fusion of fingers and the presence of webbing.
The development of life-threatening conditions is possible in patients with severe forms of the disease, especially if there is no necessary treatment and care. Frequent attacks of paralysis are accompanied by the risk of injury: patients suddenly lose control of muscle tone, fall, get bruises and injuries. Such conditions are especially dangerous when driving vehicles, crossing the street, etc. In the absence of therapeutic control of ventricular arrhythmia, there is a small chance of sudden death as a result of cardiac arrest. Several cases of such deaths have been described in the scientific literature.
Signs of pathology can be detected already in the first year of a child’s life. Pediatricians pay attention to defects in the formation of fingers and toes, the skull, especially its facial part. With a mild variant of the disease, external signs are weakly expressed or absent, then the diagnosis is determined later, after accidental detection of changes in the heart rhythm. Examination of patients is carried out by cardiologists, neurologists, geneticists. Differential diagnosis is aimed at excluding other types of arrhythmias. The following procedures allow you to confirm the presence of Andersen syndrome:
- Clinical and anamnestic study. A family history is collected, genealogical analysis is carried out. Most patients have close relatives with a confirmed diagnosis of the syndrome. During the examination, characteristic craniofacial anomalies, changes in the structure of the fingers are recorded. During the survey, there may be complaints of attacks of muscle weakness or paralysis, discomfort in the chest area, uneven heartbeat.
- ECG. According to electrocardiography, the prolongation of the QT interval is determined: the average in women is 479 ms, in men – 493 ms. Another diagnostic criterion is the high amplitude of the U teeth, which is recorded mainly in the anterior thoracic leads. The U teeth are expanded and two-phase, the descending part of the T teeth is prolonged, the T-U fusion is wide. Syncopal episodes are accompanied by pirouette ventricular tachycardia.
- Genetic research. A blood test is performed from a vein. The structure of the gene responsible for the development of the disease (KCNJ2) is being studied. Approximately 70-80% of patients have mutations in the heterozygous and companud-heterozygous state. The type of mutation is individual. The most common is the heterozygous missense mutation R218W.
Etiotropic treatment has not been developed, attempts to use large doses of potassium preparations are ineffective. The main method of therapy is the appointment of beta-blockers and calcium channel blockers (phenylalkylamines). These drugs reduce the manifestations of arrhythmia, reducing the strength and heart rate, inhibiting cardiac conduction. In severe course of the syndrome with syncopal conditions, implantation of a cardioverter-defibrillator is performed. All patients are recommended lifestyle correction: it is forbidden to take drugs that lengthen the QT interval (antianginal, antidiuretic, hypolipidemic, psychotropic and some other drugs), it is necessary to limit physical activity and other triggers of paralysis attacks.
Prognosis and prevention
Regular medical monitoring of the condition of patients helps to avoid complications of the syndrome, and properly selected treatment, compliance with recommendations on the regime of motor activity contribute to improving the quality of life of patients. It is impossible to prevent the development of hereditary diseases. Children at risk (with a burdened family history) need to undergo ECG screening and molecular genetic analysis immediately after birth. Early diagnosis and regular monitoring of the disease ensure a higher effectiveness of therapy.