Wilson-Konovalov disease – symptoms and treatment

Definition of the disease. Causes of the illness

Wilson-Konovalov disease is a rare inherited degenerative disorder that develops due to excessive accumulation of copper in the body. The metal accumulates most in the brain, eyes (forming characteristic pigmentation), liver, and kidneys. This disrupts metabolism in the organs and leads to progressive degenerative changes.

The disease was first described in 1912 by the English neurologist Samuel Wilson. In his printed work, he described the symptoms and peculiarities of internal organ changes in this disease. Typically, the first manifestations become noticeable at a young age, with later progression of rigidity, swallowing difficulties, decreased motor ability of the soft palate, tongue, and lips (the cause of speech disorder – dysarthria). Involuntary movements develop, mental disorders occur – lowered or unreasonably elevated mood, unmotivated aggression, which in later stages is replaced by indifference, delusional ideas, hallucinations.

Russian neurologist Nikolai Vasilievich Konovalov studied Wilson’s disease for many years. This allowed him to create an original comprehensive classification of various forms of the disease. For his enormous contribution to the study of the problem, the scientist’s name forever complemented the name of the disease.

Incidence rate – from 1 to 9 cases per 100,000 population.
The main cause of the disease is a mutation in the gene called ATP7B, which is responsible for the incorporation of copper ions into the ceruloplasmin protein. More than 300 mutations of this gene have been described. The mutation database is constantly expanding with new variants. According to international estimates, approximately 1 in 100 people is a carrier of the abnormal gene. In this type of inheritance, the disease manifests symptoms only if the pathological gene was inherited from both parents. Boys and girls are affected at the same rate.

Symptoms of Wilson-Konovalov disease are classified into four groups:

Affected OrganDisease Manifestations
Liver Damage– Asymptomatic hepatomegaly (enlargement of the liver)
– Isolated splenomegaly (enlarged spleen)
– Cytolytic activity of biochemical indicators (cell destruction indicators)
– Steatohepatitis
– Acute (fulminant) hepatitis
– Autoimmune hepatitis
– Cirrhosis of the liver
Central Nervous System– Motor disturbances (tremor, involuntary movements)
– Drooling, dysarthria (unclear speech)
– Rigidity dystonia (muscle tone disturbance)
– Pseudobulbar syndrome (involuntary laughter, crying, automatic chewing, swallowing difficulties)
– Migraine-like headaches
– Insomnia
– Dystonic attacks (sudden, paroxysmal increase in muscle tone) provoked by sound, bright light, or attempts to actively move
Psychiatric Symptoms– Depression
– Neurotic behavior (inadequate, painful actions with retained criticism of the situation)
– Personality changes (mood swings, subsequent emotional impoverishment, learning stoppage, loss of skills and abilities, goals, interests, and motivation, inability to satisfy needs)
– Psychosis (abnormal perception of oneself and surroundings, hallucinations, or illogical thinking with obsessive convictions and loss of self-criticism)
Other Systems– Hemolytic anemia
– Dermatological manifestations: “blue nail lunulae”
– Kidney pathology: aminoaciduria (excretion of amino acids in urine), nephrolithiasis with pain syndrome
– Skeletal pathology: early osteoporosis, arthritis (joint inflammation)
– Heart involvement: cardiomyopathy, rhythm disorders
– Pancreatitis, cholelithiasis
– Hypoparathyroidism, gigantism
– Menstrual cycle disturbance, infertility, recurrent miscarriages
– Eye involvement: appearance of Kayser-Fleischer rings with characteristic color change of the corneal periphery to shades of green, cataract – clouding of the lens resembling a sunflower

Changes in the liver are among the first symptoms of Wilson-Konovalov disease (often manifesting around the age of 4-5 years). Sometimes Wilson-Konovalov disease presents as acute or chronic hepatitis, which can be mistaken for bacterial or viral liver inflammation. The pathological process begins with rapid development of jaundice: the skin, visible mucous membranes, and the whites of the eyes turn yellow. Symptoms of intoxication and asthenia (general weakness, increased fatigue, mood instability) may accompany the change in skin color. Anorexia, loss of appetite, and aversion to food are also possible.

Neurological symptoms and manifestations of psychiatric disorders in Wilson-Konovalov disease occur in 35% and 10% of cases, usually between the ages of 10 and 35, although late-onset cases at 55 years old are also observed. Neurological manifestations include coordination disturbances with tremors in the limbs during posture holding, as well as tremors at rest. Muscle dystonia syndrome develops – involuntary muscle contractions leading to changes in body position. Muscle tone changes lead to gait disturbances. Speech is also affected due to muscle dysfunction. Increased salivation occurs.

Psychiatric symptoms precede all other symptoms in about a third of patients. Since the manifestations are nonspecific, they are usually not associated with Wilson-Konovalov disease. In children, there may be delays or cessation of mental development, decreased academic performance, and ability to concentrate. There are abrupt mood swings – inappropriate feelings of happiness and joy are replaced by fleeting feelings of fear and unwarranted anxiety. Outbursts of aggression or sexual deviations may occur. Acute psychiatric disorders (psychoses) are rare.

Kaiser-Fleischer rings

In adults, there is a decrease in the speed of cognitive processes while memory for past events remains intact. As dementia develops, aggression and depression are replaced by groundless euphoria. Regarding eye involvement in Wilson’s disease, Kayser-Fleischer rings and copper cataracts resembling a “sunflower” are attributed. However, only a specialist can correctly interpret these symptoms as they also occur in copper poisoning. Kayser-Fleischer rings are not always visible to the naked eye; sometimes they are only detected during ophthalmological examination using a slit lamp. Emotional dullness and indifference increase. Symptoms such as unfounded laughter and crying, painful reflexes of the oral musculature, and grasping automatisms worsen.

Pathogenesis of Wilson-Konovalov disease

The pathogenesis of Wilson-Konovalov disease involves disruptions in metabolic processes in the body, leading to the accumulation of copper in various organs and tissues, ultimately impairing their functions. Mutations in the ATP7B gene play a role in determining the diverse symptoms of the disease.

The ATP7B gene encodes proteins that accelerate chemical reactions involving copper: ATPase 7A and ATPase 7B. Deficiency of the latter enzyme leads to Wilson-Konovalov disease. Copper accumulation in the body causes chronic poisoning and cell destruction in the liver and brain, resulting in inflammation, liver fibrosis, and the formation of cysts in the brain. Sudden release of copper into the blood can cause massive red blood cell breakdown and fulminant liver failure. Additionally, symptoms are also caused by poisoning from the breakdown products of damaged cells.

Classification and stages of Wilson’s disease:

In Russia, the classification of Wilson’s disease is often based on its clinical features, specifically the combination of liver and central nervous system involvement. The disease is classified into:

  1. Asymptomatic form.
  2. Hepatic form.
  3. Cerebral form.
  4. Mixed form.

Additionally, the Konovalov classification includes five forms of hepatocerebral dystrophy:

  1. Abdominal form: Severe liver involvement leading to hepatitis, cirrhosis, and fulminant liver failure. It can be fatal before neurological symptoms appear.
  2. Rigidity-arrhythmohyperkinetic (early) form: Rapid onset in childhood with predominant muscular rigidity, joint changes, slowed movements, involuntary muscle contractions, speech and swallowing difficulties, emotional disturbances, and moderate intellectual decline. Duration is 2-3 years, ending in death.
  3. Tremor-rigid form: More common, starts in adolescence, progresses slowly with periods of recovery and sudden exacerbations, accompanied by fever. Features include severe muscle stiffness, rhythmic tremors, worsened by movements and excitement but relieved during rest and sleep. Dysphagia and dysarthria may occur. Average lifespan is about 6 years.
  4. Tremor form: Onset at 20-30 years, relatively slow progression (10-15 years or more) with predominant tremors. Rigidity appears late in the disease, sometimes with decreased muscle tone. Other features include masked facial expression, slow monotonous speech, severe psychiatric changes, frequent emotional outbursts, and seizures.
  5. Extrapyramidal-cortical form: Less common, characterized by typical hepatocerebral dystrophy symptoms, later complicated by sudden onset motor disorders like paralysis (pyramidal paresis), convulsive (epileptiform) seizures, and severe mental retardation. Lasts 6-8 years, ending in death.

The disease progresses through two stages:

  1. Latent stage: No external manifestations, characteristic changes are detected only by laboratory tests.
  2. Clinical manifestation stage: Specific symptoms of hepatocerebellar degeneration appear.

During treatment, a stage of negative copper balance may be identified, characterized by regression of clinical symptoms and characteristic laboratory changes.

Diagnosis of Wilson-Konovalov disease

The diagnosis is based on a combination of clinical symptoms, laboratory data, and molecular genetic testing. No single laboratory test, except for the identification of the disease-causing ATP7B gene at the molecular level, provides a 100% guarantee of disease diagnosis.

Key diagnostic indicators of Wilson’s disease include:

  • Ceruloplasmin: A decrease by 50%. It may be within normal range. According to other data, it’s less than 20 mg/dl. Due to various reasons (Menkes disease, liver failure, nephrotic syndrome, prolonged parenteral nutrition, etc.), the analysis may yield false-negative results.
  • Urinary copper excretion: >100 µg/day, or >40 µg/day in children. In asymptomatic cases, levels do not exceed the normal range of 40 µg/day.
  • “Free” copper in serum: >1.6 µM/L
  • Copper in liver tissue: >4 µM/g or >250 µg/g dry weight.
Symptom/Laboratory TestScore/Result
Kaiser-Fleischer RingsPresence (0 points) / Absence (2 points)
Urinary Copper ExcretionNormal (0 points) / 1-2 times normal (1 point) / >2 times normal or >5 times normal with penicillamine challenge (2 points)
Neuropsychiatric Symptoms (changes on MRI)Present (2 points) / Absent (0 points)
Quantitative Copper Determination in Liver BiopsyNormal (-1 point) / 50-250 µg/g (1 point) / >250 µg/g (2 points)
Negative Coombs Hemolytic AnemiaPresent (1 point) / Absent (0 points)
Rhodamine-positive Hepatocytes (if quantitative copper determination in liver biopsy is not possible)Present (0 points) / Absent (1 point)
Serum Ceruloplasmin Level (if normal >20 mg/dl)Normal (0 points) / 10-20 mg/dl (1 point) / <10 mg/dl (2 points)
Molecular Genetic Testing (ATP7B gene mutations)Homozygous or compound heterozygous (4 points) / Heterozygous (1 point) / No mutations detected (0 points)

Total Score:

  • 4 or more: High probability of Wilson’s disease.
  • 2-3: Disease is probable, but further patient evaluation is required.
  • 0-1: Disease is doubtful.

Computerized tomography (CT) of the brain can detect enlargement of the ventricles, cortical atrophy, and brainstem atrophy in cases of Wilson’s disease. However, magnetic resonance imaging (MRI) is the preferred diagnostic method for the cerebral form of the disease.

“Giant panda face” in Wilson’s disease – Konovalov

To identify areas of copper accumulation and non-surgical assessment of brain metabolism, magnetic resonance spectroscopy (MRS) may be necessary. This method evaluates changes in biochemical concentration in tissues affected by various diseases.

Positron emission tomography (PET) is also used to determine the degree of substance exchange and transport in the body.

Transcranial ultrasound of the brain is a promising method for early diagnosis.

Changes detected by ultrasound (US), CT, and MRI of the liver and kidneys are not strictly specific to Wilson’s disease and may be present in other conditions. They are mainly used to assess treatment effectiveness.

Elastography of the liver is a new diagnostic method for assessing the severity of liver cirrhosis (fibrosis). This technique utilizes ultrasound’s ability to pass through tissues of varying densities to determine changes in normal organ density.

Treatment for Wilson’s disease

Treatment for Wilson’s disease aims to prevent symptoms and normalize laboratory parameters during the asymptomatic stage. During the clinical stage, the goal is to stabilize and regress the main symptoms of the disease, as well as normalize laboratory parameters. Treatment can be divided into several directions:

  1. Medication Therapy: This includes the use of medications to remove copper from the body (copper chelation therapy) and medications to reduce copper absorption. This treatment is typically lifelong. Commonly used medications include penicillamine, trientine, tetrathiomolybdate, and unitiol.
  2. Symptomatic Therapy: Medications such as vitamins B, C, and E, neuroprotective and neurometabolic agents, anticonvulsants for seizure management, and drugs for correcting psychiatric symptoms are used to treat symptoms and aid in the recovery of affected organs.
  3. Dietary Therapy: While complete removal of copper from the diet is not possible as it is present in all foods, certain copper-rich foods should be avoided. A diet characterized as lacto-vegetarian with adequate protein content is recommended. Foods with copper content exceeding 0.5 mg/100 g should be avoided, such as organ meats, shellfish, nuts, cocoa products, mushrooms, legumes, buckwheat, and oatmeal. Consumption of sugar, refined carbohydrates, and trans fats should be reduced.
  4. Surgical Treatment: Liver transplantation may be considered in cases of fulminant liver failure, unsuccessful drug therapy for three months, or in patients with decompensated cirrhosis.

Liver transplantation is performed in cases of:

  • Fulminant liver failure
  • Unsuccessful drug therapy for three months
  • Patients with decompensated liver cirrhosis showing progressive symptoms of liver failure.

Decompensated liver cirrhosis is a disruption of normal liver function characterized by symptoms of severe digestive dysfunction. It manifests as follows:

  1. Jaundice of the skin, sclerae, and oral mucosa.
  2. Reddening of the palms (liver palms).
  3. Itching of the skin due to toxin accumulation.
  4. Spider angiomas, as well as a tendency to bleed and bruise easily with minor skin injuries.
  5. Loss of appetite, weight loss leading to exhaustion.
  6. Pain in the right upper abdomen, sometimes abdominal pain without clear localization.
  7. Accumulation of fluid in the abdominal cavity (ascites).
  8. Hepatic encephalopathy – progressive impairment of brain function (memory, attention, thinking), personality changes with varying degrees of inappropriate behavior, and consciousness disturbance (up to coma). Untreated, the disease can be fatal.
Decompensated cirrhosis of the liver

During transplantation, donor liver transplantation is used, where the liver is transplanted either entirely or partially. Liver transplantation improves neurological symptoms in more than 50% of cases. Survival rates after liver transplantation for decompensated cirrhosis are 95% within the first year, 83% at 5 years, and 80% at 10 years.

Plasmapheresis and hemadsorption are also used to remove copper from the body. In plasmapheresis, blood is filtered: the patient’s blood passes through a device where cells are returned to the bloodstream immediately, while plasma passes through pores of a special high-tech filter, removing breakdown products and returning purified plasma to the body. In hemadsorption, the patient’s whole blood passes through a container filled with sorbent substances.

The treatment of Wilson’s disease can be divided into two phases: the initial phase and the maintenance therapy phase. The transition to maintenance therapy is indicated by normalization of copper metabolism parameters in two consecutive tests performed with a 3-month interval.

Prognosis and Prevention

Wilson’s disease is a progressive condition, and without timely treatment, patients may die from liver cirrhosis or rarely from infectious-toxic complications. Progressive neurological symptoms can lead to immobility in patients. However, with treatment using copper-chelating medications and liver transplantation, long-term survival is achievable.

Factors that increase mortality in Wilson’s disease include:

  1. Late diagnosis.
  2. Voluntary refusal of treatment.
  3. Unfortunate accidents related to neurological symptoms.
  4. Inability to find effective treatment.

The one-year survival rate after liver transplantation due to fulminant liver failure reaches 70%. Without transplantation, survival is rare. For decompensated liver cirrhosis, the survival rates after transplantation are 95% within the first year, 83% at 5 years, and 80% at 10 years. More than 50% of cases show a reversal of neurological symptoms after transplantation.

Liver function recovery occurs within 1-2 years of treatment and does not progress with full compliance to recommendations. In cases of fulminant disease, only surgical treatment is effective.

Due to its genetic nature, there is no specific prevention (vaccines, serums) for Wilson’s disease. Patients diagnosed with Wilson’s disease during routine examinations without noticeable symptoms may not perceive medication treatment as mandatory. In such cases, the focus should be on preventing the external manifestations (clinical symptoms) of Wilson’s disease and raising awareness.

Prevention measures include:
  • Medical-genetic counseling.
  • Prenatal (antenatal) diagnostics.
  • Preimplantation genetic diagnosis.

Screening for patients with unexplained elevation of serum aminotransferases, chronic hepatitis, liver cirrhosis, and neurological disorders of unknown origin should be conducted between the ages of 2 and 18. All blood relatives of patients diagnosed with the disease should undergo routine examination for the presence of the disease.

During pregnancy, when there is a risk of giving birth to a patient with Wilson’s disease, molecular genetic analysis of fetal cells is performed at 15-18 weeks of pregnancy or chorionic villus sampling at 10-12 weeks.

Preimplantation genetic diagnosis of Wilson’s disease involves in vitro fertilization (IVF), allowing the diagnosis of diseases before fertilization and subsequent implantation of the fertilized embryo into the woman’s body. This can prevent the conception of a child with genetic diseases and may be a choice in families where mutant genes capable of causing the disease have already been identified.