Mental retardation (RM) is defined by the existence, before the age of 18, of “intellectual functioning significantly below the average associated with limitations of adaptive functions” (DSM IV-R classification). Standardized tests for the measurement of the intelligence quotient (IQ) are used to quantify the cognitive deficit. Thus, RM is referred to when the IQ is less than 70 and the RM can be classified according to the severity of the overall intellectual deficit.The most widely used classification is that of DSM IV, which distinguishes between deep, severe, moderate and mild RMs corresponding to IQs of less than 20, between 20 and 35, between 35 and 50 and between 50 and 70. The other fundamental aspect of the definition of RM in DSM IV is the limitation of adaptive functions in areas of aptitude such as communication, autonomy, school learning, social life, individual responsibility, work, leisure, health and security. The quantification of these adaptive limitations is therefore complementary to the study of IQ and is possible thanks to evaluation scales (Vineland scale). These definitions actually conceal major diagnostic and nosological difficulties, a lack of knowledge of the molecular and cellular bases, as well as the physiopathological mechanisms involved in the majority of genetic RMs.
The prevalence of RM is estimated at 3% of the general population. Deep, severe and moderate RMs have a prevalence of 3.8 ‰ while the prevalence of mild RM is 2.5%: mild RM is 10 times more frequent than moderate to deep RM. Etiologic diagnosis is only carried out in about 60% of severe MR and 25% of mild MR, whether anoxo-ischemic, toxic, infectious, traumatic or genetic.
The identification of the genetic origin of an RM is essential, both in terms of the positive diagnosis which is essential to ensure proper management and in terms of genetic counseling.
In the first place, an early diagnosis of an RM of genetic origin allows a better individual care of the child. Indeed, in some cases, it will be interesting to develop different pedagogies depending on the diagnosis.
For example, a child with Angelman’s syndrome may be initiated into other modes of communication than verbal communication. Early diagnosis will also make it possible to institute a medical follow-up and to prevent the added handicaps. For example, children with Williams-Beuren syndrome will benefit from cardiac and renal monitoring (search for aortic supravalvular stenoses, high blood pressure and renal insufficiency), children with Prader-Willi syndrome will be as soon as possible on a dietetic, endocrinological and orthopedic basis (prevention of obesity and scoliosis).
The identification of an etiological diagnosis can also be a decisive step in the psychological progress of the family and bring positive elements to the care of the child and the accompaniment of his family by the medicaloeducational teams. It seems important to stress the importance of seeking a match between the parents’ request and the etiological approach of the clinicians, to inform the family of the hypotheses and examinations proposed in order to facilitate the acceptance of the investigations and their results. The announcement of a diagnosis of RM of genetic origin is in fact only understood in response to an interrogation of the parents.
Finally, the early diagnosis of genetic RM makes it possible to answer the question of genetic counseling. This is a crucial and painful step. The question, whether openly formulated or not, is: Is there a risk of having another child with RM in the family? It is possible to reassure certain parents perfectly because an RM of genetic origin is not always hereditary and some of these MR are meiosis accidents which are therefore sporadic.
For other RMs where there is a high risk of recurrence, it is essential to conduct a family survey to identify those at risk of having an affected child in order to inform them of this risk.
A genetic cause is thought to be involved in 30-50% of MR cases. In everyday practice, when an obvious cause is not identified by history or clinical examination, the etiologic diagnosis of a RM becomes highly complex and often requires the multidisciplinary collaboration of neuropediatricians, psychiatrists, clinical geneticists , cytogenetics and molecular biologists.
With the progress of medical genetics in the field of syndromology and dysmorphology, hundreds of syndromes with RM have been counted. This underscores the need for fine clinical expertise to make an accurate diagnosis. The multiplicity of these syndromes and the low prevalence of each syndrome explain the difficulties encountered by the clinician. In some cases, this diagnosis may be confirmed on molecular or cytogenetic bases; in other cases, genetic substratum not being identified, a clinical diagnosis will be made.
The etiological investigation of a RM follows a rigorous approach including a clinical evaluation, a family survey, a paraclinical assessment and genetic investigations according to the clinical evaluation.
Different consultation situations:
Consultation of the index case with his parents:
It’s the most frequent case. The child is brought by his parents in search of an explanation for a delay in acquisitions.
Consultation in genetics is either spontaneous or advised by a pediatrician, neuropediatrician or psychiatrist. The family’s demand is then generally complex, combining, depending on the case, a request for treatment or treatment, a request for explanation, a request for assessment of the prognosis and a request for genetic counseling for a project. other child in the couple.
Consultation before a case of malformative syndrome in the first months of life while mental retardation is not yet objectified:
This is a very different situation in which parents often ask for explanations about malformations and are not in a questioning about the appearance of a possible RM in the years to come.
The diagnostic announcement must therefore be particularly careful.
Early diagnosis is of great interest if it modifies early medical and surgical management, but can be traumatic and endanger the parent-child relationship.
Consultation of the index case with his spouse for an application for genetic counseling for the offspring:
This situation is relatively rare. They are most often adults with mild to moderate RM. Consultation
may be suggested by the attending physician, obstetrician or midwife in early pregnancy. It is a delicate situation where it is essential to try to appreciate the real demand of the couple. Has the couple been sent by a third party (doctor or family) and does they express anxiety for their offspring? The interest of this type of approach is often mainly to detect pathologies of dominant transmission and, a fortiori, those for which there is a risk of more severe pathology in the child. For example, women with Steinert myotonic dystrophy who may have mild RM are in demand for prenatal diagnosis only to prevent the death of a newborn with a severe congenital form of the disease and certainly not a pathology of severity similar to theirs.
Consultation of a related case index:
This situation is more and more frequent: a healthy subject consults because of a family history for which he raises the question of the risk of recurrence in his own offspring.
The clinical geneticist then takes care to gather the elements of the file concerning the subject reached, after having obtained an authorization of access to the file. If genetic counseling can not be done on the basis of a medical record, then a consultation should be proposed for the patient himself.
The collection of the history is a major time of the diagnostic procedure, detailing the information concerning pregnancy, childbirth, the first months of life, until the patient’s age at the consultation. This interrogation seeks behavioral, nutritional and sleep disorders and traces the psychomotor development of the child and any associated pathologies. The description of the age of onset of parental concerns, the chronology of signs, and the notion of progress or regression are diagnostic elements that are very important and sometimes difficult to find accurately and objectively.
Clinical examination should be complete: growth, cranial perimeter, cardiorespiratory, abdominal, neurological, osteoarticular, cutaneous examination (pigmentation abnormalities, nail, hair or hair abnormalities), external genital organs. Morphological examination in search of dysmorphism is an integral part of the systematic examination of a patient with MR and must be rigorous. This morphological examination must be complete (skull, face, extremities, thorax, endobuccal examination) and obeys precise criteria even if it must of course take into account the individual variations and a certain number of minor anomalies which can be found in the general population. The search for family resemblances helps in the interpretation of the different dysmorphic elements. The clinical evaluation of a child or adult with MR is not conceivable without the complementary expertise of neuropediatric, ophthalmologist and ENT clinicians.
At the end of this examination, we distinguish syndromic RM (associated with malformations, dysmorphia, specific neurological signs, growth disorders, sensory deficits, etc.) and non-syndromic RM.
The collection of the family history is essential and must pass through the realization of a detailed genealogical tree whose consultation often leads the parents to mention elements of which they would not have spontaneously spoken during a more succinct interrogation. At the end of this family survey, it will be proposed to meet in consultation with any relatives related to the family or to collect, with their written consent, the elements of their medical file. This family survey makes it possible, in a number of cases, to evoke a mode of heredity and is therefore an essential step in the diagnostic procedure.
Complementary examinations are prescribed in a manner adapted to each clinical situation.
Complementary neurological and neurosensory examinations:
Cerebral imaging and electroencephalogram are most often proposed. A neurosensory complementary assessment is essential (visual acuity, examination with the slit lamp and fundus of eye, oculomotricity, audiogram, evoked potentials).
Malformative signs are systematically examined for clinical examination (craniofacial dysmorphism, craniosynostosis, abnormalities of the extremities, sacrococcygeal dimple, body asymmetry, cyphoscoliosis) and, at the lowest point of the call, radiological examinations are prescribed in order to clarify the anomalies (skeletal radiography, renal ultrasound, cardiac, medullary etc.).
Considerable advances in research to locate and identify many genes involved in these RMs have led to the development of new diagnostic and genetic counseling tools. The geneticist currently has three categories of tools that differ in their level of resolution. Thus these methods of investigation are complementary.
The karyotype allows the observation and classification of the chromosomes present during the metaphase or prometaphase of mitosis. It makes it possible to demonstrate abnormalities in the number or structure of chromosomes.
While a standard karyotype can visualize 300 to 500 bands per haploid batch of chromosomes, the high-resolution karyotype performed on prometaphase cells allows, by observing 700 to 850 bands per haploid batch of chromosomes, to improve resolution of the karyotype. Thinner revisions of the chromosomal structure, at least 3 megabases (Mb), can be observed but the interpretation is tricky and more effective if it is focused on a chromosome or chromosomal region, oriented by the clinical picture.
Molecular cytogenetics, a relatively recent phenomenon, is a frontier discipline between cytogenetics and molecular genetics that has revolutionized the traditional approach to cytogenetics. Currently, its main tools are fluorescence in situ hybridization (FISH) on chromosomal preparation and comparative genomic hybridization (CGH) -array on microchip. Their resolution power, a few thousand base pairs, allows a fine analysis of the structure of chromosomes.There are multiple applications, both in research and in diagnostics.
The principle of FISH is based on molecular hybridization: a probe specific to the region to be explored and marked by a fluorochrome can hybridize, thanks to the complementarity of the nucleotide bases, specifically with its target sequence on a preparation of nuclei in interphase or metaphase. The combination of several fluorochromes makes it possible to detect structural changes that sometimes involve several chromosomes. The practical use of FISH is relatively easy and fast (2-3 days).
Many probes are currently available and marketed. There are four types: chromosomal paint probes that hybridize over the entire length of a given chromosome, telomeric probes, centromeric probes and locus-specific probes.
The main indication of FISH is the identification and characterization of fine or complex karyotype abnormalities detected by conventional cytogenetic techniques.
The FISH also makes it possible to characterize non-detectable micro-remedies on a standard karyotype but evoked before a particular clinical picture. This is the case of microdeletion syndromes.
The better knowledge of the structure of the genome makes it possible to target certain regions as candidates for chromosomal rearrangements which will be explored as a priority. Thus, given the metaphase linkages between telomers, these regions are particularly prone to rearrangements, found in about 6% of patients with syndromic RM, and explorations of the subtelomeric regions are among the proposed investigations.
CGH-array is a rapidly expanding technique. Its principle is the following: clones which correspond to sequences of deoxyribonucleic acid (DNA) regularly distributed over the genome are immobilized on a glass microchip. The DNA of a patient and a control subject, each labeled with a different fluorochrome, are cohybridised on this DNA chip.Fluorescence signals are read and integrated.
In a given patient, a deletion, that is, loss on a chromosome of a segment of genetic material, will be detected by over-representation of the fluorochrome of the subject’s DNA, while a duplication, which corresponds to the situation where a chromosome segment is present in more than one copy in the haploid genome, will be detected by the overrepresentation of the fluorochrome in the patient’s DNA. This sensitive and precise method makes it possible to explore the entire genome with a better resolution than the karyotype in high resolution since some chips contain more than 3,500 clones and therefore have a resolution of the order of 1 Mb or 1 million pairs of bases. However, this is a costly method that is still rarely used routinely.
Finally, the ultimate step of resolution for the exploration of the genome, the techniques of molecular biology and, in particular, sequencing allow the identification of mutations in a given gene.
The complexity of molecular diagnosis varies greatly depending on the pathology and the type of mutation. Some syndromes are characterized by the existence of a single mutation in a given gene, the same mutation in all patients with this syndrome. This explains why the diagnosis can be confirmed easily and quickly. This is the case of fragile X syndrome. The situation is quite different for other pathologies in which the mutations are numerous or even private, that is to say specific to each patient and distributed throughout the coding region. The diagnosis then requires to undertake the screening of the gene in search of the particular mutation of each patient, which requires the use of heavy and costly techniques and takes several months of work. The work is all the more complex as the gene is long and split into multiple exons. The identification of the mutation in the index case reached RM then makes it possible to search very easily and quickly this mutation in the members of his family within the framework of the genetic counseling.
The metabolic assessment is an integral part of the etiological assessment of an MR. The biochemical diagnosis of metabolic diseases is based on the demonstration of excess or deficient metabolites in biological fluids on assays carried out under strict sampling conditions and, for some, in specialized laboratories. Metabolic diseases that can produce MR are very numerous and the systematic screening of all metabolic diseases is technically difficult. The aetiological approach therefore consists in using clinical signs of orientation that must be sought.
For example, an organic aciduria will be evoked in phases of unexplained disorders of consciousness, acute or relapsing neurological or behavioral disorders, especially if accompanied by digestive signs. Abnormalities of the urea cycle will be evoked before a disgust for proteins, phases of vomiting or disorders of consciousness, acute liver failure.Stagnation by weight, aggravations during intercurrent infections, muscular signs or other associated organ damage (deafness, ophthalmoplegia, retinitis pigmentosa, hepatopathy, nephropathy) will evoke mitochondrial cytopathy.
A lysosomal disease, in general, will be evoked before an inevitable progression of the symptoms without obvious link with intercurrent events. A mucopolysaccharidosis will be evoked before a macrocrania, a dysmorphy with hirsutism and coarse facies, thick hair, retractions, hepatosplenomegaly, stagnation then a regression of acquisitions.
Sometimes, however, the clinical presentation of metabolic diseases can be relatively non-specific and more and more cases of metabolic diseases have been described in recent years in the presence of clinical presentation of MR or non-specific behavioral disorders and with no obvious clinical signs . However, despite the great diversity of clinical presentations, it is absolutely crucial to diagnose metabolic diseases, not only for genetic counseling and prenatal diagnosis, but also for therapeutic management. Indeed, some of these metabolic diseases are treatable efficiently if the diagnosis is early. A MR with no found cause should therefore benefit from a minimal metabolic assessment.
Some examples of genetic syndromes with mental retardation:
Fragile X syndrome:
With an estimated incidence of 1/4 500 in boys and 1/7 000 in girls, fragile X syndrome is the most frequent cause of hereditary RM. Clinically, in the boy, the definition of the syndrome is based on a triad of clinical signs that are neither specific nor constant:
• RM associated with language and behavioral disorders (autistic traits, psychomotor instability);
• a facial dysmorphism associating an elongated face, a relative macrocrania and large, poorly hemmed ears with a certain degree of prognatism;
• a postpubertal macro-orchid, found in 80% of cases.
In girls, the diagnosis is more difficult because of the inconstancy of the abnormalities of the phenotype. The RM observed in 40 to 60% of them is dominated by a delayed language.
The existence of breaks on the end of the long arm of chromosome X (Xq27.3) in the affected subjects allowed the localization of the gene involved in this syndrome and gave its name to this syndrome. In 1991, the cloning of the fragile X mental retardation gene (FMR1) revealed an entirely unexpected mutation mechanism. This is the unstable expansion of a repeat of the trinucleotide CGG, located in the first exon of the FMR1 gene. The particularity of this repetition lies in its propensity to extend over generations in fragile X syndrome families. Patients with fragile X syndrome have more than 200 repetitions (CGG). Subjects capable of transmitting the disease but without MR have an increased number of repetitions (premutation) compared to the general population (54 to 200 [CGG] versus 5 to 50 [CGG] in the general population). But the number of repetitions tends to increase in the next generation and, beyond 200 (CGG), appears the RM.
The discovery of an expansion of CGG by molecular genetics confirms the diagnosis of fragile X syndrome. Since no neomutation has ever been described in fragile X syndrome, any diagnosis of fragile X syndrome in a child implies that her mother is a premutation or a complete mutation and therefore has a risk high recurrence. This diagnosis should involve an expanded genetic survey in the maternal family to inform women who wish to have MR risk in their offspring and possibilities for prenatal diagnosis.
Rett syndrome is a severe neurodegenerative condition that affects only girls. Its incidence is estimated at 1/15 000 births of girls. It is characterized by a four stage evolution: the first signs of the disease appear between 6 and 18 months after a normal neonatal period, and consist of a stagnation of the motor development, a regression of the social interactions and a reduction of the cephalic perimeter. Then, between 1 and 4 years, the rapid regression phase takes place from a few weeks to a few months, with a deterioration in behavior, autistic manifestations, loss of language, loss of use of hands, manual stereotypes, convulsive seizures.
Then the apparent stabilization phase takes place between 2 and 10 years: if the autistic features are modified, the convulsive seizures are more numerous and the RM is severe. Finally the last phase of late motor deterioration appears with complete loss of motor function, extrapyramidal and pyramidal syndromes.
The gene in question, the MECP2 gene, located in Xq28, is a small gene consisting of four exons. To date, more than 100 mutations have been reported. These mutations occur in a great majority of de novo, which explains why this syndrome is most often sporadic. The frequency of de novo mutations is indicative of the hypermutability of this gene.In practice, in every child diagnosed with Rett syndrome, the screening of the MECP2 gene should be undertaken to identify the causative mutation that confirms the diagnosis of Rett syndrome and to establish the counseling genetic.
Steinert myotonic dystrophy:
Steinert myotonic dystrophy is a pathology of autosomal dominant transmission with variable expressivity, the frequency of which is estimated in Europe at 1/25 000 births. This pathology is characterized by the phenomenon of anticipation, that is to say that the gravity of the pathology and the precocity of appearance of the clinical signs increase from generation to generation. The classic form, which begins in the grand child or the young adult, associates muscular involvement with myotonia and facial amimia, cardiac involvement with rhythm and conduction disorders, cognitive impairment with slow ideation or mild RM, respiratory insufficiency, endocrine disorders and cataracts. If the pathology is of early juvenile revelation, the RM is constant. In addition to these classical forms of the disease, there exist other clinical presentations of very different severity, defining a very wide clinical spectrum, serious congenital forms (hydramnios, fetal hypomobility, hypotonia, disorders of sucking sweat, neonatal respiratory distress involving the immediate life prognosis) to the paucisymptomatic forms of the adult (early baldness, cataract, heart rhythm disorders).
The gene involved in the vast majority of cases of Steinert myotonic dystrophy is located in 19q13.2 and encodes a protein kinase DMPK whose exact function is not known. The mutations responsible for this pathology are abnormal repeats of CTG triplets in the 3 ‘non-coding part of the DMPK gene. In the normal population, this region has 5 to 37 repetitions (CTG). Expansion is considered pathological from 50 repetitions and can be up to 3,000 repetitions.Molecular diagnosis of certainty of Steinert’s disease is based on the demonstration of the expansion of repetition (CTG) by polymerase chain reaction (PCR) and southern blot. This molecular mechanism makes it possible to understand the phenomenon of anticipation since these abnormal expansions are unstable and tend to amplify to the meiosis. It may be considered that the greater the size of the expansion, the more early and severe the symptomatology, even if the phenotype-genotype correlation is not absolutely perfect. Genetic counseling is difficult due to the high intra-familial clinical variability, the lack of precision of the phenotype-genotype correlation. To this complexity resulting from the molecular mechanism are sometimes added difficulties due to the slowness of ideation or RM of the patients, often entangled with social problems. However, genetic counseling is of major importance for these families, making it possible to detect the affected subjects in order to propose to them a multidisciplinary surveillance, essentially cardiac given the great risk of sudden death, but also ophthalmologic, respiratory, endocrinological and neurological. It also allows for prenatal diagnosis.
Smith-Magenis syndrome is a rare syndrome with an estimated incidence of 1/25 000 births and is characterized by MR, sleep and behavioral disorders and dysmorphic syndrome. Dysmorphism associates brachycephaly, coarse traits, prognatism and short hands. RM with language delay is constant, associated with hyperactivity with attention deficit and auto- and heteroaggressivity. The diagnosis of this syndrome is difficult in the first months or years before the onset of sleep disorders because delayed acquisition, behavioral disorders and dysmorphy can be without specificity.On the other hand, the most characteristic sign of this syndrome is the existence of specific sleep disorders that generally appear during the second year of life. Typically, the child falls asleep early in the evening and wakes up in the second part of the night without being able to fall asleep again. Behavioral disturbances, agitation, aggressiveness, sociability disorders are major and extremely difficult to manage for families that are also struggling with sleep deprivation. Sleep disorders are partly explained by the reversal of the circadian rhythm of secretion of melatonin.Other signs include: hoarse voice, congenital heart disease, renal abnormalities, otolaryngology (ENT) and ophthalmology, scoliosis, peripheral neuropathy.
The majority of patients with a microdeletion of this region 17p11.2, the clinical diagnosis is confirmed by FISH using a probe recognizing the 17p11.2 region.
Few patients have point mutations in the RAI1 gene.
Early behavioral, educational and speech-language management is necessary. Treatment with beta-blockers and melatonin corrects the reversal of the circadian rhythm and in some cases improves sleep and behavioral disorders.
Williams-Beuren syndrome is another rare developmental anomaly with an incidence of 1/25 000 births, associated with RM, recognizable facial dysmorphism (periorbital edema, low and full cheeks, thick lips, stellar iris) cardiopathy in 70% of cases (mostly aortic supravalvular stenosis) and characteristic behavior. The psychomotor delay is global and initially not very specific, with associated language delay. Growing up, these children become very talkative and sociable, easily reaching unknown people. They have a great sensitivity to the noise, dreading the aggressions sound and appreciating the music. The RM of these children is moderate to severe (mean IQ to 50) with a heterogeneous cognitive profile. In
a great discrepancy between correct and retarded verbal acquisition and a deficit in perceptual functions, especially landmarks in space, which are the cause of difficulties in the kindergarten classes. Cardiovascular follow-up should be initiated; it sometimes leads to a surgical gesture. Kidney complications may develop during the course of development (arterial hypertension, stenosis of the renal arteries, renal insufficiency).
The Williams-Beuren syndrome results from a microdeletion in 7q11.23. The detection by FISH of this microdeletion confirms the diagnosis suspected clinically.
Genetic counseling will be reassuring in the vast majority of cases, microdeletion occurring de novo.
Williams-Beuren syndrome is a syndrome of contiguous genes, each cardinal point of the syndrome resulting from the deletion of distinct genes in 7q11.23. Thus, the identification of point mutations in the elastin-encoding gene, the ELN gene, in families with only dysmorphic and vascular abnormalities (supraaortic valvular stenosis) and without MR and behavioral disorder, asserts that the deletion of the ELN gene is responsible only for dysmorphy and vascular abnormalities in the Williams-Beuren syndrome. Different candidate genes for RM, visuospatial disorders and behavioral disorders are currently being investigated.
The diagnosis of DiGeorge’s syndrome is evoked in a neonatal period in a child with a malformative combination of conotronal congenital heart disease, thymus agenesis or hypoplasia, sometimes with immune deficiency, hypoparathyroidism with hypocalcemia, and discrete facial dysmorphism. feature.
Bike-cardio-facial syndrome associates congenital congenital heart disease, cleft palate, or velar insufficiency, which can be complicated by deafness, facial dysmorphism and learning disabilities. These two syndromes, described separately, ultimately represent two clinical forms of the same entity resulting, in the majority of cases, from a microdeletion of the long arm of chromosome 22 in region 22q11.2. In fact, the phenotypes associated with the 22q11 deletions are variable, including in the same family, depending on the case, velar or palatine abnormality, conotronal heart disease, learning difficulties or authentic MR and hypoparathyroidism. The characteristic facial aspect is constant and associates narrow palpebral slits, a tubular nose with enlarged bones of the nose, a small mouth, a retrognatism, small round ears with attached lobe and absence of a rising branch of the helix. Fingers and toes are long.
Most of these children have learning disabilities that are compounded by language delay. There is little objective data on long-term mental prognosis. A study of a series of 37 patients found a significant RM (IQ <70) in 40 to 50% of the children. This delay is generally slight or moderate. Despite initial language delay, the verbal IQ is higher than the performance IQ. The importance of psychomotor developmental disorders is not correlated with the severity of malformations. These children often exhibit a particular behavioral profile with shyness and social difficulties in contrast to hyperactivity. Later, psychotic disorders may appear.
With an incidence of 1 / 5,000 births, this is the most frequent microdeletion syndrome. Microdeletion usually occurs de novo, by meiotic accident, without risk of recurrence. However, in 10 to 20% of cases, it is inherited from one parent and is then transmitted in the autosomal dominant mode with a risk of recurrence of 50% at each pregnancy. More rarely, the malformative association of DiGeorge syndrome can be found in children with other chromosomal abnormalities (deletion of the short arm of chromosome 10).
Some examples of metabolic diseases associating mental retardation and psychiatric disorders may be at the forefront:
Sanfilippo disease (mucopolysaccharidosis type III):
It belongs to the very heterogeneous group of lysosomal overload diseases. The symptomatology associates a delay of the acquisitions observed between 18 months and 3 years followed by a regression of the acquisitions, behavioral disorders and dysmorphy. Elements leading to a lysosomal overload disease are hepatosplenomegaly, tendon retractions, bone deformations and facial dysmorphic signs (coarse face, hyperpolarity, thick hair, etc.).
Growth is initially rather accelerated on the three parameters, weight, height and cranial perimeter, and then gradually slows down. These clinically associated features of mucopolysaccharidoses are inconsistent in Sanfilippo disease or appear only in a delayed manner in relation to mental impairment and behavioral disorders. The early diagnosis of Sanfilippo disease is therefore difficult.
Medium and long-term progression is extremely severe leading to deep dementia, mixed deafness, spastic tetraparesis and cyphoscoliosis.
The diagnosis is made by assaying urinary mucopolysaccharides (increase of heparan sulfate) and then confirmed by enzymatic assay on lymphocytes. There are four types of Sanfilippo disease (A to D) defined by four different enzymatic deficiencies: sulfamidase (type A), a -Nacetyl glucosaminidase (type B), AcCoA: a -glucosaminide-Nacetyltransferase (type C) and N-acetylglucosamine 6 -sulfatase (type D). Transmission is autosomal recessive.There is no specific treatment at present.
The classical homocystinuria is due to an enzymatic deficiency in cystathionine b synthase involved in the metabolism of methionine. Its frequency is estimated at 1 / 100,000 births and the transmission is autosomal recessive. The main clinical manifestations are neurological (frequent but inconsistent, psychotic disorders, epilepsies, extrapyramidal dystonic arrays), vascular (venous thromboses that can affect all the organs), ophthalmologic (ectopic lens, myopia), osseous osteoporosis ), and morphological (marfanoid aspect, fragile skin, hyperlaxity). Each of these signs is inconstant and the clinical presentation of this pathology is therefore very heterogeneous. It is a progressive disease, the first clinical signs appearing at the earliest after the first months of life, but the disease can be found in small children, adolescents or even adults. The diagnosis is based on evidence of a significant increase in methionine on plasma amino acid chromatography associated with the abnormal presence of homocysteine. Vascular risk is significant and considerably increased by situations such as oral contraception and surgery. The treatment of classical homocystinuria is based on a diet low in methionine and, in some patients, on vitamin B 6 supplementation. This treatment should be combined with measures to prevent thrombotic situations. Treatment has proven to be effective in preventing vascular accidents, improving behavioral disorders, and preventing RM if it is initiated early. Homocystinuria is therefore one of the examples of metabolic disease which illustrates the major interest of the etiological diagnosis in terms of therapeutic management.
4-hydroxybutyric aciduria is a rare disease, probably underdiagnosed, due to a deficiency of succinyl-semialdehyde dehydrogenase, an enzyme involved in the catabolism of gamma-amino-butyric acid (GABA). The deficiency results in an accumulation of gammahydroxybutyric acid, toxic to the central nervous system and sometimes used as a narcotic.Biological diagnosis is difficult because the increase in 4-hydroxybutyric acid in biological fluids can be difficult to demonstrate (indeed the peak of 4-hydroxybutyric acid can be masked by the urea peak) and several examinations by an informed biochemist and fine techniques of chromatography of the urinary organic acids are sometimes necessary.The symptomatology includes MR and behavioral disorders of varying severity. Epileptic manifestations and neurological signs (incoordination, ataxia) may be associated. Psychomotor retardation and delayed language are the first symptoms.
The precise evaluation performed in some patients showed that the language disorder was explained by a very deficient auditory perception (verbal agnosia). Disorders such as phobias, visual and auditory hallucinations and possible sleep disorders by access have been described in adult patients. Late presentations with moderate cognitive retardation can therefore be essentially psychiatric.
There is no specific treatment to date, neuroleptics are effective on psychotic disorders. Prenatal diagnosis can be performed by biochemical or molecular method if the mutations of the ALDHA gene encoding succinyl semi-aldehyde transferase are identified.
It is estimated that 30-50% of MRs are due to genetic causes. The quest for an etiology at the RM of a child is a fundamental objective. It is essential to carry out a precise etiological diagnosis, if possible confirmed on molecular, cytogenetic or metabolic bases, both for the management of the child and for the evaluation of the risk of recurrence.
This involves the collaboration of the neuropediatrician, the geneticist and the psychiatrist / psychologist. Clinical evaluation of these children by a clinical geneticist specializing in dysmorphology-syndromology is an important step in the etiological investigation. Significant technological advances have made it possible to develop new tools that revolutionize the diagnostic approach. These tools can be used to confirm a clinical hypothesis, but also make it possible to broadly screen the genome in search of small rearrangements that have gone unnoticed on the karyotype, involving, for example, telomeres or repeated regions favoring microdeletions or microduplications. In turn, the characterization of molecular abnormalities allows to more precisely describe clinical entities and to establish genotype-phenotype correlations.
During this etiological procedure, the psychiatrist / psychologist intervenes both for the evaluation of the psychological disorders of the child and the evaluation of his impairment and for the accompaniment of the child and the parents during this heavy and destabilizing period. Making a diagnosis of specific syndromic RM in a child, besides responding to a fundamental questioning of his parents, makes it possible to adapt the care of the child and to address the thorny problem of risk of recurrence in the family during the genetic counseling stage. The geneticist expects a lot from the partnership with psychiatrists and psychologists. Joint geneticist-psychiatrist / psychologist consultations are spreading. The departmental texts encourage the recruitment of psychologists within the genetics team. In parallel with this daily diagnostic aid, a fundamental reflection between geneticists and psychiatrists / psychologists is fundamental.
The topics covered are, for example, the psychoanalytic scope of the etiologic assessment, the diagnosis of a genetic disease, parental guidance and assistance to discernment in certain ethically difficult situations.
Lastly, the nosological classification and the understanding of the physiopathological bases of the RM constitute great medical and scientific challenges for the next years. For nosological research, it is essential to establish large cohorts of patients with idiopathic RMs in national collaborations and to collect as homogeneous as possible the clinical, biological and neuropsychiatric data . In this context, the standardization of neuropsychological assessment tools is fundamental.
Major research on the understanding of the physiopathological basis of MR is under way with the objective of targeting a metabolic pathway or an embryonic development pathway. This would allow a high-throughput screening of chemical molecules to be selected in order to select those that would be active on this biological pathway. In this perspective, the characterization of the alteration of the long-term potentiation in fragile X syndrome offers pathways for the development of therapeutic molecules that modulate this pathway.
Thus, new therapeutic approaches could result from this fundamental work.