Behavioural phenotypes

'Behavioural phenotypes' is a relatively new concept and in a broad sense seems to mean an association between a constellation of specific behaviours and a specific disorder, often of genetic aetiology. (3d) As most of the behavioural phenotypes described so far are associated with conditions leading to mental retardation, this concept is particularly relevant to this chapter. The behaviours that have been reported under various behavioural phenotypes could broadly be described under the following headings: cognitive deficit, discrepancy in verbal and non-verbal performance, autistic-type features, speech and language abnormalities, behavioural problems, hyperactivity and lack of concentration, social anxiety, abnormal response to external stimuli, stereotyped behaviours, and sleep problems. Some have also controversially included psychiatric illness within some behavioural phenotypes. However, conceptual and methodological difficulties exist in the understanding of the concept of behavioural phenotypes.

Specific conditions Fragile X syndrome Prevalence and causes

Fragile X syndrome is the most common inherited cause of mental retardation. This syndrome affects approximately 1 in 4425 to 6045 males and causes mental retardation in 1 in 8000 females. However, almost all the prevalence studies are conducted on mentally retarded children so the prevalence in the general population is difficult to estimate. This syndrome accounts for half of all the X-linked mental retardation cases (there are several other genes for specific and non-specific X-linked mental retardation) and around 0.6 per cent of mentally retarded population. However, even in well-developed countries, more than half of the cases could remain undiagnosed. The fragile X mental retardation 1 (FMR-1) gene responsible for fragile X syndrome (FRAXA) was discovered in 1991. (5) The genetic abnormality is caused by abnormal trinucleotide CGG repeat at a fragile site on the X chromosome (Xq27.3).

Between six and 54 CGG repeats are expected in normal individuals with an average of 30 repeats. In cases of phenotypically manifested fragile X syndrome, CGG repeats range from 230 to over 1000. In phenotypically normal male carriers and in a proportion of female carriers, a premutation stage of between 43 and 200 CGG repeats exist. Most genetic laboratories in the United Kingdom are now able to detect the molecular genetic abnormality associated with fragile X syndrome using either blood or salivary epithelial cells. Recently an FMR-1 protein antibody test has been devised for a fast detection of this condition from a blood smear. An interesting phenomenon of 'anticipation' is described in relation to fragile X syndrome when premutations often expand to full mutations while transmitted by female carriers. A milder form of mental retardation expressed in FRAXE, caused by FMR-2 mutation has also been described in the literature.

Clinical features

The observable clinical features associated with fragile X syndrome are subtle and often cannot be detected until the subjects reach their adulthood. Although fragile X infants have above average height, in adult life they have a shorter than average height with a larger than average head circumference. Macro-orchidism is a feature associated with many X-linked mental retardation syndromes and is found in a proportion of adults with fragile X syndrome. In some adults, there is a characteristic facial appearance, with a large forehead with supraorbital fullness, long face, long nose, prominent jaws, high arched palate, and large ears with a bat-eared appearance. Characteristic eye abnormalities such as pale irises may be a subtle finding in some adults. (6) Fragile X adult males show normal semen analysis and are able to father children, but may have subtle genital abnormalities such as hypospadias which is caused by non-fusion of the urethral folds.

Signs of connective tissue dysplasia such as hyperextensible finger joints, flat feet, inguinal and hiatus hernia, enlarged aortic root, and mitral valve prolapse can be detected in some cases. Foot abnormalities such as flat feet, a sandal gap, and long broad toes with recurrent paronychia of the first toes have also been reported. In a certain number of adult males, hypogonadal appearance with decreased body hair, gynaecomastia, and striae have been reported. Other occasional features associated with fragile X syndrome include torticollis, kyphoscoliosis, pectus excavatum, hyper-reflexia, and nystagmus. Epilepsy is reported in about 25 per cent of these individuals. In some cases an abnormal response of thyroid-stimulating hormone release in response to administration of thyrotropin-releasing hormone has been reported. Other medical conditions such as strabismus, otitis media, sinusitis, joint dislocation, orthopaedic problems, and apnoea may also affect subjects with fragile X syndrome.

Cognitive deficits

The level of cognitive deficit varies widely among the subjects with fragile X syndrome. Recent studies have suggested on average a moderate to mild mean IQ between 35 and 55 among affected boys and a lower mean IQ ranging from 20 to 40 among affected adult males. Between 30 per cent and 50 per cent of the female carriers also show cognitive deficit. The mean IQ score in fragile X males seems to decline with increasing age, a phenomenon also described in people with Down syndrome.(7) A curvilinear relationship exists between the length of CGG repeat and the level of intelligence in fragile X adults. (8) The use of a battery of neuropsychological tests revealed evidence of differential rates of performance in different aspects of cognitive skills by people with fragile X syndrome. (9)

Language deficits

Delay and abnormality in language development are commonly observed in fragile X males, although their hearing has been reported to be normal. It also appears that the delay in language development is somewhat proportional to their intellectual development. The following speech abnormalities have been reported as characteristic in subjects with fragile X syndrome: perseveration of words and phrases, echolalia, palilalia (repetition of words with increasing speed and decrescendo of volume), 'cluttering', narrative speech (language which is often devoid of content, yet the language structure remains intact), and speech sound substitution difficulties. It has been shown that while the syntactic competency (ability to put words together to form a sentence) and semantic concept (knowledge of word meanings) remain intact in fragile X males, they often show problems in comprehending sentences with high associate compounds and show productive semantic error and pragmatic competence (normal social behaviour associated with language). (1.9 It has been proposed that hyperarousal is the main contributory factor in the production of deviant language by fragile X males.

Behavioural phenotype

Subtle personality problems consisting of social and psychological disabilities have been reported in intellectually normal female carriers. ^J,ยป Controversy persists regarding a relationship between autism and the fragile X syndrome.(6) Approximately 14 per cent of mentally retarded children also have a diagnosis of autism (12) and neuroimaging studies show evidence of underlying brain damage in autism. (13> Reiss and Freund(14) suggested a behavioural phenotype for fragile X syndrome which incorporates features of autism and attention-deficit hyperactivity disorder yet is distinct from both these disorders. Their suggested phenotype includes behaviours such as dysfunction in social play, verbal communication (e.g. speech rate, volume, word/phrase preservation, etc.), non-verbal communication (e.g. gaze aversion, gesturing, etc.), repetitive motor behaviours (e.g. hand-flapping, hand-biting, rocking), attention deficit, hyperactivity, poor mathematical skills, abnormal sensitivity to external stimuli (including hyperacusis), and increased mouthing or smelling of objects. However, the specific relationship between these proposed behavioural phenotypes and fragile X syndrome still remains to be established. Behavioural symptoms in fragile X syndrome seem to originate from a complex interaction between underlying brain damage and the environment. Some recent neuroimaging studies have highlighted abnormalities in the brains of people with fragile X syndrome. (15>

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