Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Andresen's disease is a glycogenosis of the fourth type, in which there is a deficiency of the enzyme involved in the biotransformation of glycogen.

History of the study

The clinical picture of this pathology was first described by Andersen in 1956. It is noteworthy that a blood relative of patient Andersen was diagnosed with glycogenosis type 1.

Etiology

The clinical picture characteristic of this glycogenosis is associated with a mutation of the gene that determines the synthesis of amylo-1,4/1,6-transglucosidase, which realizes its enzymatic activity in microsomes of the liver, fibroblasts, erythrocytes, leukocytes and myocytes.

It should be noted that the activity of this enzyme in microsomes of skeletal muscles and myocardium is manifested to a sufficient extent. The gene encoding this enzyme is located on the twelfth chromosome, and its mutation is inherited in an autosomal recessive manner.

Pathogenesis

As a result of low activity of amylo-1,4/1,6-transglucosidase, pathological glycogen is synthesized, which in its chemical structure resembles amylopectin due to long and branched side chains.

Such glycogen is deposited in liver cells and is surrounded by connective tissue structures, which causes disruption of the functional activity of the liver and changes in its architectonics. This chemical compound also accumulates in other cellular structures, thereby disrupting their functionality.

Clinical picture

The first clinical manifestations of this pathology appear quite early - in the first year of a child’s life. Most often we are talking about the development of gastrointestinal syndrome with diarrhea and vomiting. As pathological glycogen accumulates, the size of the liver increases, a picture of liver failure is formed, and muscle atrophy or malnutrition develops.

In most cases, progressive cardiomyopathy is diagnosed as a secondary pathology. Since the liver is the most important organ of the human body and performs a wide range of functions, its failure determines the formation of serious disturbances in the functioning of all organs and systems.

With glycogenosis of the fourth type, the protein synthetic, hematopoietic, and detoxification functions of the liver are disrupted one after another with the development of corresponding clinical manifestations. It is progressive liver failure that in most cases causes death in children in the first three to five years of life.

Liver cirrhosis, acting as a trigger for impaired functionality of the heart muscle, can cause heart failure.

Diagnostics

As with all glycogenosis, with Andersen's disease the level of free glucose in the blood decreases, and a deterioration in the general condition is recorded after a long break from eating. Ultrasound examination of the abdominal organs reveals cirrhotic changes in the liver due to necrosis of hepatocytes and accumulation of amylopectin. The spleen has fibrous inclusions.

Treatment

Specific treatment for this glycogenosis has not been developed. Therapeutic measures are symptomatic in nature and are aimed primarily at combating developed metabolic disorders, primarily the phenomena of acidosis.

At a consultation with an endocrinologist, the issue of prescribing age-specific doses of glucocorticoids, anabolic steroids, and glucagon is decided. Hypoglycemia, recorded in this pathology, is an indication for the prescription of frequent meals, which should replenish all the body's nutritional needs and contain easily digestible carbohydrates.

You can either write your own.

A rare hereditary disease from the group of multisystem channelopathies. The mode of inheritance is autosomal dominant, with incomplete transtransition and significant variability among members of the same family. Sporadic cases are common. The defective gene (KCNJ2) is located on the long arm of chromosome 17 (locus 17q23.1-q24.2). The gene product is involved in the formation of potassium channels, through which potassium enters muscle cells. When a gene mutation occurs, the structure of potassium channels is disrupted, as is the regulation of the entry of potassium ions into the cell (the regulatory molecule PIP2 cannot contact the channel). Impaired penetration of potassium ions into muscle cells leads to the development of characteristic signs of the syndrome (the role of the KCNJ2 gene in the formation of the skeletal system is still being studied). Clinically, the syndrome is represented by a triad of signs:

characteristic dysmorphism of the face and skeleton;

potassium-sensitive periodic paralysis;

ventricular arrhythmias.

Damage to the valvular apparatus of the heart and renal hypoplasia are also possible.

Dysplastic features are represented by short stature, low-set ears, hypertelorism, defects of the soft and hard palate, hypoplasia of the lower jaw, clinodactyly, and scoliosis.

The face of a patient with Andersen-Tawil syndrome. Noteworthy are the characteristic dysplastic features: hypertelorism, hypoplasia of the lower jaw and low-set ears (source Katz J.S., Wolfe G.I., Iannaccone S., Bryan W.W., Barohn R.J. The exercise test in Andersen syndrome // Arch. Neurol., 1999. – Vol.56. – P.352-356)

Potassium-sensitive periodic paralysis without myotonic manifestations characteristic of this syndrome is clinically indistinguishable from other forms of hyperkalemic periodic paralysis. However, there is an opinion that, due to the extreme variability of changes in potassium concentrations during paralytic attacks, the traditional criteria for hypo-, normo- and hyperkalemic forms in Andersen-Tawil syndrome are unacceptable. Often attacks develop against a background of prolonged general weakness.

Cardiac symptoms include prolongation of the QT interval of varying severity, ventricular bigeminy, paroxysmal ventricular (up to biventricular) tachycardia, sudden cardiac arrest.

There are reports in the literature of sudden death syndrome in patients suffering from this disease.

Patients often experience paradoxical reactions to the administration of various medications and refractoriness to antiarrhythmics. A persistent positive effect from therapy with amiodarone and acetazolamide (Diacarb) was shown (relief of cardiac and muscle symptoms).

For the first time, the combination of periodic paralysis and arrhythmia was noticed by Klein et al. in 1963 ( Klein R., Ganelin R., Marks J.F., Usher P., Richards C. Periodic paralysis with cardiac arrhythmia // J. Pediatr., 1963. – Vol.62. – P.371- 385) and Lisak et al. in 1970 ( Lisak R.P., Lebeau J., Tucker S.H., Rowland L.P. Hyperkalemic periodic paralysis with cardiac arrhythmia // Neurology, 1970. – Vol.20. – P.386). The syndrome was first described by Danish physician Ellen Damgaard Andersen and co-authors in 1971. ( Andersen E. D., Krasilnikoff P. A., Overvad H. Intermittent muscular weakness, extrasystoles and multiple developmental abnormalities: a new syndrome? // Acta paediatrica Scandinavica, Stockholm, 1971. – Vol.60. – P.559–564 ); she described a case of the disease in an 8-year-old child with a characteristic triad of periodic paralysis, arrhythmia and developmental anomalies. Subsequently, such a triad was described only in a single work in 1985. And only a detailed description by an American neurologist of Lebanese origin, Rabi Tawil et al. ( Tawil R., Ptacek L. J., Pavlakis S. G., DeVivo D. C., Penn A. S., Ozdemir C., Griggs R. C. Andersen‘ s syndrome: potassium— sensitive periodic paralysis, ventricular ectopy, and dysmorphic features // Annals of Neurology, 1994. – Vol.35. – N.3. – P.326-330 ), attracted the attention of specialists to this nosological form, stimulating its further study.

What is glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)- a hereditary disease that is caused by a deficiency of enzymes involved in glycogen metabolism; characterized by a violation of the structure of glycogen, its insufficient or excessive accumulation in various organs and tissues.

What provokes glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Andersen's disease occurs as a result of mutations in the microsomal amylo-1,4:1,6-glucan transferase gene, leading to its deficiency in the liver, muscles, leukocytes, erythrocytes and fibroblasts. The gene is mapped on chromosome 3p 12. The mode of inheritance is autosomal recessive.

Pathogenesis (what happens?) during glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Amylo-1,4:1,6-glucan transferase is involved in glycogen synthesis at branch points of the glycogen tree. The enzyme connects a session of at least six α-1,4-linked glucosidic residues of the outer glycogen chains to the glycogen “tree” via an α-1,6-glycosidic linkage. When the enzyme is deficient, amylopectin is deposited in liver and muscle cells, which leads to cell damage. The glycogen concentration in the liver does not exceed 5%.

Symptoms of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Disease manifests itself in the first year of life with nonspecific gastrointestinal symptoms: vomiting, diarrhea. As the disease progresses, hepatosplenomegaly, progressive liver failure, generalized muscle hypotonia and atrophy, and severe cardiomyopathy occur. Death of patients usually occurs before 3-5 years of age due to chronic liver failure, rarely in older childhood (up to 8 years).

Diagnosis of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Laboratory diagnostics based on the detection of glycogen with an altered structure in a liver biopsy and a decrease in the activity of amylo-1,4:1,6-glucan transferase.

Treatment of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Treatment is aimed at combating metabolic disorders, incl. with acidosis. In some cases, the use of glucagon, anabolic hormones and glucocorticoids is effective. Frequent meals high in easily digestible carbohydrates are necessary for hypoglycemia. In muscular forms of glycogenosis, improvement is noted by following a diet high in protein, administering fructose (orally 50-100 g per day), multivitamins, and ATP. Attempts are being made to administer missing enzymes to patients.

Patients with glycogenosis are subject to dispensary observation by a doctor at the medical genetic center and a pediatrician (therapist) at the clinic.

Prevention of glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Prevention has not been developed. To prevent the birth of a child with glycogenosis in families where there were similar patients, medical and genetic counseling is carried out.

Which doctors should you contact if you have glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

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The occurrence of the disease Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Course of the disease Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Symptoms of the disease Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Diagnosis of the disease Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Laboratory diagnostics based on the detection of glycogen with an altered structure in a liver biopsy and a decrease in the activity of amylo-1,4:1,6-glucan transferase.

Treatment of glycogenosis type IV disease (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Patients with glycogenosis are subject to dispensary observation by a doctor at the medical genetic center and a pediatrician (therapist) at the clinic.

Prevention of glycogenosis type IV disease (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)

Prevention has not been developed. To prevent the birth of a child with glycogenosis in families where there were similar patients, medical and genetic counseling is carried out.

The clinical picture of the disease was first described by Andersen in 1956. The disease is inherited in an autosomal recessive manner. In type IV glycogenosis, there is a defect in the enzyme amylo-1,4 → 1,6-transglucosidase, which is involved in the formation of branch points in the glycogen molecule:

In type IV glycogenosis, abnormal glycogen, similar to amylopectin (a component of starch in plant cells), is synthesized in the affected organs. The abnormal glycogen molecule has a reduced number of branch points and longer external and internal chains compared to the norm.

The disease is rare and is generalized (cardiac and skeletal muscles and liver are most often affected). Clinically, the disease is manifested by hepatosplenomegaly, ascites, mental development is not affected. Progressive portal fibrosis of the liver leads to cirrhosis. Cirrhosis probably develops as a result of the accumulation of amyl-like glycogen.

Death in childhood from liver failure. A pathological examination reveals an increase in the size of the kidneys, liver, and spleen. Hepatocytes are increased in size and contain amylopectin-like polysaccharide.

Lafora disease- cerebral glycogenosis (myoclonic epilepsy). In this disease, an accumulation of abnormal glycogen is detected in the brain, resembling the properties of the polymer in type IV glycogenosis. The activity of the branching enzyme is not changed in this disease.

Glycogenosis type V (McArdle disease)

First described by B. McArdle in 1951. Autosomal recessive type of inheritance. Characterized by deficiency of muscle phosphorylase in skeletal muscles. The absence of muscle phosphorylase is not combined with a violation of hepatic phosphorylase (controlled by various genes). The activity of phosphorylase of leukocytes, erythrocytes, and platelets in McArdle disease is not changed.

With this disease, up to 3-4% of glycogen that is normal in structure accumulates in the muscle fibers. Excess glycogen is deposited under the sarcolemma in the cytoplasm. At rest, energy needs are provided by myocyte glucose. During muscular work, the need for energy supply is not met due to an enzymatic defect, which causes pain and cramps in this type of glycogenosis.

McArdle disease is heterogeneous. Clinical signs more often appear in adults; in childhood, the symptoms of the disease are not pronounced. The disease occurs in 3 stages:

1. In childhood and adolescence, muscle weakness, fatigue, and possible myoglobinuria are observed.

2. Between the ages of 20 and 40, muscle pain becomes more intense, and cramps appear after physical activity.

3. After 40 years, progressive weakness occurs due to muscular dystrophy.

It has been established that phosphorylase activity decreases sharply with vitamin B6 deficiency (60% of pyridoxine in skeletal muscles is associated with phosphorylase). Therefore, phosphorylase deficiency affects the content of pyridoxine in the body. The prognosis for type V glycogenosis is favorable.