Prader's syndrome - Willie

Description:

Prader's syndrome — Willie — rare genetic anomaly. At Prader's syndrome — Willie are absent or about 7 genes from the 15th chromosome inherited from the father do not express.

Karyotype 46 XX or HU, 15q-11-13. The disease is for the first time described by the Swiss pediatricians And. Prader and H. Willi in 1956.

According to the register of association of patients with Pradera-Willie's syndrome, in the USA and Canada for December, 1986 there were 1595 patients. In recent years it was succeeded to establish the population frequency of pathology, a component 1: 10 000 - 1: 20 000.

The reasons of a syndrome of Prader - Willie:

The authors who for the first time described a syndrome suggested about an autosomal and recessive mode of inheritance of a disease. Then there were messages on a possibility of autosomal and dominant transfer of a disease. The observed family cases of pathology could serve as confirmation of these hypotheses. However the majority of the described clinical observations of a syndrome of Prader - Willie had sporadic character.

The subsequent researches allowed to establish at children with Prader's syndrome - Willie certain chromosomal disturbances. The cytogenetic analysis showed that chromosomal anomalies at patients were presented by either translocations (t 15/15), or mosaicism. In 1987 the first messages on microdeletion of a chromosome 15 appeared. However final identification of chromosomal changes at Prader's syndrome - Willie became possible only after implementation in practice of molecular and genetic methods of a research.

Now it is established that development of a syndrome of Prader - Willie is connected with damage of the critical region of a chromosome 15 (q11.2-q13 segments). At the same time it turned out that damage of the same site of a chromosome 15 is observed also at other disease - a syndrome of Angelman which clinical picture significantly differs from Prader's syndrome - Willie and is characterized early (at the age of 6-12 months) by delay of psychomotor development, a nanocephalia, disturbance of the speech (in 100% of cases), an ataxy, uncontrollable violent laughter, frequent epileptiform attacks, a specific look.

Thus, despite damage at Prader's syndromes - Willie and Angelman of the same locus of a chromosome 15, clinical displays of both diseases are sharply opposite.

The explanation of phenotypical distinctions is received only in recent years. It turned out that development of these diseases is connected with the new genetic phenomena - genomic imprinting and a uniparentalny disomy.

Genomic imprinting - the new phenomenon opened thanks to achievements of molecular genetics. It means various expression of genetic material (homologous alleles) in chromosomes depending on a fatherly or maternal origin, i.e. demonstrates influence of parents on the child's phenotype. So far was considered that the contribution to a proyavlyaemost (expression) of genes of the father and mother is equivalent.

In fact genomic imprinting is a sexual and tkanevozavisimy difficult modifier of gene activity of some loci of chromosomes depending on their parent origin. Manifestations of genomic imprinting are revealed also at other diseases - Sotos, Bekvita-Wiedemann, Silvera-Russell's syndromes, a mucoviscidosis and others.

Uniparentalny (one-parent) disomy - inheritance of both chromosomes only from one of parents. For many years was considered that such inheritance is impossible. Only by means of molecular and genetic markers it was succeeded to prove a possibility of a one-parent disomy. The nature of a uniparentalny disomy is finally not found out, however is established that she is obliged by the origin to a number of genetic and biochemical disorders.

It should be noted that by means of an ordinary research of chromosomal structure of a karyotype it is impossible to reveal microdeletion or a uniparentalny disomy. Special cytogenetic and molecular and genetic methods - the prometaphase analysis, use of DNA markers of certain sites of a chromosome 15 (a research of processes of methylation), etc. are for this purpose applied.

Today Prader's syndromes - Willie and Angelman serve as the standard model for studying new in clinical genetics and the difficult phenomena - genomic imprinting and a uniparentalny disomy.

It is established that Prader's syndrome - Willie can be caused by two main mechanisms. The first of them - microdeletion of a chromosome 15 (15q11.2-q13), which always a fatherly origin. The second - a maternal isodisomy i.e. when both chromosomes 15 are received from mother. Development of a syndrome of Angelman, on the contrary, is connected with microdeletion of the same site of a chromosome 15, but a maternal origin, or a fatherly isodisomy. The majority (about 70%) of cases of a syndrome of Prader - Willie is caused by microdeletion, the others - a disomy. At the same time lack of clinical distinctions between patients with microdeletion and an isodisomy attracts attention.

Pathogeny:

The pathogeny of a syndrome of Prader - Willie remains low-investigated so far. Are suggested that obesity at patients is caused considerable (more than by 10 times) by strengthening of synthesis of fat from acetate and extremely low processes of a lipolysis.

The hypogonadism on hypogonadotropic type can be connected with hypothalamus dysfunction, preferential, in the field of ventromedialny and ventrolateralny kernels. This point of view is validated by efficiency of treatment of patients with the pharmaceutical drugs (clomifene) leading to increase in plasma of content of luteinizing hormone, testosterone, normalization of indicators of renal excretion of gonadotrophins, a spermatogenesis and to emergence of secondary sexual characteristics.

Decrease of the activity of a tyrosinase serves one of explanations of a hypoxanthopathy, hair and an iris in hair follicles and melanocytes, and also reduction of a pigment in a retina.

The attention to the increased risk of development of leukemia in patients with Prader's syndrome - Willie is paid. Researches revealed decrease in DNA repair (to 65% in comparison with 97% at the healthy child) in lymphocytes of patients with this pathology. It is not excluded that low reparation ability of DNA can play a fatal role in development of malignant new growths in persons with Prader's syndrome - Willie.

Symptoms of a syndrome of Prader - Willie:

Children with Prader's syndrome - Willie usually are born full-term with an insignificant pre-natal hypotrophy and is frequent in asphyxia. In 10-40% of cases buttock presentation is observed.

During a disease it is possible to allocate two phases: the first - is inherent to children of 12-18 months of life. It is characterized by the expressed hypomyotonia, decrease in reflexes - Moro, sucking and deglutitory that complicates feeding of the child. The second - comes later, in several weeks or months. There are a polyphagia, constant feeling of hunger leading to development of obesity, and the adiposity is observed preferential on a trunk and in proximal departments of extremities.

The hypomyotonia gradually decreases and to school age almost completely disappears. Feet and brushes of patients disproportionally small - an acromicria. At children the hypogonadism is noted (boys have a hypoplasia of a penis, a scrotum, a cryptorchism, and girls have an underdevelopment of vulvar lips and in 50% of cases - a uterus).

Growth of patients is quite often reduced. At 75% of children the hypoxanthopathy, a hair and irises is observed. The nanocephalia is often diagnosed. Psychomotor development lags behind age norm - coefficient of intellectual development - from 20 to 80 units (at norm of 85-115 units). The speech is complicated, the lexicon is reduced. Patients are benevolent, the mood is characterized by frequent change. Lacks of coordination, spasms, a strabismus are described.

Also other anomalies meet: mikrodontiya, hypoplasia of cartilages of auricles, scoliosis, ectropion (ectropion of a century), glaucoma.

Development of a diabetes mellitus which tends to improvement with age is frequent.

At a morphological research of a brain and a nuclear magnetic resonance tomography cysts of a worm of a cerebellum, anomaly of a cerebral cortex can be observed (approximately in 12% of cases).

Life expectancy of patients can reach 60 years and more.

Treatment of a syndrome of Prader - Willie:

Therapy of a syndrome of Prader - Willie is finally not developed. According to literature, the complex of medical actions includes only a diet with restriction of fats and carbohydrates and the drugs promoting formation of secondary sexual characteristics (gonadotrophins).