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Fragile-X Syndrome

In addition to being associated with characteristic physical and behavioural features, Fragile-X syndrome causes intellectual disabilities ranging from mild to severe. It is the most common cause of inherited intellectual disability and is second only to Down's syndrome as the most common genetic cause of intellectual disability.

Manga Sabaratnam and  Yogesh Thakker

Abstract  

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability worldwide. It is caused by a mutation of the FMR-1 (fragile-X mental retardation) gene located on the X chromosome. This contribution explores the genetic and molecular basis of the disease and methods for its detection, as well as neuropathological findings. The issues involved in genetic counselling and screening are also discussed. The presentation of FXS is variable, but common physical, behavioural and developmental features are outlined. The specific deficits, in terms of intellectual disability, are also explored; for example, males with FXS have particular difficulties in sequential processing of information. Broad differences between male and female intellectual disability have also been discovered. The relationship between FXS and autistic spectrum disorders is mentioned, as are comorbidities with other neurological (epilepsy) and psychiatric disorders. There is no definitive treatment for FXS, but a number of interventions can raise the quality of life of the individual and their family and carers. These include pharmacological treatments for comorbid conditions such as epilepsy and attention deficit hyperactivity disorder, as well as behavioural and cognitive interventions. Newly developed targeted treatments for FXS like mGluR5 antagonists, GABA agonists and MMP-9 inhibitors have been described. However, there is still much scope for new research into both the molecular basis and the potential treatments of FXS.

Introduction

FXS is an X-linked semi-dominant condition with reduced penetrance. It is caused by an expansion of an unstable CGG trinucleotide repeat in the fragile X gene (FMR-1). In addition to being associated with characteristic physical and behavioural features, causes intellectual disability ranging from mild to severe. It is the most common cause of inherited intellectual disability and is second only to Down’s syndrome as the most common genetic cause of intellectual disability. There is a wide spectrum of clinical features, but life expectancy is not greatly reduced.

Epidemiology

 There are about 100–200 affected births in the UK each year. The population prevalence is estimated at 1 in 4000 males and 1 in 8000 females (Hagerman and Hagerman, 2002). It occurs in all races and ethnic groups. It accounts for approximately 10% of all males with severe intellectual disability and 10% of mild intellectual disability. The average age at diagnosis of FXS is 35 to 37 months (Bailey et al., 2009).

History 

FXS was first documented by Martin and Bell in 1943. They described a pedigree with 11 affected males and four mildly affected females in three generations. They believed that this pedigree suggested X linked inheritance since males were more severely affected than females. The break on the long arm of the chromosome (the fragile site) was first demonstrated in 1969 by Lubs, but was not confirmed until 1977, with the discovery that a folate-deficient culture medium was required to show the fragile site. Verkerk et al. isolated the long-awaited FMR-1 (fragile-X mental retardation) gene using a positional cloning strategy in 1991 and it became diagnostic test for FXS.

 The fragile site was found at region Xq27.3 on the long arm of the X chromosome

FIGURE 1:  

Genetics and Aetiology

After the detection of FMR-1 gene by Verkerk et al (1991) it was identified that FXS is caused by abnormal expansion of a trinucleotide repeat (CGG) in the FMR-1 gene. The diagnosis of FXS was originally made by visualizing the folate-sensitive fragile site at Xq27.3 (FRAXA) induced by culturing the cells in folate-deficient culture media. The mutational basis of FRAXA was recognized to be due to the expansion of a trinucleotide repeat (CGG)n present in the 5' untranslated region of the identified gene. The lack of expression of the FMR-1 gene results in non-production of the protein (fragile-X mental retardation protein, or FMRP), resulting in FXS. FMR-1 is the first cloned gene to be linked to human intelligence. 

Ninety-five per cent of cases of FXS are due to expansion in the CGG sequence (Fu et al., 1991). Normal individuals carry between 5 and 54 copies of CGG repeat. In normal carriers, the number of CGG repeats (the premutation) is between 55 and 200. In individuals clinically manifesting the syndrome (full mutation), the CGG repeats increase to 200–2000 or more. Such a large mutation is usually accompanied by hypermethylation of the DNA sequence, whereby methyl groups attach to the CGG triplets. This renders the FMR-1 gene transcriptionally inactive. 

It is also possible for the CGG expansions to vary from cell to cell, resulting in somatic heterogeneity in allele size. Up to 40% of affected males are ‘mosaics’ – i.e. they exhibit both a premutation and a full mutation in the blood (Nolin et al., 1994). There are two kinds of mosaicism in FXS: repeat size mosaicism and methylation mosaicism. In repeat size mosaicism, an individual has some cells that have a full mutation and some cells that have a premutation. In methylation mosaicism, all the cells have a full mutation, but the methylation pattern may not be the same in all cells. 

Under normal circumstances, the FMR-1 gene encodes FMRP. The absence of FMRP is likely to be responsible for the development of the Fragile X phenotype. The exact role of FMRP is unknown, but it is thought to act to regulate protein synthesis. FMRP usually helps the connection between neurons that underlie learning and memory; absence of FMRP seems to delay the development of such neurons. In normal individuals, FMRP is ubiquitously expressed, but at higher levels in the brain and the testes. The major characteristics in affected individuals with FXS relate to the functioning of the brain and macro-orchidism. People with the premutation make FMRP; those with the full mutation do not. Females with the full mutation on one X chromosome and normal FMR-1 on the other make a reduced amount of FMRP. 

Inheritance 

The identification of the FMR-1 gene led to an increased understanding of the unusual and previously unexplained features of its inheritance. FXS is an X-linked, dominantly inherited disorder, with reduced penetrance, but its pattern of inheritance is atypical. Both females and males can be affected, although it is less common and often less severe in females. In addition, both males and females can be unaffected carriers. Four-fifths of males with the full mutation are clinically affected, while only half the females with the full mutation are affected. In females with the premutation, the CGG trinucleotide expansion in the FMR-1 gene is hereditarily unstable. There is, therefore, a high risk of the premutation expanding to a full mutation when it is transmitted from a woman to her children. However, when the premutation is passed through men (also known as carrier males or normal-transmitting males), it does not significantly increase in size. The sons of an unaffected man do not receive the X chromosome and so are neither affected nor carriers. His daughters, on the other hand, receive the premutation and are all unaffected carriers, although their own children are at risk of inheriting the full mutation. Heterozygous females who receive the full mutation from their mothers may have clinical features of FXS. The transmission of the mutation through phenotypically normal daughters to their grandchildren, (the so-called Sherman paradox, or ‘genetic anticipation’) occurs when the disease severity increases through successive generations. About 25% of female carriers have intellectual disability, and they are more likely to have similarly affected offspring than are intellectually normal carrier females.   

Genetic testing 

As the fragility at Xq27.3 is visible under the microscope in only 4–50% of cells, cytogenetic testing has been superseded by more accurate DNA tests. These are less expensive, less time-consuming and can accurately detect both full mutation and premutation and provide details about the allele size and methylation in affected individuals as well as normal-transmitting males and carrier females. 

The following tests are available to detect FXS: 

  • Polymerase chain reaction (PCR) is the routine screening test used on Fragile X samples. It is particularly effective for small increases (premutation) but is not very sensitive in detecting full mutations.
  • If PCR fails, Southern blotting is performed. This can detect full mutations and methylation status of the regulatory site and the presence of mosaicism. It is more labour-intensive than PCR and requires larger amounts of genomic DNA. Southern blot analysis detects alleles in all size ranges, but precise sizing is not possible. The technique looks for amplification of the length of the FMR-1 gene.
  • Willemsen et al. (1995) developed a diagnostic test based on use of antibody to FMR protein (product of FMR-1 gene) to detect presence or absence of FMR protein in lymphocytes or hair root. This can detect the full mutation in males; it is not useful in mosaic males or females as some FMRP is still formed.
  • A method recently developed, called methylation-specific melting curve analysis (MS-MCA), relies on the fact that the transcription errors seen on the FMR1 gene results in hypermethylation of the genetic material (Dahl et al., 2007). It can be used in males only, but allows rapid and reliable identification of patients. 

Other fragile sites 

Of the other nearby fragile sites identified on the X chromosome, namely FRAX-D, FRAX-E and FRAX-F, only the FRAX-E mutation is associated with intellectual disability (Figure 2). Distinguishing these sites from FRAX-A on standard chromosome cultures has become easier with improving techniques, especially fluorescent in situ hybridization (FISH). 

FIGURE 2:

Other Fragile X conditions: 

In addition to FXS, there are other two genetic conditions caused by changes in the FMR1 gene has been described. 

  1. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder that affects older adult carriers, predominantly males. FXTAS is found among carriers of premutation (55-200 CGG repeats) alleles of the FMR1 gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. (Greco et al., 2006)
  2. Fragile X-associated primary ovarian insufficiency (FXPOI) affects ovarian functioning and can lead to fertility and early menopause. Carriers of the FMR1 premutation (55-200 CGG repeats) are at risk for FXPOI. 

Physical features 

The common physical, behavioural and developmental features of FXS are shown in Table 1. The somatic phenotype is well formed and easily distinguishable in adults

FIGURE 3: Men and boys with fragile-X syndrome, showing classical facial features.

 

  • Pregnancy is usually unremarkable, and affected babies are normally born at full term. The failure to achieve normal developmental milestones may first alert parents to intellectual handicap. Macro-orchidism is rare before puberty, but the phenotype is more evident as the child grows
  • In typical Fragile X males characteristic physical features are long, narrow face, prominent ears, joint hypermobility and flat feet (Hagerman et al., 1984). The forehead is large and quadrangular with relative macrocephaly.
  • Macro-orchidism is almost invariable in DNA-confirmed post-pubertal males (Lachiewicz & Dawson 1994). This phenotype has also been described in patients with acquired central nervous system lesions, patients with no abnormality of the FMR-1 gene, and it sometimes co-occurs in Klinefelter, Prader-Willi, Sotos, Rubenstein-Taybi and Down’s syndromes.
  • Affected females usually resemble affected males, though with enlarged ovaries. Unaffected (premutation) females have high rates of premature ovarian failure and dizygous twinning.
  • Previous studies have consistently reported a high risk (30–40%) for ocular problems in FXS individuals (Storm et al., 1987; Maino et al., 1990). Refractive errors of various degrees up to 93% and strabismus ranging from 30% to 40% have been reported (Storm et al. 1987). Musculoskeletal manifestations such as pes planus (flat feet), excessive joint laxity with hyperextensible metacarpophalangeal joints and scoliosis are common. The skin is usually soft and smooth, but there may be calluses from hand-biting. Cardiac abnormalities include mitral valve prolapse and aortic root dilatation, hypoplasia of the aorta and post-ductal coarctation. These are thought to develop during late childhood and adolescence, as in the general population. Taken together, these findings may suggest an underlying connective tissue dysplasia. 

Cognitive functioning 

Males: Although the level of severity of intellectual disability among boys is equally distributed between mild and severe, the majority of men with FXS have moderate-to-severe degrees of intellectual disability. The average IQ in adult men with the completely methylated full mutation is approximately 40 (Merenstein et al., 1996). Specific cognitive profiles show that they have particular difficulties in sequential processing, with short-term memory deficits manifesting as a weakness in arithmetic. In spite of the reported decline in IQ test scores with age, adaptive behaviour improves with appropriate training. Although there is no correlation between the size of the CGG repeat (within the full mutation range) and degree of intellectual impairment in males, lower expression of FMRP is thought to correlate with IQ in mosaic males and males with a partially methylated full mutation. 

Females – Approximately 50 percent of women with the full mutation have IQs in the borderline or mild intellectual disability range (Hagerman et al., 1992). Affected females without intellectual disability may have specific deficits in the areas of attention, visuo-spatial skills and executive functions. The less serious effects in females may be due to the fact that they have two X chromosomes, of which only one is active in each cell. This increases the chances a normal FMR-1 gene owing to random X chromosome inactivation. 

Speech and language delay is an early symptom, with first words appearing at about 2 years and short sentences at 3 years. Some children do not develop speech at all. Language ability may be appropriate for an individual’s cognitive level, but others often display ‘jocular litanic phraseology’ with echolalia and speech dysfluency, or ‘cluttering’.

Epilepsy and EEG findings 

Individuals with FXS have increased risk for seizures, with rates of 13% to 18% for boys and ~5% for girls (Hagerman et al., 2009). They are usually generalized and usually in the first 15 years of life. They respond well to anticonvulsants, particularly carbamazepine, and half of them disappear by age 20. The most common abnormal EEG findings are rhythmic theta activity, and slowing of background activity. Initial reports of characteristic sleep EEG patterns, such as quasi-rhythmic temporal lobe spikes of medium/high voltage, have not been replicated. (Sabaratnam 2001) 

Pathological and neuropathological findings 

Pathological findings include abnormal mitral valves with mucoid degeneration and excess mucopolysaccharide; ventricular hypertrophy; cardiac enlargement; and interstitial cell hyperplasia, which causes megalo-testes (Sabaratnam 2000) 

Neuropathological findings include increased brain weight; mildly dilated cerebral ventricles; and loss of Purkinje cells in the cerebellum (which normally shows high expression of FMRP). 

Lee et al. (2007) studied the brain structure in 36 subjects with FXS using tensor-based morphometry (TBM). The results of the study showed that subjects with FXS had 10% increase in caudate and 19% increase in lateral ventricle volumes compared to controls. The authors also found structural abnormalities in the cerebellum in the form of mainly small volumes bilaterally. 

The amygdala plays an important role in social behaviour and emotion processing and shows significant enlargement in children with idiopathic autism (Lightbody & Reiss, 2009). As individuals with FXS often display these behaviours, many studies focused on studying size of amygdala in individuals with FXS.  Hazlett et al. (2009) investigated this relationship in their study of brain development in FXS. Overall, the young boys with FXS (18–42 months) demonstrated smaller amygdala volumes than the control group by 8%. 

Behavioural phenotype 

In ICD-10, FXS is noted as one of the medical conditions associated with pervasive developmental disorder (PDD). In children, it is the behavioural features such as hand-flapping, hand-biting, tactile defensiveness, poor eye contact, hyperactivity and perseverative speech that are more notable. Most boys have attentional problems and hyperactivity. Only a minority of males with FXS have autism, although autism-like behavioural features are seen in almost all people with FXS. The prevalence rate of autism in FXS ranges between 21% and 33% (Hatton et al. 2006, Rogers et al. 2001). The majority show the characteristic profile of social anxiety, gaze aversion to strangers, vocal perseveration, delayed echolalia, and stereotypies such as hand-biting and hand-flapping. 

Associated psychiatric disorders 

In a 10 years follow up study by Sabaratnam et al. (2003), it was found that there was ten-fold increase in the prevalence of psychiatric morbidity in the individuals with FXS compared to general population.  The most common DSM-IV diagnosis among the Fragile X boys is ADHD (73%), followed by oppositional defiant disorder, anxiety disorders (Baumgardner et al., 1995). 

Screening 

The discovery of the FMR-1 gene means that, theoretically, DNA-based screening for the premutation could forewarn all potentially affected families. Population-based screening is neither feasible nor ethical mainly because of the current inability to distinguish full-mutation female fetuses with mental impairment from fetuses whose intelligence is not affected. Therefore, screening would be targeted at individuals who are at a higher risk. The various proposed strategies include preconceptual testing and routine prenatal screening of all carrier pregnancies. Other strategies could include systematic testing in affected families (‘cascade’ screening or extended family follow-up); case finding in paediatric or adult practice; or a combination of these. 

Barriers to implementing even limited paediatric screening and cascade screening in affected families include inadequate resources, difficulties in counselling those with intermediate-range alleles, and the need to achieve uniformly high standards in the existing screening programmes as a prerequisite for any population-based programme. 

Management 

While there is no cure for FXS, many areas of intervention can improve the lives of those affected and their families. All affected people can make progress with proper education, therapy and support. A multidisciplinary approach is necessary to manage the multifaceted problems encountered. Each child should be formally assessed to establish his or her needs. Speech therapists, behavioural therapists, special educators and paediatricians are all likely to be involved. 

The early years are of vital importance for stimulating maximum learning in children with the syndrome, and intervention at this stage can prevent many problems later. Services that can be offered include family training to encourage physical, speech and sensory training, and the promotion of a routine for the child, which helps to alleviate anxiety. 

Genetic counselling 

If a positive FXS test is discovered, the proband and family should be referred for genetic counselling and cascade testing of family members at risk of carrying a full mutation or permutation (McConkie-Rosell et al., 2007). Genetic counselling aims to educate families about the syndrome, its implications and prognosis, supporting them in making informed decisions about the future and in dealing with the emotional impact of the diagnosis. Counselling also identifies others who might need to be alerted about the diagnosis and the availability of testing. 

Non-pharmacological management 

Family education and counselling is essential to facilitate parents’ acceptance and understanding of the child and to encourage patience and persistence with a child who may seem uncooperative. Despite the wealth of knowledge regarding the behavioural phenotype of FXS, there are almost no empirical studies on the effectiveness of behavioural treatments among patients with FXS (Reiss and Hall, 2007). Both animal and human studies have shown that variations in the environment have an impact on behaviour (Restivo et al., 2005). A higher-quality home environment is associated with fewer autistic behaviours, better adaptive behaviour, and higher IQ scores in children with FXS (Glaser et al., 2003).  Weiskop et al. (2005) evaluated a parent training programme using behavioural principles to reduce sleep problems in children with autism or FXS. The authors found that as a result of the programme settling problems, night waking, and co-sleeping were effectively reduced. 

Psychotherapy and counselling has been applied for higher functioning individuals with FXS (Hills-Epstein et al., 2002). Psychotherapy or cognitive-behavioural interventions can focus on anxiety reduction through desensitization and other behavioural tools, the discussion and treatment of sexuality issues (especially fetishism and other paraphilias), or management of depression (Schneider et al., 2009). 

As autism-like behavioural features are commonly found in the individuals with FXS treatment models used in individuals with autism can be modified and applied to the individuals with FXS. Treatment models that are well established in autism management like Treatment and Education of Autistic and Related Communication-Handicapped Children model (Schopler et al., 1984), Denver model (Rogers et al., 2001) and Applied Behavior Analysis model (Smith et al., 2007) can be effective in management of individuals with FXS (Hagerman et al., 2009). 

Pharmacological management 

  • Treatment of ADHD: Hagerman et al. (1988) did a controlled trial of stimulant medication in children with the FXS. The authors found that in addition to behavioural intervention and individualized therapies, stimulants were shown to improve symptoms of ADHD in individuals with FXS. Stimulants may not be helpful for children under the age of five as they may cause increased irritability. Hagerman et al. (1995) did a survey of clonidine use among 35 children with FXS. They found that 63% of parents thought that clonidine was very helpful for their child.  

Among the nonstimulants, two controlled trials demonstrated that L-acetyl-carnitine was beneficial for the treatment of ADHD symptoms in children with FXS. In both the studies, effects were more remarkable in the parent report rather than teacher report. (Torrioli et al., 2008, Torrioli et al., 1999) 

  • Treatment of Aggressive behaviour: Antipsychotic medications have been frequently used to address challenging behaviours like aggression and irritability. In a study by Berry-Kravis & Potanos (2004), about 80% of individuals with FXS responded to one or more antipsychotic drugs, without significant adverse effects. Risperidone has been the most frequently prescribed antipsychotic medication and has been found to be safe and effective for aggressive individuals with FXS (McCracken et al., 2002). Aripiprazole is also used in individuals with FXS (Berry-Kravis & Sumis, 2006) with good response rate. 
  •  
  • Treatment of Anxiety: Selective serotonin reuptake inhibitors (SSRI) like Fluoxetine have been used in individuals with FXS with co-morbid social anxiety, autism, or selective mutism (Berry-Kravis & Potanos, 2004). In about 20% of individuals with FXS, Fluoxetine use may result in disinhibited behaviour, irritability or aggression (Hagerman et al. 1994). 
  •  
  • Treatment of Epilepsy:  Seizures in FXS generally are easily controlled with a single anticonvulsant. (Hagerman et al., 2009). Medications like Carbamazipine and Valproate have been used historically to achieve good seizure control. More recently, medications like Lamotrigine, Oxcabazepine, Zonisamide and Levetiracetam have proven to be effective anticonvulsants for patients with seizures that are difficult to control, with the advantage of minimal cognitive adverse effects (Hagerman et al., 2009). Side effect profile of the antiepileptic medication should be taken into consideration before prescribing to individuals with FXS.

Other targeted treatments for FXS 

  • Metabotropic glutamate receptor (mGluR5) antagonists: mGluR theory of Fragile X pathogenesis has been proposed by Bear et al. (2004). It has been hypothesised that many psychiatric and neurological symptoms of FXS could be due to unchecked activation of mGluR5. It has been suggested that mGluR5 antagonists would be an effective treatment for FXS (Bear, 2005). Fenobam, selective mGluR5 antagonist has been found to have anxiolytic properties and have been used safely in the trials in non- FXS populations. New mGluR5 antagonists are being developed and will be tried in the individuals with FXS in the future. 

Berry-Kravis et al. (2008) did open-label treatment trial of lithium to target the underlying defect in FXS.  Lithium has been found to down regulate the mGluR5 system. The study found that lithium can be helpful for stabilising mood in FXS and provides functional benefit.  The study results were consistent with the results of previous animal studies. 

Gamma-amino butyric acid (GABA) agonists: GABA is the main inhibitory neurotransmitter in brain. Animal studies have demonstrated that there is reduced GABA inhibition in brains of the individuals with FXS. Aarbaclofen is a selective GABA-B receptor agonist. Aarbaclofen inhibits glutamate signalling in the brain and thereby indirectly inhibit excessive mGluR mediated protein synthesis in FXS. Aarbaclofen is currently been studied in clinical trial in individuals with FXS. 

  • Matrix metalloproteinase-9 (MMP-9) inhibitor: Minocycline belongs to a group of antibiotics called synthetic tetracyclines. Minocycline inhibits MMP-9 protein. MMPs are involved in normal development and physiological processes such as wound repair and tissue remodelling. Excessive MMP-9 activity is believed to contribute to the lax connective tissue phenotype often seen in children with FXS. A recent pilot open-label trial suggest that minocycline has positive effects on behavioural symptoms in individuals with FXS (Paribello et al., 2010)

Managing associated medical conditions

Cardiac functioning of individuals with FXS needs to be assessed because of the increased incidence of mitral valve prolapse and cardiomegaly. Individuals with FXS should also be tested for conductive hearing loss which could result from frequent ear infections.

The future

There have been significant developments in FXS research in the last two decades. It is now possible to diagnose FXS early in its course by molecular genetic techniques. Despite in the advances in the genetic testing many individuals with FXS continue to remain undiagnosed. In the future we may see further efforts to implement newborn or infant screening for FXS. While there is no cure for FXS yet, interventions with multidisciplinary approach can improve quality of life of those affected and their families. There has been growing excitement in the Fragile X research community and among the families of people that have FXS about new developments in the targeted treatments for FXS. It is hoped that future molecular therapies, whether they are aimed at mGluR5, the AMPA receptor, or other molecular targets, will be directed at preventing the development of some of the symptoms of FXS. In future we may also see Gene therapy interventions developed which may involve placing a functioning copy of the FMR1 gene into the cells of the brain so that the right form of FMRP could be produced in the right place at the right time and in the right amounts.       

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USEFUL ADDRESS

The Fragile X Society, 53 Winchelsea Lane, Hastings, East Sussex TN35 4LG, UK. Tel: 01424 813147. Website: www.fragilex.org.uk

TABLE 1: Common physical, behavioural and developmental features of fragile-X syndrome

Physical features
Behavioural Features
Developmental Features
Broad forehead

Elongated face

Large, prominent ears

Strabismus

High arched palate

Malocclusion of teeth

Hand calluses (due to self-injury)

Dermatoglyphics:
↑radial loops, whorls and arches
↓A-B ridge count and ulnar loops

Pertus excavatum

Mitral valve prolapse, cardiomegaly, hypoplasia and dilation of aorta, post-ductal coarctation

Macro-orchidism

Soft, fleshy skin

Scoliosis, pes planus, joint laxity and hyperextensible joints

↑Brain weight

↑Size of fourth ventricle

↑Hippocampal volume

↓Volume of superior temporal gyrus

↓Posterior cerebellar vermis

Epileptic seizures (25%)
(usually generalised tonic-clonic which respond to carbamazepine - half disappear by age 20)

Attention deficit hyperactivity disorder

Short attention span

Impulsivity

Enuresis, encopresis

Autistic-like features:

  • Gaze aversion (especially to strangers)
  • Social anxiety & shyness
  • Hand-flapping and hand biting
  • Sensory defensiveness (aversion to loud noise, touch, strong smells or eye contact)
  • Poor adaptation to changes in routine

 

Psychiatric disorders
Increased incidence of familial bipolar affective disorders

  • Perseverative mumbling and stereotypic behaviours mask psychosis
  • Psychosis in association with epileptic seizures
  • Mood instability with aggression and depression (particularly in adolescence)
  • Premutation females show increased incidence of schizotypal features and depression

Intellectual disabilities:

  • =80% males
  • =50% females
  • Mild to moderate (children)
  • Moderate to severe (adults)
  • Gradual decline in IQ as they grow older but adaptive functioning can be improved
  • Specific cognitive profiles; difficulties in sequential processing, short-term memory deficits and weakness in arithmetic.

Fine and gross motor delay

Problems with co-ordination

Speech abnormalities:

  • Delayed and distorted speech and language (2 years for words, 3 years for short sentences)
  • Tachyphemia
  • Tachylalia
  • Perseveration and delayed echolalia
  • Cluttering of speech

 

 

First published in Psychiatry; Volume 2:8 August 2003 and reprinted with the kind permission of The Medicine Publishing Company.

 Article updated in 2011

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