Generality
Prader-Willi syndrome is a rare genetic disorder that causes physical, behavioral and intellectual abnormalities. The most characteristic clinical signs are obesity (and the related diseases) and reduced muscle tone.
Physical examination is usually sufficient to establish the correct diagnosis, but reliable genetic tests can also be performed.
Unfortunately, there is still no definitive therapy; however, some pharmacological and behavioral countermeasures may limit the associated symptomatology.
Brief reminder of genetics
Before describing Prader-Willi syndrome, it is good to make a brief reference to genetics.
CHROMOSOMES AND DNA
Every cell of a healthy human being has 23 pairs of homologous chromosomes : 23 are maternal, that is, inherited from the mother, and 23 are paternal, or inherited from the father. A pair of these chromosomes is sexual, that is, it determines the sex of the individual; the remaining 22 pairs, instead, are composed of autosomal chromosomes . In their entirety, the 46 human chromosomes contain the entire genetic material, better known as DNA . In the DNA of an individual are written his somatic traits, his predispositions, his physical abilities etc.
GENES AND MUTATIONS OF DNA
DNA is organized in many sequences, more or less long, called genes .
Figure: the organization of a gene within a pair of homologous chromosomes. A pair of homologous chromosomes contains specific genes, all having two variants, the alleles, occupying the same chromosomal position and doing the same functions (except mutations). The left pair of chromosomes has two equal alleles (both blue); the right pair instead has two different alleles (one is red, the other is blue).
Each gene occupies a specific chromosome and its counterpart, as it is present in two copies, called alleles . An allele comes from the mother and resides in the maternal chromosome; the other allele comes from the father and is housed in the paternal chromosome.
From the genes the proteins originate, present in our body. When a DNA mutation occurs, a gene (usually an allele) of a given chromosome can either be defective and therefore produce a defective protein or be missing altogether.
What is Prader-Willi syndrome?
Prader-Willi syndrome is a rare genetic disorder characterized by a series of physical, intellectual and behavioral deficits dependent on an alteration of chromosome 15.
During early childhood, the syndrome manifests itself with unusual muscle weakness and developmental delay. Later, during childhood, other problems begin to arise, such as continual appetite, learning difficulties and behavioral anomalies.
Individuals with Prader-Willi syndrome are, very often, people who suffer from obesity, from which various cardiac problems arise. These are the main cause of death.
Epidemiology
Prader-Willi syndrome is a rare disease: in fact, the birth of an affected child is recorded on average every 15, 000-30, 000 newborns.
It affects males and females equally and has no predilection for certain breeds.
Causes
The cause that causes Prader-Willi syndrome is a genetic mutation on chromosome 15 . The exact gene struck has not yet been clarified; the suspicions fall, more than anything else, on a chromosomal region, which includes more genes.
Figure: a chromosome 15 and the genes suspected of having a role in Prader-Willi syndrome. From the site: www.kreatech.com
THE GENES ON THE CHROMOSOMA 15
Usually, our body's cells use both alleles to create proteins. In other words, this means that both chromosomes, maternal and paternal, are useful and provide their genetic contribution.
However, in some particular cells, due to an evolutionary and non-pathological issue, only one (paternal or maternal) allele works and its work is more than satisfactory. The non-active allele is called silent, precisely because it exists, but it does not "express" itself.
The cells of our brain all contain chromosome 15, but, in some regions, only the maternal genetic line is expressed, while, in others, only the paternal one. In the hypothalamus, which is the brain area responsible for Prader-Willi syndrome, only the genes of the paternal chromosome are normally expressed.
CHROMOSOMA 15 AND THE PRADER-WILLI SYNDROME
Through genetic testing, it was found that patients with Prader-Willi syndrome lack a normal paternal chromosome 15. This is deleterious in the hypothalamus, where the only active chromosomal line is the paternal one.
The main functions of the hypothalamus:
- Appetite regulation
- Adjustment of sleep-wake rhythms
- Expression of emotional states
- Body temperature regulation
- Hormone production
But what triggers the malfunction or absence of the paternal chromosome 15? There are at least three possible reasons:
- Absence of a specific region of the paternal chromosome 15: in fact, the chromosome lacks an essential part.
- Two chromosomes 15 maternal. This anomaly occurs due to an error during the formation of the embryo.
- Change of some genes present on the paternal chromosome 15.
GENETIC AND HEREDITARY? OR ONLY GENETICS?
Geneticists consider Prader-Willi syndrome a genetic disease, since, according to studies, it emerged that the three aforementioned modes of mutation are not inherited from parents (who possess a normal chromosomal outfit), but arise, by chance, just before conception ( sporadic mutation ).
However, the veracity of this statement is undermined by the detection of some pairs of parents with more than one child suffering from Prader-Willi syndrome. In these cases, there is reason to believe that there may be some hereditary component, still to be demonstrated, at the origin of the disease.
PRADER-WILLI SYNDROME AND ANGELMAN'S SYNDROME
The Prader-Willi syndrome is, in some ways, the opposite of Angelman syndrome : in the latter, in fact, it is the maternal chromosome 15 that does not function properly.
Symptoms and Complications
To learn more: Symptoms Prader-Willi syndrome
Prader-Willi syndrome manifests itself, with the first symptoms and signs, already during the earliest infancy (first year of life); in this period, it mainly causes a reduction in muscle tone (hypotonia) and a developmental delay. Over time, the disease then undergoes a sort of evolution, which further enriches the symptomatic picture.
CHILDHOOD
The main signs, during the first year of life, are:
- Muscular hypotonia . It means that the tone of the muscles is reduced compared to normal: it is usually revealed with soft and not very reactive limbs, as well as with a difficult sucking of the mother's milk.
- Development delay . It tends to be favored by sucking difficulties due to hypotonia.
- Strabismus .
- Characteristic facial features . Almond eyes, narrowing of the head at the temples, mouth downwards and thin upper lip.
- Partial or complete absence of response to stimuli . The child is tired and it is not easy to wake him up.
FROM THE AGE TO AGE? ADULT
Since the first year of life, a long series of problems has arisen, which can have dramatic results.
- Remarkable appetite and obesity . Patients show a constant desire for food, which leads them to eat a lot and gain considerable weight. If they find nothing to eat, they come to consume frozen food and waste, in other words, anything edible. All this is due to the altered functions of the hypothalamus.
- Hypogonadism . It means that the genital organs (testicles, in humans, and ovaries, in women) produce few sex hormones (male testosterone and female estrogen). The patient does not complete pubertal development and is not usually fertile. The first menstruation, in women, is delayed (if not entirely absent); in humans, no change of voice is observed.
- Reduced growth and development . To the problem of muscular hypotonia, which remains, is added a reduced statural development, even after the period of puberty (in which, usually, adolescents rise several centimeters).
- Learning deficits . The intellectual faculties of patients are almost always reduced.
- Behavioral problems . Especially during adolescence, individuals are stubborn, capricious and suffer from the so-called obsessive-compulsive disorder.
- Motor delay . Children learn to walk very late.
- Language difficulties . Usually, patients start talking with considerable delay and their language always remains poor and difficult.
- Sleep disorders . The normal alternation between REM and NON-REM sleep phases is not respected. Furthermore, patients, when they sleep, suffer from breath interruptions (sleep apnea).
- Scoliosis . The problem is reserved only for some patients.
WHEN TO REFER TO THE DOCTOR
In the infant. The signs that should prompt you to suspect Prader-Willi syndrome are: lack of development, muscular hypotonia, difficulties in sucking breast milk, facial features and lack of response to stimuli.
In the child. Two fundamental clues are: the persistent search for food and the rapid increase in weight.
COMPLICATIONS
The main complications of Prader-Willi syndrome are due to obesity and all those related problems, such as diabetes, heart disease, hypertension, hypercholesterolemia, atherosclerosis, etc. Moreover, remaining within the context of continuous nutrition, it is easy for the patient to suffocate due to a meal consumed with voracity.
Another series of very important complications is related to hypogonadism : the lack of sex hormones very often causes sterility and osteoporosis .
Diagnosis
Before resorting to genetic tests, a correct pre-diagnosis of Prader-Willi syndrome can also be established by means of a simple physical examination and some blood tests.
Clinical signs to be found on physical examination
in the infant:
- Muscular hypotonia
- Almond eyes
- Shrinking of the temples
In the child / adolescent:
- Insatiable appetite
- Obesity
- Behavioral problems
Genetic tests serve as confirmation and help to clarify the type of mutation that caused the disease.
Treatment
Unfortunately, since it is a genetic disease, Prader-Willi syndrome is not curable.
The only applicable therapeutic treatments are to limit symptoms (for example, obesity), moderate some abnormal behaviors and, in general, improve patients' standard of living.
To succeed in all this, it is advisable to turn to a team of doctors and experts, specialized in various fields, from endocrinology to dietology, from physiotherapy to psychotherapy.
The most common therapeutic measures are listed below.
NUTRITION IN THE CHILDHOOD AND IN THE NEXT STEPS
During early infancy, to overcome the difficulties of sucking and the lack of development, it is good to give the child highly caloric meals.
In the later stages, the situation completely changes: the meals given should be carefully checked, paying maximum attention to the calories.
The most suitable specialist to ask for advice is the dietician .
GROWTH HORMONE
The exogenous administration (ie from the outside) of the growth hormone ( GH ) has three effects:
- Encouraging growth, which would otherwise be lacking
- Improve muscle tone
- Reduce body fat levels
The treatment begins at the age of about 3-5 years.
Today, there are hormonal preparations created in the laboratory, effective and with reduced side effects.
The most indicated specialist, in this case, is an endocrinologist .
SEXUAL HORMONES
The exogenous administration of testosterone, for men, and of estrogens, for women, is essential to restore the reduced levels of these two hormones. In addition to improving fertility, hormone therapy also has effects against osteoporosis.
The treatment begins at puberty.
To learn more: Drugs for the Treatment of Prader-Willi Syndrome ยป
PHYSIOTHERAPY AND LOGOPEDIA
Patients with Prader-Willi syndrome need physical and language rehabilitation . The first aims to limit muscular hypotonia and the effects of obesity; the second remedy to communication deficiencies, both spoken and written.
The experts, to turn to, are, respectively, a physiotherapist and a speech therapist.
PSYCHOTHERAPY AND EMPLOYMENT THERAPY
Psychotherapy is essential for those patients with obsessive-compulsive disorders and mood in general. The support of a psychiatrist or a psychologist can greatly improve the behavioral aspect.
Occupational therapy, on the other hand, aims to teach the patient how to take care of themselves, how to dress etc., in other words how to carry out the main daily activities.
THE HELP OF FAMILIES
The proximity of family members is essential to help the sick relative, especially during his youth. The advice that is usually given to families is to follow the patient in all his activities (especially when he is fed), to inquire about the most appropriate behavior to reserve for him, not to exclude him etc.
Prognosis and prevention
Given that Prader-Willi syndrome is an incurable disease, the prognosis can never be positive. The greatest danger is represented by obesity and by the pathologies connected with it: death is usually due to one of these.
The available treatments (balanced diet, hormonal therapy, psychotherapy, etc.) improve the quality of life, even in a sensitive way; however, there are still measures of symptom control and nothing more.
The closeness of relatives is fundamental: their support, in fact, can extend the life of the patients.
PREVENTION
When the disease arises in the embryo due to a genetic mutation, there is no way to prevent it.
If, instead, two parents have already given birth to a child with Prader-Willi syndrome, before a second pregnancy they can undergo specific genetic tests to find out whether they are carriers of the disease or not.
