© Borgis - New Medicine 1/2001, s. 48-50
Dorota Gieruszczak-Bialek, Agata Skórka
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).
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