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Practitioners' Section 407 408 GENETICS OF MENTAL RETARDATION [2] [4] PRACTITIONERS’ SECTION epiphenomena. A specific cause for mental a group heritability of 0.49. The aetiology of retardation can be identified in approximately idiopathic mental retardation is usually 80% of people with SMR (IQ<50) and 50% of explained in terms of the ‘polygenic GENETICS OF MENTAL RETARDATION people with MMR (IQ 50–70). multifactorial model.’ The difficulty is that there A. S. AHUJA, ANITA THAPAR, M. J. OWEN are too few studies to provide sufficiently In this article, we will begin by considering precise estimates of the likely role of genes ABSTRACT what is known about the genetics of idiopathic and environment in determining idiopathic mental retardation and then move onto discuss mental retardation. Given the dearth of Mental retardation can follow any of the biological, environmental and psychological events that are capable of producing deficits in cognitive functions. specific genetic causes of mental retardation. published literature we are reliant on Recent advances in molecular genetic techniques have enabled us to understand attempting to draw conclusions from family and more about the molecular basis of several genetic syndromes associated with mental Search methodology twin studies, most of which are very old and retardation. In contrast, where there is no discrete cause, the interplay of genetic Electronic searching was done and the which report widely varying recurrence risks.[5] and environmental influences remains poorly understood. This article presents a relevant studies were identified by searching Recent studies of MMR have shown high rates critical review of literature on genetics of mental retardation. Medline, ClinPSYC, CINAHL, EMBASE, of chromosomal abnormalities and this raises PubMed and The Cochrane library using the the possibility that a proportion of individuals Key words: chromosomal abnormalities; genetic; mental retardation; X-linked. keywords: mental retardation, genetics, with idiopathic mental retardation may have learning disability, chromosomal abnormalities, undetected or unknown chromosomal Mental retardation is characterized by Early literature made a distinction between single-gene defect and X-linked mental aberrations or single-gene defects. Further significantly below average intellectual ‘pathological’ severe mental retardation (SMR) retardation. The references cited in the above advances in molecular genetics may find functioning existing concurrently with related and ‘familial’ (usually mild) mental retardation. studies were also searched in order to identify idiopathic mental retardation to be an impaired limitations in two or more of the More recently it has been customary to divide more studies. Also high yield journals related aetiologically heterogeneous group with some following applicable adaptive skills areas: it into two groups according to IQ. Those who to the topic were identified and were hand individuals showing retardation secondary to communication, self-care, home living, social show IQ scores between 50 and 70 are searched for relevant articles. specific genetic causes, others because of skills, community use, self-direction, health and categorized as having mild mental retardation environmental effects and the remainder due safety, functional academics, leisure and work, (MMR) and those with IQ scores of below 50 IDIOPATHIC MENTAL RETARDATION to multifactorial causes. manifest before the age of 18.[1] The term are considered as having moderate-severe mental retardation is not in itself a diagnosis, mental retardation (SMR).’ Idiopathic mental retardation refers to SINGLE-GENE DEFECTS as it does not inform about aetiology, individuals who show no evidence of gross prognosis, or specific treatments. Rather, it The impact of molecular genetics on our chromosomal defects or single-gene Single-gene defects account for only a small refers to a clinical state that is developmental understanding of disease processes has been anomalies. It is sometimes considered as proportion of mental retardation and are more in origin and which affects intellectual and enormous and is likely to increase even further. representing the lower end of the IQ likely to be seen in individuals with SMR. social functioning. The resurgence of interest in phenotypes distribution. IQ scores have been shown to These are well-recognized Mendelian combined with the new genetic techniques has have an average weighted correlation of 0.86 conditions and are characterized by autosomal for monozygotic twins and 0.61 for dizygotic recessive, autosomal dominant or X-linked Department of Psychological Medicine, Cardiff reduced the proportion of those with moderate/ Unive rsity, Heath Park, Cardiff, UK severe mental retardation in whom the cause twins and an average correlation between first- patterns of inheritance. Many single-gene is unknown to 20%. Genetic causes may be degree relatives of 0.4, suggesting an overall disorders are syndromic. Syndrome Correspondence hereditary or nonhereditary and may not produce heritability of 50%.[3] A recent study found twin recognition facilitates diagnosis and has Dr. AS Ahuja Department of Psychological Medicine, specific syndromes. Over 500 recognized concordances for mild mental impairment was allowed discrete phenotypes to be delineated. Cardiff University, Heath Park, syndromes involving a genetic disorder have 74% for monozygotic twins, 45% for same-sex It may be aided by the reference to a Cardiff CF14 4XN, UK E-mail: [email protected] now been isolated and many have behavioural and 36% for opposite sex dizygotic twins with dysmorphology database such as the London Indian J Med Sci, Vol. 59, No. 9, September 2005 Indian J Med Sci, Vol. 59, No. 9, September 2005 INDIAN JOURNAL OF MEDICAL SCIENCES 409 410 GENETICS OF MENTAL RETARDATION Dysmorphology Database-LDDB (http:// disorders causing mental retardation is the in- clinical phenotypes, depending on how the associated with mental retardation [Table 2]. dhmhd.mdx.ac.uk LDDB.html). The second born errors of metabolism, which have been mutation affects the production and function of There are also a considerable number of X- database is the Online Mendelian Inheritance well documented by Scriver et al.[6] In some protein involved. This phenomenon is known linked nonsyndromic mental retardation in Man-OMIM (http://www.ncbi.nlm.nih.gov/ circumstances, different mutations occurring as allelic heterogeneity. The majority of inborn syndromes, where certain clinical phenotypic Omim/). Another large group of single-gene within the same gene may cause different errors of metabolism follow an autosomal features are associated with learning recessive pattern of inheritance, with some difficulties.[7] Over 200 heritable X-linked Table 1: Single-gene defects causing mental retardation notable exceptions, e.g. Hunter syndrome. disorders associated with mental retardation Inheritance and are known and almost a third of these fall into Disorder Prevalence Clinical features gene location [Table 1] describes some of the common the category of nonspecific XLMR, with no Tuberous sclerosis 1 in 7000–1 Normal IQ to severe Autosomal dominant in 10 000 mental retardation, adenoma TSC1 9q34, single-gene defect disorders causing mental other features present apart from mental sebaceum, hypo pigmented patches, TSC2 16p13.3 [8] hamartoma of brain, heart and kidneys, retardation. retardation. The commonest cause of XLMR hyperactivity, autistic spectrum disorders, is the Fragile X syndrome. Manifesting females self-injurious behaviour Phenylketonuria Commonest inborn Mental retardation, Autosomal recessive X-linked mental retardation have been described in several of the XLMR of metabolism retarded growth, microcephaly, Phenylalanine X-linked disorders are due to germline disorders. In some conditions, such as Coffin– (1 in 10 000) epilepsy, fair hair and skin, eczema, hydroxylase deficiency [9] hyperactivity, autistic features are common 12q24.1 mutations in genes on the X-chromosome and Lowry syndrome, females always manifest, Dihydropteridine characteristically affect males. Carrier women whereas in other disorders, carrier females are reductase deficiency 4p 15.31 Homocystinuria 1 in 300 000 Mental retardation, ectopia lentis, Cystathionine β-synthetase usually have few, if any, manifestations. The usually phenotypically normal but may skeletal abnormalities, fair, poor deficiency large contribution of X-linked genes to mental occasionally manifest symptoms as a result of peripheral circulation, thromboembolic 21q22.3 episodes, epilepsy, liver degeneration retardation is striking and estimated to occur altered Lyonization[10] or the presence of an X- Cornelia de Lange 1 in 100 000 Severe mental retardation, Autosomal dominant in about 1 in 600 male births. Many X-linked autosome translocation. In the latter case, the syndrome (Brachmann–de hypertricosis depressed Chromosome 3 Lange syndrome) nasal bridge, ocular anomalies, conditions with characteristic phenotypes are breakpoint on the X-chromosome affects the limb deformities, gastrointestinal abnormalities. Language deficits involving Table 2: X-linked disorders expressive speech, feeding difficulties, self-injurious behaviour and autistic Disorder Clinical features Gene location features Fragile X syndrome Macrocephaly, large ears, long face and Inactivation of FMR-1 gene at Xq 27.3 Noonan syndrome 1 in 1500 Mild mental retardation, short stature, Autosomal dominant (1 in 4425–6045 males, macro-orchidism, speech
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