Andersen syndrome. Glycogenosis type IV (Andersen's disease, amylopectinosis) Promotions and special offers
described by the American pathologist Dorothy H. Andersen, 1901–1964; synonyms - glycogenosis, type IV, amylopectinosis) - a rare hereditary disease from the class of storage diseases, due to the absence of 1,4-alpha-glucan-branching enzyme, which leads to the accumulation in various organs, tissues and cells (liver, muscles, heart, leukocytes) of atypical poorly soluble glycogen. Main clinical manifestations: hepatosplenomegaly in the first years of life, progressive portal fibrosis with the development of liver cirrhosis, ascites, esophageal varices, liver failure; muscle hypotension; myocardial damage and heart failure. The diagnosis is clarified by examining the activity of 1,4-alpha-glucan-branching enzyme in the liver, muscles, etc. The type of inheritance is autosomal recessive. Treatment is symptomatic, the use of glucocorticoids may contribute to the onset of a temporary remission. The prognosis of the disease is poor, death occurs in childhood, usually due to liver failure.
D. H. Andersen. Familial cirrhosis of the liver with storage of abnormal glycogen. Laboratory Investigation, Baltimore, 1956; 5:11–20.
ANDERSEN SYNDROME
described by the Danish physician E. D. Andersen) is a rare hereditary disease: a prolonged Q-T interval, ventricular extrasystole, muscular hypotension; craniofacial features are characteristic - macrocephaly (an increase in the size of the skull by more than 10% of the age norm), dolichocephaly (lengthening of the skull in the anteroposterior direction due to premature ossification of the sagittal suture), scaphocephaly (a long skull with a protruding forehead and occiput, a raised vault, resembling an overturned boat), low-lying auricles, hypertelorism (wide-spaced eyes), micrognathia (small size of the upper jaw), brachydactyly (short-fingered), clinodactyly of the V fingers (lateral or medial curvature). The type of inheritance is autosomal dominant. Most of the reported cases are sporadic. Treatment is symptomatic.
E. D. Andersen, P. A. Krasilnikoff, H. Overad. Intermittent muscular weakness, extrasystoles and multiple developmental abnormalities: a new syndrome? Acta paediatrica Scandinavica, Stockholm, 1971; 60:559–564.
A rare hereditary disease from the group of multisystem channelopathies. The mode of inheritance is autosomal dominant, with incomplete transgression and significant variability among members of the same family. Sporadic cases are not uncommon. 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 the muscle cells. When the gene is mutated, the structure of potassium channels is disrupted, as is the regulation of the entry of potassium ions into the cell (the PIP2 regulatory molecule cannot bind to the channel). Violation of the penetration of potassium ions into muscle cells leads to the development of the 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 artemia.
It is also possible to damage the valvular apparatus of the heart, hypoplasia of the kidneys.
Dysplastic features are represented by short stature, low-set auricles, hypertelorism, soft and hard palate defects, mandibular hypoplasia, clinodactyly, and scoliosis.
The face of a patient with Andersen-Tavila syndrome. Attention is drawn to the characteristic dysplastic features: hypertelorism, hypoplasia of the lower jaw and low-set auricles (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)
The 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 inconsistency of drops in potassium concentrations during paralytic seizures, the traditional criteria for hypo-, normo- and hyperkalemic forms in Andersen-Tavila syndrome are unacceptable. Often, seizures develop against the background of prolonged general weakness.
Cardiac symptoms include prolongation of the Q-T 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 have paradoxical reactions to the administration of various drugs and refractoriness to antiarrhythmics. A persistent positive effect of therapy with amiodarone and acetazolamide (diacarb) was shown (stopping of cardiac and muscular 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 the Danish physician Ellen Damgaard Andersen et al. in 1971. ( Andersen E. D., Krasilnikoff P. A., Overvad H. Intermittent muscular weakness, extrasystoles and multiple developmental abnormalities: a new syndrome? // Acta paediatrica Scandinavian, Stockholm, 1971. – Vol.60. – P.559–564 ); she described the case of 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, made by an American neurologist of Lebanese origin, Rabbi 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 type IV glycogenosis (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)
Type IV glycogenosis (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)- a hereditary disease, which is caused by a lack 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 type IV glycogenosis (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)
Andersen's disease occurs as a result of mutations in the microsomal amyl-1,4:1,6-glucantransferase 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 the synthesis of glycogen at the branch points of the glycogen tree. The enzyme connects a session of at least six α-1,4-linked glycosidic residues of the outer chains of glycogen to the glycogen "tree" α-1,6-glycosidic bond. With an enzyme deficiency, amylopectin is deposited in the liver and muscle cells, which leads to cell damage. The concentration of glycogen in the liver does not exceed 5%.
Symptoms of type IV glycogenosis (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)
Disease manifests 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. The death of patients usually occurs before 3-5 years due to chronic liver failure, rarely in older children (up to 8 years).
Diagnosis of type IV glycogenosis (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)
Laboratory diagnostics based on the detection of glycogen with a modified structure in the liver biopsy and a decrease in the activity of amylo-1,4:1,6-glucan transferase.
Treatment of type IV glycogenosis (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 with a high content of easily digestible carbohydrates are necessary for hypoglycemia. In muscle forms of glycogenosis, improvement is noted when following a diet high in protein, prescribing fructose (orally 50-100 g per day), multivitamins, ATP. Attempts are being made to administer the missing enzymes to patients.
Patients with glycogenosis are subject to dispensary observation by a doctor of the medical genetic center and a pediatrician (therapist) of the clinic.
Prevention of type IV glycogenosis (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 genetic counseling is carried out.
Which doctors should be contacted if you have Glycogenosis type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis)
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Andersen's disease (type IV glycogenosis, amylopectinosis) occurs due to a deficiency of the 1,4-a-glucan branching enzyme, which leads to the accumulation of abnormal, poorly soluble glycogen.
This disease is called amylopectinosis because the glycogen in such cases is less branched and has longer linear regions containing a-1,4-glycosidic bonds, which is characteristic of the structure of amylopectin.
Andersen's disease is inherited in an autosomal recessive manner. The 1,4-a-glucan-branching enzyme gene is located on chromosome 3; its mutations underlying the disease are known, and their characterization in each individual case makes it possible to predict the clinical picture of the disease.
Symptoms of Andersen's disease
Amylopectinosis is clinically heterogeneous. The most common classical form is characterized by progressive cirrhosis of the liver. Initial signs - hepatosplenomegaly and poor development - appear in the first 18 months. life. Gradually develop portal hypertension, ascites, varicose veins of the esophagus, liver failure, from which patients die by the age of 5. In rare cases, liver damage does not progress.
There are also reports of a neuromuscular form of Andersen's disease. Its manifestations are varied:
- severe hypotension, muscle atrophy; damage to neurons from the moment of birth; death occurs in the neonatal period;
- myopathy and myocardial damage in older children;
diffuse damage to the central, peripheral nervous system, accompanied by accumulation of polyglucosane bodies in neurons (the so-called polyglucosane body disease) these cells.
Diagnosis of Andersen's disease
Atypical glycogen deposition is found in the liver, heart, muscles, skin, intestines, brain and spinal cord, and peripheral nerves. Small-nodular cirrhosis develops in the liver. When examining hepatocytes, faintly stained basophilic inclusions are visible, which are coarse-grained PAS-positive deposits, partially resistant to amylase. Electron microscopy reveals, in addition to glycogen particles, fibrous aggregates characteristic of amylopectin. The characteristic staining of cytoplasmic inclusions and the electron microscopic picture could be of diagnostic value, but similar histological signs were observed in polysaccharidoses without deficiency of 1,4-a-glucan-branching enzyme. To confirm the diagnosis, it is necessary to establish the insufficiency of this particular enzyme in the liver, muscles, in the culture of skin fibroblasts or in leukocytes. For the purpose of prenatal diagnosis, the activity of 1,4-a-glucan-branching enzyme is determined in cultured amniocytes or chorionic villi.
Andresen's disease is a fourth type of glycogenosis, in which there is a deficiency of an enzyme involved in the biotransformation of glycogen.
History of study
For the first time, the clinical picture of this pathology was described by Andersen in 1956. Notably, a blood relative of Andersen's patient was diagnosed with type 1 glycogenosis.
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 implements 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 the low activity of amylo-1,4 / 1,6-transglucosidase, the synthesis of pathological glycogen is noted, which in its chemical structure resembles amylopectin due to long and branched side chains.
Such glycogen is deposited in the liver cells, surrounded by connective tissue structures, which causes a violation of the functional activity of the liver and changes in its architectonics. Also, this chemical compound accumulates in other cellular structures, thereby violating 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, it implements a wide range of functions, its failure determines the formation of serious disorders in the work of all organs and systems.
With glycogenosis of the fourth type, one after another, the protein-synthetic, hematopoietic, detoxification functions of the liver are disturbed with the development of the corresponding clinical manifestations. It is progressive liver failure that in most cases causes death in children of the first three to five years of life.
Cirrhosis of the liver, acting as a trigger for impaired functionality of the heart muscle, can cause heart failure.
Diagnostics
As with all glycogenoses, with Andersen's disease, the level of free glucose in the blood decreases, deterioration in the general condition is recorded after a long break in food. 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 the developed metabolic disorders, primarily with the phenomena of acidosis.
At the consultation of an endocrinologist, the issue of prescribing age doses of glucocorticoids, anabolic steroids, and glucagon is decided. Hypoglycemia recorded in this pathology is an indication for the appointment of frequent meals, which should meet all the body's needs for nutrients and contain easily digestible carbohydrates.
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