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© Borgis - New Medicine 1/2001, s. 48-50
Dorota Gieruszczak-Bialek, Agata Skórka
Mental retardation
Department of Paediatric Diabetology and Birth Defects, Second Department of Paediatric, The Medical University of Warsaw, Poland
Head of Department: Lech Korniszewski, MD, PhD
The authors present a review of causes and major steps in clinical diagnosis of a complex problem of mental retardation in children. The role of subtle chromosomal rearrangements in the aetiology of unexplained mental retardation is highlighted.
Mental retardation is not a separate nosological entity, but a clinically recognised sign of many disorders, and may appear as an isolated finding or in company with syndromes with different aetiologies comprising hereditary disorders.
According to the official definition, mental retardation is defined as significantly subaverage intellectual functioning and limitations in adaptive skills, with an onset before 18 years, with the latter feature being nowadays considered very important but difficult to measure (16). Clinical heterogeneity and aetiological complexity are responsible for difficulties in diagnosis.
Differentiation between a constitutional and pathological mental retardation is crucial in the first steps of assigning a diagnosis. The constitutional mild form of mental retardation, also termed familiar, is characterised by higher IQ scores (IQ > 50), no evidence of organic changes in the central nervous system, often multifactorial aetiology, symptoms presented at school age, and there is a correlation with parental IQ scores and their socioeconomic status. The pathological mental retardiation usually comprises the categories of moderate to severe disability; it is usually possible to establish a diagnosis of a specific condition or point out the single aetiological factor. Parental IQ or their socioeconomic status is of no importance. This form is identified much earlier, usually in infancy or in the preschool period.
The prevalence of mental retardation is estimated to be 1 to 3% of the general population (1, 4) and 80-95% of persons with mental retardation function within the mild range. The incidence of mental retardation depends on age and is the highest among school children. This is due to the fact that children who did not show a marked delay in psychomotor development in the early years are identified after starting school, when they present learning difficulties. Some of these children, after accomplishing the education programmes (usually specialized and limited) can attain a level of independence, and are assimilated into a normal adult world, which results in a decline in the reported incidence rates of mental retardation in older age groups.
The reported prevalence of severe mental retardation (moderate to profound) defined by an IQ < 50 is 3-6 per 1000 (3, 5). The prevalence is higher in developing countries which may be attributed to less adequate pre- and perinatal care, nonexistent genetic counselling, and a high proportion of consanguineous marriages. According to Yaquoob, the incidence of mental retardation in Pakistan is 11 per 1000 (17).
A reported factor influencing the prevalence of mild mental retardation is the socioeconomic status of the study population. Low annual income is a factor associated with increased prevalence rates of mental retardation.
Aetiology and pathogenesis
Aetiological factors associated with mental retardation differ, depending on the level of handicap. As was mentioned above, moderate to profound mental retardation (IQ < 50) is more likely to be due to a single pathological cause compared with mild mental retardation, which is considered to be multifactorial. Genetic and environmental factors explain in equal proportions about 30% of cases of mild mental retardation (11). Genetic causes include fragile X syndrome, Klinefelter syndrome, tuberous sclerosis, and neurofibromatosis type I. Environmental factors are foetal alcohol syndrome, foetal asphyxia, infections during pregnancy, serious nutritional deficiencies, and impairment of appropriate stimulation of development. Constitutional factors have to be taken into account as well. The aetiology of mental retardation remains unexplained in at least 50 to 70% of cases of mild mental retardation (2, 12).
The aetiology can be determined in 60 to 70% of cases of moderate and profound mental retardation (5, 12) with chromosomal aberrations being the most common cause. Down´s syndrome accounts for 20-30% of mental retardation in that group, followed by aberrations of the sex chromosome and other autosomal chromosomes. Syndromes of combined congenital malformations cause 15-20% of moderate to profound mental retardation. Monogenic disorders (autosomal dominant, recessive and X-linked) represent the next group of aetiological factors, with fragile X syndrome being the most common cause of mental retardation in man and second after Down´s syndrome as a cause of intellectual handicap (although there are many studies which indicate foetal alcohol syndrome to be equally common).
The fragile X syndrome is characterised by mental retardation with other phenotypic features, such as: long face, large protruding ears, prominent jaw, and macro-orchidism in postpubertal males. This phenotype is associated with mutations in the fragile X mental retardation (FMR 1) gene. This X-linked disorder is caused by an expanded CGG repeat in 5´ region of the first exon of the FMR 1 gene (Xq27.3). In normal indviduals the range of allele sizes vary from 6 to 54 repeats, and in males with premutation from 43 to 200. The carriers of premutations are clinically normal. Many woman with a full mutation also show no symptoms of mental retardation. In males with a full mutation the FMR 1 gene is totally methylated and lack of gene expression results in the absence of the protein product and abnormal production of other proteins responsible for learning and memory process (15). Untill recently the fragile X syndrome was diagnosed with the help of cytogenetic testing, but nowadays molecular studies help do confirm the clinical diagnosis and help in establishing the carrier status. Prenatal diagnosis is also possible.
There is a highly heterogeneous group of non-specific mental retardations linked to chromosome X (X-linked non-specific mental retardation - MRX, MIM 3095530) with many forms described from MRX 1 to MRX 75. The prevalence in the male population is estimated to be 0.15%. During the past few years seven MRX genes which participate in different stages of intracellular signalling have been identified. Recently the gene VCX-A has been mapped to Xp22.3 (6 other diseases gened have been localized in that locus) which is thought to be involved in the pathogenesis of X-linked mental retardation (6).
Recently much attention has been given to syndromes due to small chromosomal rearrangements either due to impairment of transcription of telomeric sequences or parental imprinting (e.g. Prader-Willi and Angelman syndrome).
During the last few years there have been many studies with the use of molecular techniques (FISH studies with specific probes for subtelomeric regions of 23 pairs of chromosomes) which emphasize the role of small chromosomal rearrangements involving the terminal bands of chromosomes (subtelometric regions) in the aetiology of mental retardation (7, 8, 10). According to Knight et al. (8) the prevalence of subtelomeric chromosomal rearrangements is 7.4% in the group of children with moderate to severe mental retardation, and 0.5% in children with mild mental retardation. The results of the study by Higgins et al. showed that in the subtelomeric region of chromosome 3p (3p25-pter) a gene involved in the pathogenesis of mental retardation is localized (8).
Other aetiologies of mental retardation include structural malformation of the central nervous system (neural tube defects, hydrocephalus, microcephaly etc.). It is assumed that every type of brain insult may result in delayed and impaired development. Infections and other teratogens in the embryonal and foetal period, hypoxia, infections and intracranial haemorhages in the perinatal period may lead to mental retardation. Recently McDermott reported a statistically significant difference between the incidence of mental retardation in children of women with treated and un-treated urinary tract infections in pregnancy (13). The postnatal risk factors in mental handicap are postinfectious CNS lesions, CNS trauma and psychosis of childhood (3, 5, 13).
Clinical symptoms
Mental retardation is not characterised by any single typical phenotype. Delayed achievement of developmental milestones and failure to meet age-appropriate expectations are the cardinal symptoms of mental retardation (14). Children with physical findings suggestive of recognizable syndromes that are associated with mental retardation may be identified at birth or during early infancy. There are many atypical physical features associated with chromosomal abnormality or known teratogenic effects. It should be emphasised that they may also be found in normal children (14).
Psychotic disorders and EEG abnormalities are often found in children with mental retardation. In children with profound mental retardation the diagnosis of significant delay in development can be made in the first year of life, whereas children with moderate mental retardation are usually identified when the development of language is delayed. Mild mental retardation may remain unrecognised until after entry to school (especially in families with IQs below the mean).
Assigning a diagnosis of delayed psychomotor development remains in the hands of the primary care pediatrician. The most widely used developmental screening test to assess the level of development of a child is the Denver Developmental Screening Test. This can be administered in 20-30 minutes. In older children various age-relevant tests may be used, with specialized tests for blind children or those with impaired hearing. All scales used to assess intelligence quotient (IQ) ascertain the general intellectual functioning. The mean IQ score is 100. Mental retardation is defined as an IQ less than two standard deviations below the mean and is categorised into mild (IQ 62-67), moderate (IQ 36-51), severe (IQ 20-35) and profound (IQ 0-19). Making the child into a group member allows us to see the skills the child can achieve. The child of 6 years with an IQ of 60 has the developmental skills of a three and a half year old child.
It has to be emphasized that in every case of mental retardation various studies must be considered in order to explain the aetiology, which may help in identifying particular treatment and rehabilitation needs. In some cases it may initiate a prenatal diagnosis.
A comprehensive paediatric history is essential in evaluating a child with mental retardation. It needs a pedigree analysis and the gathering of available data from the foetal and perinatal period, together with information about psychomotor development in infancy. Physical examination may reveal dysmorphic features and congenital defects. It is necessary to examine hearing and ophtalmic, psychological, neurological and genetic evaluations are also essential. A range of laboratory studies include a variety of metabolic screening tests and neuroimaging studies. If physical examination suggests a specific syndrome, standard karyotyping and molecular testing are performed. An interesting finding was reported by Hunter, that molecular and FISH studies had a positive rate of > 60% when ordered by a clinical geneticist compared with 0% when ordered by an other physician (9).
Management of children with mental retardation is multidimensional and highly individualized. In many cases specific therapies are not yet available. Multidisciplinary effort has to be considered with rehabilitation programme, specialized education, and management of associated disorders. It is important to ensure the provision of genetic counselling whenever the diagnosis of a hereditary disorder is considered.
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New Medicine 1/2001
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