The clinical expression of the phenotype may vary from one individual to another depending on the extent of the deletion. Since most of the patients of these contiguous syndromes many present a degree of mental retardation recommendation have been made for chromosome analyses to the patient with mental retardation and mendelian traits that are not usually associated with mental retardation.
PraderWilli syndrome PWS. PWS is caused by a chromosomal deletion on chromosome Rarely, PWS can also be caused by a chromosomal translocation, or by a mutation or other defect, that inactivates genes on the paternal chromosome Due to imprinting, the maternally inherited copies of these genes are virtually silent, only the paternal copies of the genes are expressed.
PWS results from the loss of paternal copies of this region. On average people with PWS shows mild level of mental retardation, although individually their IQ scores may range from average to profoundly mentally retarded.
Repeated studies since PWS had been discovered tried to establish a correlation between body mass index with IQ[ 28 ]. No significant relation has been found. Specifically, the syndrome includes a particular eating behaviour a compulsive search for food, non-selective non-discriminatory ingestion of large quantities of food and also, stealing food , irritability, reduced tolerance to frustration, stubbornness, anger, pinching skin, associated, in the vast majority of patients with mild mental retardation.
Typically, the behavioural difficulties reach a peak in adolescence or in early adult life. Binge eating is the most severe and debilitating behaviour disorder, leading to obesity, diabetes and severe respiratory difficulties.
Usually, patients are happy and open to interpersonal networking, participating with interest in behavioural training. They can learn to structure their daily routine activities, rewards, breaks, boundaries and firm rules. An extensive study focused on assessing self-aggressive, stereotyped and obsessive compulsive behaviour in individuals with PWS and showed that skin picking is found in From the compulsive behaviour category, the compulsive eating is the most common.
Standardized assessments have identified high levels of depressive, anxiety and compulsive symptoms, with functioning impairment, which are not explained by developmental delays, difficulties in nutrition or by obesity in patients with PWS.
Angelman Syndrome AS. AS results when a person inherits two copies of chromosome 15 from his or her father instead of one copy from each parent- uniparental disomy UPD. AS may also be caused by a chromosomal rearrangement called a translocation, or by a mutation or other defect in the region of DNA that controls activation of the UBE3A gene.
These genetic changes can abnormally turn off UBE3A or other genes on the maternal copy of chromosome Ubiquitin protein ligases is implicated in the process of removing unnecessary protein from cells and maintaining the normal function of cells. In the brain UBE3A is expressed only from maternal allele [ 29 ], and it has a higher density in hippocampus and the Purkinje cells from the cerrebellum.
Studies suggest that ubiquitin protein ligase E3A plays a critical role in the normal development and function of the nervous system. The clinical picture comprises of psychomotor development delay, a joyful mood, hyper excitable personality, EEG recording anomalies and severe mental and language retardation.
Apparent happiness is brand forthe syndrome, associated with a vague smile, rare specific laughs, exuberant background, hyperactive and stereotyped motor behaviour, and proactively social contact. Autistic symptoms lead to debates in diagnosis. Peters et al have found an association between AS and autistic spectrum disorders according to DSM IV in approximately one half of the evaluated cases.
In addition, AS can be associated in various degree with ataxia, epilepsy and microcephaly. Williams syndrome WS. The disorder is caused by a deletion of 1. ELN gene deletion responsible for the synthesis of elastin, is associated with connective and cardiovascular anomalies, which are characteristic for the syndrome supravalvular aortic stenosis, supravalvular pulmonary stenosis.
Patients with a shorter deletion, that does not involve GTF2I including those with de novo mutation do not have intellectual disability, but have the specific WS cognitive phenotype. Miller-Dieker syndrome. Miller-Dieker syndrome is characterized by lissencephaly and facial dysmorphy. The majority of the children have deletion of chromosome17p Children may present clinical features of Miller-Dieker syndrome by inheriting an unbalanced translocation.
The size of the deletion varies among affected individuals. Brain malformations cause abnormal muscle tone, spasticity or hypotonia, developmental delay, seizures severe intellectual disability, and feeding difficulties. PAFAH1B1 gene also known as LIS1 provides instructions for making a protein is thought to be involved in directing the movement of nerve cells neurokinesis in the brain. Proper neuronal migration is essential for normal brain development and function.
It also promotes neuronal migration by interacting with tubulin in microtubules. Di George syndrome. Is also referred as velocardiofacial syndrome and is caused by deletion of one copy of the 22q Children have frequently learning disabilities and behavioural problems. Developmental milestones are achieved later the peers of same age.
In school age children IQ testing revealed scores that can range from average to mild retardation an a discrepancy between verbal and non-verbal IQ. The school performance may be lower than predicted by IQ testing secondary to weak executive functioning and low verbal abilities. They have also high scores in externalising symptoms secondary to attention deficit disorder, disinhibition and impulsivity, but also at internalising symptoms — shyness, anxiety and depression. Studies looking at single genes that may contribute to intellectual disability were started by reports of numerous families in which intellectual disabilities were common and transmitted in Mendelian pattern.
In the some of them, the trait was inherited X-linked and was more frequent in males. Autosomal genes involved in MR disorders [ 31 , 36 ].
X-linked mental retardation XLMR. Since the observations of L. Penrose, in , of existence of a higher number of males than females with mental retardation in the population, several surveys were directed to elucidate the etiology of this report.
The results indicated that many genes that determine mental retardation mapped for X chromosome. X-linked mental retardation XLMR was defined as a monogenic intellectual disability affecting mostly males, having a higher prevalence of MR relative to females. The prevalence of XLMR had been estimated in different studied since the estimation made by Herbst and Miller, of 1. Establishing the distribution of the level of cognitive deficit in the XLMR individuals group was considered a important socio-economic problem giving the extensive impact of MR not only for genetic and medical services but for social system.
For mild mental retardation IQ 70—50 , the epidemiological studies found a ratio male- female of 1. For this result it was considered that the excess of cases in males is due to XLMR.
Finally, in cohorts of mentally retarded males, the prevalence of the Fragile X syndrome was 2—2. Nonspecific ornonsyndromic XLMR include mental retardation caused by mutations of genes on the X chromosome without accompanying somatic, neurologic, biological, or behavioural manifestations which allows distinction from nonaffected male or from males with identified MR. In other words, a nonprogressive intellectual disability, segregating in X linked manner that can be distinguished based on the knowledge of their causative gene.
The studies of this type of XLMR were directed to establish the relation between X chromosome genes and the cognitive and adaptive functions and processes. The difficulties in establishing a characteristic pedigree increased the difficulties in establishing the prevalence. J, [ 40 ]. The description of an case as a nonsyndromic XLMR entity implies a complex evaluation including: growth, morphological features, neuromuscular development and function, behaviour, brain imaging, and laboratory testing.
Affected males were not prove to have morphologic, neuromuscular, or behavioural manifestations that distinguish them from unaffected brothers or from other males with mental retardation.
The degree of mental retardation could vary from mild to severe in the same family but is consistent. Carrier females may experience less severe learning problems. They also lack diagnostic findings on cranial imaging, biochemical studies, or cytogenetic analysis.
Head circumferences and heights in affected males were most often in the normal range. Testicular volumes had been documented to be normal or enlarged. Rett syndrome. Was described as a form of nonsyndromal XLMR. Rett syndrome it is frequently due to the deletion or insertion mutation in MECP2 gene. MECP2 gene is expressed in the brain in the neurons but not in the glia. Rett syndrome was included in the chromatin modification disorders category because of the role of MECP2 in coding a protein that binds to chromatin and regulates transcription [ 41 ].
Clinical onset of the symptoms is early in the childhood, between month, with loss of speech, behavioural changes, stereotypical behaviours, loss purposeful use of hands. The little girls affected tend to loss contact and interest for communication, and to occupy their time with repeated hand wringing, washing, or clapping motions.
As they grew older microcephaly became evident, motor regression, seizures are added. They may also have an altered pattern of sleep and breathing difficulties. Syndromic XLMR. Syndromic or specific XLMR implies that beside mental retardation the affected individuals present other manifestations that can include them in one of the categories:. This attempt to classify XLMR has most a theoretical. Thus,because the same genes or even the same mutation can result in either a syndromic or a non-syndromic form of the disease.
One example can be ARX gene found both in patients with non-syndromic X-linked mental retardation and in the syndromic X-linked West syndrome and Partington syndrome. The explanation may be that mutations in these genes in nonsyndromic XLMR families are presumed to cause only a partial loss of function of the encoded proteins, which could explain the absence of syndromic features.
The conditions associated with MR are recognizable on the basis of a distinctive clinical presentation and they can be considerate separate nosological entities, even if the causative gene or locus is unknown.
Fragile X syndrome. It is caused by the loss of function of gene FMR1, which maps on chromosome Xq In females carriers the FRAX repeats are expanded during meiosis. In affected males repeats are present and they express fragile X mental retardation. Repeat expansion associated with hypermethylation causing reduced or absent expression of FRM protein. The accumulation of untranslated FRM1 mRNA forms inclusion in neurons and glial cells of hippocampus and cerebral cortex causing the neurological manifestations of the syndrome.
Clinical features include long narrow face, large and protruding ears, macroorchidism. Patients exhibit also moderate mental retardation, attention deficit, autistic symptoms, seizures and coordination problems. First described as a behavioral disorder in children, in by Leo Kanner, was proven to affect mostly social interactions, the interest for relation, interaction and communication, the ability to decode facial expression and emotional message.
Autism may occur in patients with monogenic diseases as tuberous sclerosis or Fragile X syndrome. Autistic like symptoms have also described in duplication of chromosome 15q [ 47 ] and deletion on chromosome 2q Between and an extended effort was carried out in the International Molecular Genetic Study of Autism Consortium.
The goal of associating a chromosome with autism was not fulfilled but association studies have found positive association on chromosome 7q, especially with a missense mutation on the LAMB1 gene, and with 17q As a result, MECP2 mutation was associated with a low percentage in autism. The same interest was raised by 15qq, secondary to the presence of autistic features in individuals with Prader-Willi syndrome and Angelman syndrome.
If the genomic regions play a role in autism, by genes defect or by common regulatory pathways are the preoccupation of further studies. The evolution of metabolic disorders may disrupt development of children with previous normal development. Genetic diseases presenting abnormal use or storage of different normal substances protein, lipids, copper , these disordersmay manifest with a complex perturbation of cognition maturation and motor impairment.
Researches led to the understanding of mental retardation in these diseases and to identification and implementation of the therapies, which prevent the consequences associated to the genetic defect. The positive results of therapies instituted in a timely manner put the basis of extensive screening programs for newborns designed to avoid irreversible changes in development processes.
A clinical phenotype is frequently the result of a complexity of interaction between different pathways including many genes, proteins and environmental factors. Such diseases are of defective cellular migration such as lissencephaly, heterotopias , neural tube defects, congenital hydrocephalus, myoclonic epilepsy, and narcolepsy.
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When in a family a baby with mental retardation is born, the family members want to know: Is this mental retardation genetic? What is the risk of having similar mental retardation in the subsequent pregnancy? How to manage the baby? References 1. Basel-Vanagaite L. Clinical approaches to genetic mental retardation.
Reddy KS. Cytogenetic abnormalities and fragile X syndrome in autism spectrum disorder. BMC Med Genet. Association between micro deletion and micro duplication at 16p N Engl J Med. Moeschler JB, Shevell M. American Academy of Pediatric Committee on Genetics: Clinical genetic evaluation of the child with mental retardation or developmental delays. These will guide appropriate evaluations and referrals to provide genetic counseling, resources for the family and early intervention programs for the child.
The family physician is encouraged to continue regular follow-up visits with the child to facilitate a smooth transition to adolescence and young adulthood.
The diagnosis of mental retardation in young children is frequently missed. Mental retardation is present in about 2 to 3 percent of the population. It can be defined as cognitive ability that is markedly below average level and a decreased ability to adapt to one's environment. The onset of the condition occurs during the developmental period, i. Mental retardation comprises five general categories: borderline, mild, moderate, severe and profound.
Categories are based on scores obtained through use of age-standardized tests of cognitive ability Table 1. Little or no communication skills but may have some understanding of speech and show some response. Mental retardation. Part II. Seeing the child within.
Fam Pract Recertification ; The inclusion of concurrent related limitations in two or more adaptive skill areas was added to the definition of mental retardation in by the American Association on Mental Retardation. A number of environmental, genetic or multiple factors can cause mental retardation.
Unfortunately, in approximately 30 to 50 percent of cases, the etiology is not identified even after thorough diagnostic evaluation. Acquired causes of retardation include near-drowning, traumatic brain injury and central nervous system malignancy.
Prenatal causes of mental retardation include congenital infections such as cytomegalovirus, toxoplasmosis, herpes, syphilis, rubella and human immunodeficiency virus; prolonged maternal fever in the first trimester; exposure to anticonvulsants or alcohol; and untreated maternal phenylketonuria PKU. Complications of prematurity, especially in extremely low-birth-weight infants, or postnatal exposure to lead can also cause mental retardation.
Metabolic disorders are another possible cause of mental retardation. In some cases e. Other disorders e. Molecular medicine has made it possible to diagnose a number of conditions referred to as mitochondrial cell diseases. A number of single-gene disorders result in mental retardation. Many of these are associated with atypical or dysmorphic physical characteristics.
Such conditions include fragile X syndrome, neurofibromatosis, tuberous sclerosis, Noonan's syndrome and Cornelia de Lange's syndrome. A complete list of syndromes associated with mental retardation is beyond the scope of this article, and the reader is referred to the reference list.
As many as one fourth of persons with mental retardation have a detectable chromosome abnormality. Children with Down syndrome trisomy 21 usually have highly recognizable physical characteristics, but features associated with other chromosomal abnormalities, such as Klinefelter's syndrome 47,XXY , may not be as obvious to family members or the physician. Other children may have a small deletion or duplication of a particular chromosome that is rarely reported; thus, the phenotype is still undetermined.
Some chromosomal abnormalities are inherited from a parent but most occur de novo. Many previously described clinical syndromes have been found to have an associated chromosomal abnormality e. The following case report highlights the importance of early diagnosis, in planning therapy for the child and in providing family planning information to the parents. He was born to a year-old woman, gravida 2, para 2, living children 2.
He was delivered at term by cesarean section with no prenatal, labor or postnatal complications. He was slightly blue at birth and required oxygen. Mother and infant went home in two days, and no other newborn problems were noted.
Birth weight was 3. The infant was breast-fed for about 12 months. Solid foods were added at 10 months, but some difficulty was noted with chewing. The boy rolled over at three to four months, sat without support at seven months and crawled at seven to eight months. He began to walk at 16 months but still did not talk.
The mother first became concerned about lack of speech when the child was 13 months old. The remainder of the medical history, the review of systems and the family history were noncontributory. At 16 months, the child's height and weight were less than the 5th percentile; head circumference was at the 25th percentile. The child was pleasant, alert, active and cooperative. No vocalization of any kind was noted during the examination. Physical findings included a slightly prominent forehead with a depressed wide nasal bridge and a flat nose.
The midface appeared depressed; the child's face closely resembled his mother's. The only other abnormal finding was a small left testis. The boy could stand for a few seconds without support and was able to take a few steps. His muscle tone was mildly low but within the reference range. The physician's impressions included the following: midface hypoplasia, small stature, rule out hearing loss, speech and language delays and global developmental delay, hypoplastic left testicle, incoordinated swallowing, rule out genetic syndrome related to hypoplastic facial features, developmental delay, small stature and familial resemblance.
In the pediatric genetics dysmorphology clinic, the above dysmorphic features were confirmed. He also had distinctive blepharophimosis, ptosis, epicanthal folds, altered palmar creases and hyperextensibility of the fingers and knees. Ohdo blepharophimosis syndrome was diagnosed, based on a London Dysmorphology Database search.
Chromosomal status was 46,XY. At 17 months' chronologic age, his developmental quotient was 61, with most delay occurring in speech, which was at the five-month level. Motor skills were at the to month level. He was evaluated by subspecialists who addressed his various problems. Initial hearing assessment revealed moderate hearing loss. The child was referred to an early intervention program. Subsequent follow-up at 52 months of age revealed that the boy still had difficulty with feedings and was not yet toilet trained.
His cognitive skills were at approximately a month level, and genetic follow-up confirmed Ohdo blepharophimosis syndrome. The mother had subsequently given birth to a second child with the same syndrome. The physician must have a high index of suspicion to consider the diagnosis of mental retardation in any child. Some helpful clues include delayed speech, dysmorphic features minor anomalies , hypotonia generally or of the extremities, general inability to do things for self and, not least, expressed concern by the parents.
The first and most important step in the diagnosis of mental retardation is to obtain a comprehensive patient and family history.
Previous gynecologic and obstetric history may reveal infertility or fetal loss. Assessment of maternal health status during pregnancy with the involved child should include questions regarding use of tobacco, alcohol and drugs prescribed and illicit ; lifestyle or other risks for sexually transmitted diseases; weight gain or loss; signs of infection; serious illness or injury; and surgery or hospitalization.
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