Alpers disease is a rare mitochondrial disease characterized by progressive encephalopathy in combination with cirrhosis of the liver. Pathology occurs due to mutation of DNA gamma polymerase (POLG1). The syndrome is manifested by epileptic seizures, depression of psychomotor functions, toxic liver damage. For diagnosis, EEG, MR brain scanning, liver ultrasound, as well as laboratory tests (biochemical blood analysis, coagulogram, genetic test) are used. Supportive therapy: anticonvulsants, metabolic drugs, parenteral nutrition.
ICD 10
G31.8 Other specified degenerative diseases of the nervous system
General information
The disease was first described by B. Alpers in 1931 in a 4-month-old girl with resistant epileptic seizures. In 1976, P. Huttenlocher clarified the nature of the inheritance of pathology, supplemented the description of the clinical picture. The incidence of Alpers-Huttenlocher syndrome is 1 case per 100,000 live births. The disease is characterized by an unfavorable course, rapid deterioration of the condition of patients, the addition of somatic diseases, therefore, despite the rarity, it does not lose relevance in modern neurology.
Causes
Alpers’ disease is caused by a mutation of the POLG1 gene (at locus 15q25), which is responsible for the functioning of gamma polymerase in mitochondria. The most common gene defects are A467T and W748S. The disease is inherited by an autosomal recessive mechanism, so the probability of recurrence of the pathology is 25% in the next pregnancy. The risk of developing the syndrome increases with closely related marriages, other predisposing factors have not been established.
Pathogenesis
The molecular basis of the disease is the insufficiency of gamma polymerase, the only eukaryotic DNA polymerase that supports DNA replication in mitochondria. In Alpers syndrome, the level of replication of genetic material decreases to critical, the activity of mitochondrial enzymes worsens. ATP deficiency affects the most energy—dependent structures – organs of the central and peripheral nervous system, liver, gastrointestinal tract.
In Alpers’ disease, the conductors of deep sensitivity located in the posterior columns of the spinal cord are the first to be affected, and the functions of the cerebellum are also disrupted. The involvement of the cortex in the process is due to pathological electrical activity in the brain. Drug-resistant seizures usually provoke hippocampal sclerosis.
Symptoms
The typical age of manifestation of the disease is from 2 to 4 years, although cases of early (3-4 months) and late onset of the disease (up to 8 years) have been described. The Alpers syndrome is characterized by a bimodal distribution, the second peak falls on the period of 17-24 years. Before the first clinical signs appear, children have normal psychomotor development, a sufficient level of intelligence. After the start of neurological symptoms, there is a sharp regression of previously acquired skills.
In half of the cases, Alpers’ disease manifests itself with convulsive seizures. These may be focal seizures, myoclonic forms (rhythmic muscle twitching without muscle spasms), generalized tonic-clonic seizures, which are called “great epileptic paroxysm”. In children, the first attacks are often provoked by febrile fever in infectious diseases.
Alpers syndrome is characterized by multiple neurological disorders. Patients have shakiness of gait, discoordination of movements, disorders of fine motor skills. Sensory polyneuropathy is manifested by a violation of all types of sensitivity, paresthesia. As a rule, visual disorders occur (cortical blindness). Migraine headaches are a concern, including as a component of the aura of convulsive seizures.
An important symptom of the disease is liver damage. Clinically, this is manifested by nausea, decreased appetite, and digestive disorders. Often the patient experiences weakness, drowsiness, his neurological deficit worsens. When the synthesis of hepatic coagulation factors is inhibited, spontaneous bleeding from the nose, gums, lungs or gastrointestinal tract opens.
Complications
The most dangerous consequence of Alpers syndrome is fatal toxic hepatitis, which occurs when taking drugs from the valproic acid group that stop seizures. At the same time, severe liver failure develops, which causes patients to die within 2-4 months, regardless of the treatment. The defeat of the hepatobiliary system can manifest itself as a change in the architectonics of the biliary tract, liver fibrosis.
With the progression of the disease against the background of muscular hypotension, dysphagia develops, gastrointestinal peristalsis disorders. There is a need for the introduction of a gastric tube or the use of parenteral nutrition. Occasionally, the defeat of the digestive system is supplemented by pancreatitis. 10% of patients develop cardiomyopathy resulting in severe heart failure.
Diagnostics
At the initial admission, an atypical epileptic encephalopathy is detected by a pediatric neurologist, which requires mandatory confirmation or exclusion of Alpers’ disease. A geneticist, a hepatologist, and a cardiologist are involved in the examination of the patient. Taking into account the polymorphism of clinical manifestations, instrumental and laboratory methods of investigation are prescribed to verify the diagnosis:
- EEG. At the beginning of the disease, bipolar or homolateral epileptic activity is determined in the form of spikes and polyspikes. For the period of the height of Alpers syndrome, diffuse slow activity is typical mainly in the occipital regions with regional accents in the temporal-parietal areas of the brain.
- Brain MRI. The images visualize zones of moderate hyperintensive signal in the occipital regions of the cerebral cortex. Resistant seizures are characterized by the appearance of areas of increased intensity in the thalamus, the medulla oblongata. Progressive atrophy is visualized in the basal ganglia, brain stem and cerebellum.
- Abdominal ultrasound. With toxic hepatitis, there is a moderate increase in the liver, a decrease in the echogenicity of its parenchyma. To clarify the nature of the pathology, a biopsy of the organ is performed, the results of which reveal fatty infiltration of hepatocytes, proliferation of bile ducts, and with prolonged existence of the disease — liver fibrosis.
- Blood test. The biochemical analysis of blood determines hypoglycemia, an increase in the level of transaminases. Hyperbilirubinemia, hyperammonemia, and hypoalbuminemia indicate the development of liver failure. When evaluating the coagulogram, the prothrombin index was reduced.
- Genetic analysis. If Alpers syndrome is suspected, a complete analysis of the POLG1 gene is performed by automatic sequencing. Verification of the diagnosis is possible when one of the 60 mutations known today is detected. Occasionally, the test is supplemented by measuring the number of copies of mitochondrial DNA.
Treatment
Conservative therapy
The complexity of providing medical care to those suffering from Alpers’ disease is associated with the lack of effective etiopathogenetic medications. The attending physician individually selects symptomatic therapy for the patient, which corrects neurological disorders, stabilizes the parameters of homeostasis. Treatment is carried out in neurological or intensive care units, the following groups of drugs are used:
- Antioxidants from the group of vitamin-like substances. They have a positive anabolic effect, improve metabolic parameters. In addition, they are the only means to stop valproate-induced hepatic insufficiency.
- Anticonvulsants. To eliminate epileptic paroxysms, modern anticonvulsant medications from the groups of sulfate-substituted monosaccharides and lamotrigines that do not cause toxic hepatitis are recommended. If they are ineffective, older generation drugs (barbiturates, benzodiazepines) are used.
- Infusion solutions. To correct water-electrolyte metabolism, crystalloid solutions are prescribed, according to indications, infusions of glucose preparations, amino acid mixtures are carried out to maintain an adequate level of energy metabolism.
Palliative care
Since the disease always ends with the death of the patient, it is necessary to provide full-fledged care and medical care at the terminal stage of the disease. Treatment involves intravenous hydration and the introduction of nutrient mixtures, relief of seizures, elimination of hypoxia by hyperbaric oxygenation, oxygen support, ventilation. As part of the palliative care, social and psychological assistance is provided to family members of the patient.
Prognosis and prevention
Alpers’ disease has an unfavorable progressive course, death occurs within 3-4 years from the manifestation of clinical symptoms. Comprehensive medical care facilitates the condition of patients, but so far there are no ways to cure the disease. The main method of primary prevention is medical and genetic counseling of couples with burdened heredity.
Of crucial importance in the secondary prevention of the disease is the control of blood parameters during the treatment of patients with epilepsy with valproic acid preparations. With an increase in liver tests and a decrease in platelet levels, neurologists should assume the possibility of mitochondrial pathology, and promptly refer the patient to a genetic center for consultation.
