18_Semple_Chap18.indd 738 12/7/2012 3:52:13 PM THE PROCESS OF ASSESSMENT 739 Needs assessment Should it be the case that the person \200\231s needs have changed, then t here may be a statutory responsibility to undertake a formal \200\230needs assessment \200 \231, taking into account the wishes of the person (if they have capacity to make the kinds of decisions required) and others involved in care provision. This includes social care, e ducational, and health care needs. Increasingly, more joint work is being done between psychiatry of learn- ing disability dep artments and social work departments. As a result, it is likely that you will be more invol ved in discussions and assessments of patients with a view to deciding on what their overal l care needs are, in addition to their particular psychiatric needs. Naturally this will be in a multidisciplinary team but will include consideration of: \200 Level of supervision by nursing/care staff, e.g. day and night staf \201 ng ratios, sleepi ng vs. waking night cover, same building or next door building. Layout of building. Locatio n of building. Compatibility of different patients if being considered for group accommodat ion. \200 \200 18_Semple_Chap18.indd 739 12/7/2012 3:52:13 PM CHAPTER 18 Learning disability 740 Considering management choices The therapeutic environment Provision of care and support sh ould always be within an appropriate set- ting. Support may be: general (care provided by u sual carers, schools, community teams) and/or speci \201 c (addressing particular needs, e .g. special education, parental support groups, physical or psychiatric prob- lems, maladap tive behaviors). Although, in general, every effort will be made to sustain a \200\230norm al \200\231 environment (remaining at home, integration into mainstream schools, use of loc al community resources), often more specialized environments are necessary (see Admission t o specialist environments). Overcoming communication dif \201 culties \200 Use of aids to overcome/improve sensory de \201 cits (e.g. hearing aids, glasses). Strateg ies for improving communication \200\224picture exchange communication system (PECS); symbo l dictionaries; Makaton; sign language. Because of often unique communication styles it is important that family/carers who know the patient are available to assist/improve communica tion and that their expertise is shared amongst new staff. Factors in \202 uencing management choices \200 \200 \200 \200 The nature of the problem (e.g. biological, psychological, social). The degree and etiology of the LD. Comorbid physical conditions (which may restrict medication choices). Situation al factors (e.g. practicalities of instituting various treatment options, supports, ability to monitor progress). Admission to specialist environments Sometimes disabilities or problems may be too severe o r too complex to be managed with standard community resources because: \200 The degree of LD or the speci \201 c cognitive impairments requires a well-structured, pre dictable environment that cannot be provided elsewhere. The degree of physical impairment r equires more intensive specialist nursing or a safer environment where medical care is clos e at hand (e.g. severe treatment-resistant epilepsy). The severity of behavioral problems p rohibits management at home (e.g. abnormally aggressive or disinhibited behavior which cons titutes a serious risk of harm to the patient or to others). The person requires treatment for a comorbid psychiatric disorder, which has failed to respond to initial treatment. Other reasons for admission may include: \200 Respite placements to allow individuals and their families some relief from the intensity o f long-term care. Assessment of complex problems \200\224to disentangle environmental from illness factors, or where treatment requires close monitoring. 18_Semple_Chap18.indd 740 12/7/2012 3:52:13 PM CONSIDERING MANAGEMENT CHOICES 741 \200\230Crisis \200\231 admissions due to an acute breakdown of usual supports. Cautionary notes \200 Attributing treatment success to a particular intervention may miss the real reason for imp rovement, e.g. return of familiar carer, more structured environment (if admitted to specia list center), or treatment effects on an undiagnosed primary condition (e.g. anticonvulsant used for aggressive behavior may actually be treating underlying epilepsy). Many condition s may run mistaken conclusions about effectiveness of an intervention, which only become cl ear when symptoms return despite treatment. Improvement (or worsening) of symptoms may re \202 ect maturational processes or, conversely, further pathological degeneration. Because of the wide variation in etiology (genetic, environmental, psychological, social) and the c omplexity (and variable degree) of cognitive impairments, most trials of treatment are by n ature empirical. Most management plans will inevitably be individually tailored and the cur rent evidence base for many treatment modalities is limited. relapsing \200\223remitting courses, leading to normal 18_Semple_Chap18.indd 741 12/7/2012 3:52:13 PM CHAPTER 18 Learning disability 742 Treatment methods Behavioral treatments May be used to help teach basic skills (e.g. feedin g, dressing, toileting), establish normal behavior patterns (e.g. sleep), or more complex s kills (e.g. social skills, relaxation techniques, assertiveness training). Behavioral techn iques may also be used to alter maladaptive patterns of behavior (e.g. inappropriate sexual behavior, pica, phobias). Pharmacological treatments Cautions \200 Comorbid physical disorders (e.g. epilepsy, constipation, cerebral palsy) increase the need to closely monitor adverse effects. Atypical responses, such as increased (or reduced) sen sitivity and \200\230paradoxical \200\231 reactions, are more common, hence low doses and gradual increases in medication are advisable. The evidence base for many drug treatments i s lacking and many claims for ef \201 cacy are at best based on small, open, uncontrolled trials. Antipsychotics For the treatment of comorbid psychiatric disorders (e.g. schizophrenia and related psychosis) and acute behavioral disturbance. May also be effective in managing auti stic spectrum disorders, self-injury, social with- drawal, ADHD, and tic disorders. Antidepressants Effective for the treatment of depression, OCD, and other anxiety disor- de rs. They have also been used in the management of violence, self-injury, \200\230non-speci \201 c \200\231 distress, and other compulsive behaviors. Anticonvulsants There is some evidence for the use of anticonvulsants in the treatment of e pisodic dyscontrol (e.g. carbamazepine), but their effectiveness may be due to better contr ol of underlying epilepsy. Lithium Aside from the treatment of bipolar affective disorder and augmenta- tion of antide pressant therapy, lithium may have some utility in reducing aggressive outbursts. -Blocke rs May be useful in conditions of heightened autonomic arousal (e.g. anxiety disorders), wh ich may be at the root of aggressive behavioral disturbance. Stimulants (e.g. methylphenidate) For the treatment of ADHD, see b p. 628. Opiate antagonis ts (e.g. naltrexone) May be effective in the treatment of repetitive self-injury. 18_Semple_Chap18.indd 742 12/7/2012 3:52:13 PM TREATMENT METHODS 743 Anti-libidinal drugs (e.g. cyproterone acetate and medroxyprogesterone, which reduce testos terone levels) Used in the treatment of sexual offending (see b p. 684). Cognitive therapies and CBT For borderline, mild, or moderate LD, cognitive approaches may be adapted to the level of intellectual impairment. These may be effective in the teaching of problem-solving skills, the management of anxiety dis- orders and depression, dealing wi th issues of self-esteem, anger manage- ment, and treatment of offending behaviors (e.g. se x offenders). Psychodynamic therapies May be helpful in addressing issues of emotional development, relat ion- ships, adjustment to life events (e.g. losses, disabilities, and bereavement). The ran ge of approaches varies from basic supportive psychotherapy to more complex group and famil y therapies. 18_Semple_Chap18.indd 743 12/7/2012 3:52:13 PM CHAPTER 18 Learning disability 744 Down \200\231s syndrome1 Down \200\231s syndrome (trisomy of chromosome 21) is the most com mon genetic cause of LD (1:800 \200\2231:1000). It is characterized by intellectual impairm ent and associated characteristic facies and habitus. Although Down \200\231s syndrome is d iagnosed at birth, LD only becomes evident at the end of the \201 rst year of life, with subsequent delayed developmental mile- stones. The IQ in adults is most often below 50 (ran ge: low to high/ mod- erate LD). Those who survive into their 40s and 50s show pathological brain changes similar to Alzheimer \200\231s disease. Etiology Risk factors for giving birth to a child with Down \200\231s syndrome are: materna l age over 40yrs; a previous child with the syndrome; and Down \200\231s syndrome in the mo ther (although pregnancy is rare). Incidence per 1000 living births is approx. 0.5 for a wo man under 25, 0.7 under the age of 30, 5.0 under 35, 25 under 40, and 34.6 over the age of 45. Most children with Down \200\231s syndrome (70 \200\22380%) are born to mothers under t he age of 35 (due to higher number of pregnancies in younger women). Genetics Full trisomy 21 (non-disjunction) in 795% of cases. Robertsonian translo- cations in 75% (of which 745% show fusion \200\224usually 14 and 21, also 13/15/22 and 21 described ). Mosaicism (a mixture of normal and trisomic cell lines) 72 \200\2235%: IQ can be in the 70s and physical abnormalities may be less marked. Clinical features \200 Short stature (mean 1.4 \200\2231.5m), overweight (730%), muscular General hypotonia. Head and neck diameter, maxilla reduced more than mandible, underdevelop ed bridge of nose, eyes close together, Brush \201 eld \200\231s spots \200\224gray or ver y light yellow spots of the iris, epicanthic fold, low-set ears, high-arched palate, protru ding tongue, instability of atlanto-axial joint, narrowed hypopharynx (may lead to sleep ap noea). Congenital heart defects defect, mitral valve disease, patent ductus arteriosus. Con genital GI abnormalities disease, umbilical and inguinal hernia. Hands syndactyly (webbed \201 ngers), clinodactyly (incurving of \201 ngers), and altered dermatoglyphics. Eye de fects nystagmus, late-life cataracts, keratoconus. Hearing defects media, sensorineural dea fness. Immunological abnormalities T-lymphocytes. Endocrine abnormalities 720%), diabetes. Brachycephaly and reduced anterioposterior (AP) (750%) e.g. atrial or ventricular septal Oesophageal atresia, Hirschsprung Short broad hands with a single palmar crease (simian crease), Strabismus 720%, myopia 730%, blocked tear ducts, Structural anomalies may lead to recurrent otitis Raised IgG and IgM, lowered Thyroid dysfunction (hypothyroidism 18_Semple_Chap18.indd 744 12/7/2012 3:52:13 PM DOWN \200\231S SYNDROME 745 Reduced brain weight 710 \200\22320%, reduced gyri, CNS abnormalities cortical thinning, underdeveloped middle lobe of cerebellum, reduced neur onal numbers in cerebellum/locus coeruleus/basal forebrain, reduced cholinergic neurones, n europathological changes similar to AD (in those over 40yrs), epilepsy (5 \200\22310%). Abn ormal sexual development Males: normal course; delayed puberty; problems with spermatogenes is (unless mosaic). Females: normal onset of menstruation; fertile, but problems with ovula tion and follicular growth; early menopause. Psychiatric comorbidity In 718% of children and 730% of adults with Down \200\231s syndrome (usually depression 710%; less commonly bipolar disor- der, OCD, Tourette \200\231s, schiz ophrenia, increased risk of autism). Dementia in Down \200\231s syndrome A clear relationship exists between Down \200\231s synd rome and dementia. While dementia of the Alzheimer \200\231s type (DAT) is the most common in Down \200\231s syndrome, all types of dementia can occur. Unfortunately, the diagnosis i s often dif \201 cult given the premorbid cognitive de \201 cits and com- munication dif \201 culties. The crucial element in diagnosis is establishing a history of change from an informant who has known the patient over a suf \201 cient period as to be able to make a useful comparison. Assessment \200 \200 Full history, focusing on previous abilities, presentation and behavior. Exclusion of other physical/psychiatric explanations \200\224e.g. sensory loss, delirium, hypothyroidism, dep ression. Use of a standardized cognitive assessment battery either to act as a baseline for decline or response to treatment. Full blood investigations including FBC, U&Es, ESR, LFTs , TFTs, glucose, folate and B12, serum drug levels if relevant. Consideration of CT/MRI bra in or EEG if indicated. Management \200 \200 \200 Make diagnosis of dementia type. Treat all reversible additional factors Optimize communica tion: use of pictures, communication dictionary, etc. (see b p. 740). Liaison with psycholo gy colleagues for potential behavioral management. Consideration of anticholinesterase inhi bitors, but titrating at a signi \201 cantly slower rate than normal (e.g. donepezil 5mg n octe for 4 \200\2236wks before increasing the dose). Seek advice from local experts. Approp riate placement, considering client mix, age group, range of available activities. 1 James Langdon Down remarked in his original observations on \200\230mongolism \200\231 ( 1866) that he was surprised it had not been described earlier. In fact, the \201 rst desc ription of this syndrome was made in 1838 by Esquirol (1772 \200\2231840), with similar obs ervations reported by S guin (1812 \200\2231880) in 1844. The typical phenotype has also b een noted in paintings dating from the Middle Ages. In 1959 the chromosomal abnormality lea ding to Down \200\231s syndrome was found by the French human geneticist J r me Lejeune ( 1926 \200\2231994). In doing so, Lejeune became the \201 rst researcher to elucidate the genetic mechanism of an inherited disorder. 18_Semple_Chap18.indd 745 12/7/2012 3:52:13 PM CHAPTER 18 Learning disability 746 Deletions and duplication syndromes Prader \200\223Willi syndrome (PWS) Microdeletion; karyotype 15q11- q13; incidence 1:10 000 \200\2231:20 000; the complement of Angelman syndrome; 75% due to deletion of paternally d erived chromosome 15, 25% due to maternal uniparental disomy (mUPD) (i.e. inheritance of 2 genes from the same parent), M:F = 4:3. Essence The striking feature of PWS is massive hype rphagia with associated compulsive food-seeking, and consequent marked obesity. At times, t he hyperphagia may be such that questions of how to appropriately limit the person \200\231 s access to food must be addressed, sometimes requiring consideration of measures under cap acity/incapacity legislative frameworks. Clinical features Neonates: hypotonia, sleepiness, unresponsiveness, narrow bifrontal diameter, triangular mouth (feeding dif \201 culties a nd swallowing problems), strabismus, acromicria (shortness of extremities). Childhood/adole scence: short stature, hypogenitalism (cryptorchidism, micropenis; amenorrhoea), behavioral disorders (overeating and obesity, self-injurious behavior), mild \200\223moderate LD, spe ech abnormalities, sleep disorders. Affective psychoses are associated particularly with th e mUPD genotype. Associated features Small hands and feet, cleft palate, almond-shaped eyes , strabismus, incurved feet, clubfoot, congenital hip dislocation, abnormalities of the kne e and ankle, scoliosis. Other physical problems Diabetes, GI problems (obstruction, duodena l ulcer, rectal prolapse, gallstones), heart disease, respiratory (asthma, cor pulmonale), renal calculi, hearing de \201 cits, hypothermia. Angelman ( \200\230happy puppet \200\231) syndrome Microdeletion (60 \200\22375% of cases); karyotype 15q11-q13; incidence 1:20 000 \200\22330 000; a contiguous gene syndrome (the co mplement of PWS) with 80% due to deletion of maternally derived chromosome 15, 2% paternal uniparental disomy (pUPD), the remainder due to direct mutations. Clinical features Ataxia (jerky limb movements, gait problems); epilepsy (86%); paroxysms of laughter; absence of sp eech; facial features (blond hair, blue eyes, microcephaly, \202 attened occiput, long fa ce, prominent jaw, wide mouth, widely spaced teeth, thin upper lip, mid-facial hypoplasia); severe/ profound LD; other behaviors (hand \202 apping, tongue thrusting, mouth movement s); other problems (URTIs, ear infections, obesity). -Thalassaemia mental retardation Small deletion; karyotype 16pter-p13.3 (cryptic terminal deletion). Clinical features LD. Cri du chat Partial monosomy; karyotype 5p- (varies from deletion of a small band at 5p15.2 to the entire arm of 5p); usually sporadic, occasionally inherited; incidence 1:20 000 \200\22350 000. Clinical features \200\230Cat-like \200\231 cry (possibly due to abnormal laryngeal development), microcephaly, rounded face, hypertelorism, micrognathia, dental mal occlusion, epicanthic folds, low-set ears, hypotonia, severe/profound LD. Puberty occurs no rmally and some may survive to adulthood. DiGeorge (velo-cardio-facial) syndrome Microdeletion; karyotype 22q11.2; incidence 1:5000. Clinical features 750% have LD (mild: 2/3; moderate: 1/3), cardiac abnormalities (75%: Fall ot tetralogy, VSD, interrupted aortic 18_Semple_Chap18.indd 746 12/7/2012 3:52:14 PM DELETIONS AND DUPLICATION SYNDROMES 747 arch, pulmonary atresia, truncus arteriosus), facial features (microcephaly, cleft palate/s ubmucous cleft, small mouth, long face, prominent tubular nose, hypoplasia of adenoids \200 \224nasal speech, bulbous nasal tip, narrow palpebral \201 ssure, minor ear abnormalities , small optic disks/tortuous retinal vessel/ cataracts), hypocalcaemia (60% \200\224seizure s, short stature, hearing problems, renal problems, inguinal/umbilical hernia), hypospadias (10% of males), long, thin hands (hypotonia and hyperextensible \201 ngers), associated behavioral and psychiatric disorders (including schizophrenia, blunted/inappropriate affect ). Rubenstein \200\223Taybi syndrome Microdeletion of the gene encoding human cAMP-regulated e nhancer binding protein; karyotype 16p13.3; incidence 1:125 000. Clinical features LD and d ysgenesis of the corpus callosum. Broad thumbs and great toes; persistence of fetal \201 nger pads; facial features (short upper lip, pouting lower lip, maxillary hypoplasia, beake d nose, slanted palpebral \201 ssure, long eyelashes, ptosis, epicanthic fold, strabismus , glaucoma, iris coloboma); cardiac problems (pulmonary stenosis and hypertension, mitral v ale regurgitation, patent ductus arteriosus); propensity to keloid formation; genitourinary features (hypoplastic kidneys, cryptorchidism, shawl scrotum); GI problems (constipation, megacolon); collapsible larynx (leading to sleep apnoea); epilepsy (25%); behavioral proble ms (sleep problems, stereotypies, e.g. rocking, self-injurious behavior). Smith \200\223Magenis syndrome Deletion in 17p11.2; incidence 1:50 000. Clinical features M oderate LD; facial features (brachycephaly, broad face, \202 attened mid-face, strabismus ); myopia; short broad hands; upper limb deformity; insensitivity to pain. Behavioral probl ems \200\230Self-hugging \200\231 posturing, aggression, self-injury, hyperactivity, sever e sleep problems, other autistic features. Williams syndrome Small deletion; karyotype 7q11.23 (possibly gene for elastin or protein k inase \200\224LIMKI); 1:55 000 live births; may also be related to excessive maternal vitam in D intake. Clinical features Hypercalcaemia (in 750%) with supravalvular aortic stenosis and unusual facies. Neonates: may be irritable, have feeding problems and failure to thrive . Childhood: growth retardation, \200\230el \201 n \200\231 facial features, hoarse voice , premature wrinkling and sagging of the skin, cardiovascular anomalies (e.g. supravalvular aortic stenosis), urinary tract abnormalities (asymmetrical kidneys, nephrocalcinosis, bla dder diverticuli, urethral stenosis), pulmonary artery stenosis, mild to moderate LD (verba l often better than visuospatial and motor abilities). Often there is abnormal attachment b ehavior (manifest as anxiety, poor peer relationships, hypersensitivity, or conversely as s ocial disinhibition, excessive friendliness). Wolf \200\223Hirschhorn syndrome Partial monosomy; karyotype 4p-. Clinical features Severe LD; many survive to adulthood. 18_Semple_Chap18.indd 747 12/7/2012 3:52:14 PM CHAPTER 18 Learning disability 748 Autosomal dominant syndromes Noonan \200\231s syndrome Occuring in 1:1000 \200\2231:2000; M = F. Initial descrip- tion of 9 children seen in the congenital heart disease clinic who s hared a characteristic facies, anterior chest wall deformities (pectus carinatum or excavat um) and short stature. Whilst a number of genes (including PTPN11, SOS1 and KRAS) have been identi \201 ed which can cause Noonan \200\231s syndrome, it remains a clinical diagnosis . Clinical features Varying degree of LD (from none to severe), short stature (80%), cardia c abnormalities (>80%), hepatosplenomegaly (25%), distinctive facies. The following group of disorders is also termed the phakomatoses \200\224 a variety of cond itions of ectodermal origin with neurocutaneous signs. Although Von Hippel \200\223Lindau s yndrome is not associated with LD, it is included for completeness. Tuberous sclerosis (TSC) Occurring in 1:7000 \200\22310 000; M = F. Clinical features Varyi ng degree (usually severe) of LD (50%), seizures (e.g. \200\230Salaam attacks \200\231 and other types, in 90%), hamartomas of the CNS (including the retina) as well as ependymomas and astrocytomas, facial angio \201 broma, adenoma sebaceum, depigmented skin patches ( \200\230ash leaf spots \200\231 in 96%), shagreen patches, depigmented naevi, subcutaneous nodules, \200\230caf -au-lait \200\231 spots, \201 bromas of the nails, pitted tooth en amel, hypoplasia, and occasionally tumors of the heart (rhabdomyeloma, hamartoma), kidney p roblems (Wilm \200\231s tumor, renal cysts), olfactory hamartomas, hypertension, and aortic aneurysm. Subtypes TSC1: 1:12 000; associated with a gene (for hamartin \200\224believed t o be tumor-suppressant) near the ABO blood group locus on chromosome 9 (9q34 \200\22440% of cases). TSC2: associated with a gene for tuberin (a guanosine triphosphatase-activating pr otein also believed to be tumor-suppressant) on chromosome 16 (16p13.3-); more psychiatric and behavioral problems. TSC3: a rare translocation of a gene on chromosome 12. Neuro \201 bromatosis Type 1 (NF1, von Recklinghausen \200\231s disease) Occurring in 1:25 00; M = F. Autosomal dominant condition, responsible gene on chromosome 17 (approx. 50% spo ntaneous mutations). Clinical features Caf -au-lait spots, freckling, dermal neuro \201 b romas, nodular neuro \201 bromas, Lisch nodules. Associated with mild learning disability in approx. 50%. Type 2 (NF2) Occurring in 1:35 000. Autosomal dominant condition, responsib le gene on chromosome 22. Clinical features Bilateral vestibular schwannomas, caf -au-lait spots, juvenile posterior subcapsular lenticular opacities. Sturge \200\223Weber syndrome Caused by spontaneous genetic mutation in unknown location. C linical features \200\230Port-wine stain \200\231 typically covering part of the forehead and at least one eyelid, angiomas of the meninges in the temporal and occipital areas on th e same side as the port-wine stain. Associated to varying degrees with LD. Epilepsy is the most common early problem, often starting before the age of one. Hemiparesis may develop, u sually contralateral to the port-wine stain. Buphthalmos (bulging of the eye) and glaucoma are common in the affected eye. 18_Semple_Chap18.indd 748 12/7/2012 3:52:14 PM AUTOSOMAL DOMINANT SYNDROMES 749 Von Hippel \200\223Lindau (VHL) syndrome A rare genetic condition caused by a mutation of t he VHL tumor suppressor gene on chromosome 3p. 80% inherited, 20% new mutation. Symptoms ca used by angiomas in various areas of the body. Clinical features Renal cysts/carcinomas, ph aeochromocytomas, CNS haemangioblastomas, pancreatic cysts/ tumors (can be neuroendocrine), subretinal hemorrhages s to retinal vessel tortuosities/aneurysms. Not associated with LD. 18_Semple_Chap18.indd 749 12/7/2012 3:52:14 PM CHAPTER 18 Learning disability 750 Autosomal recessive syndromes These conditions include some of the lysosomal storage diseas es, e.g. mucopolysaccharide storage \200\224Hurler syndrome, San \201 lippo disease, sphin golipid storage \200\224Tay \200\223Sachs disease, Niemann \200\223Pick disease (sphin- gom yelins), glycoprotein storage \200\224sialidosis; phenylketonuria; and rare disorders such as Laurence \200\223Moon syndrome and Joubert syndrome (see b p. 751). Phenylketonuria A preventable cause of severe LD, due to de \201 ciency of phenylalanine h ydroxylase (long arm of chromosome 12), leading to phenylalaninaemia and phenylketonuria; p revalence 1:15 000; diagnosed postnatally ( \200\230Guthrie test \200\231). Clinical featur es Fair hair/skin and blue eyes (lack of pigment \200\224tyrosine de \201 ciency), neurolo gical signs (stooped posture, broad-based gait, increased tone and re \202 exes, tremor, s tereotyped movements). Behavioral problems Hyperactivity, temper tantrums, perseveration, e cholalia. Management Supervised early dietary restriction of phenylalanine. Prognosis Even with dietary treatment, lower than average IQ. San \201 lippo disease Due to disorders of the breakdown of heparan sulfate, of which ther e are 4 subtypes (types A \200\223D). Prevalence 1:25 000 \200\223325 000. Clinical feature s Severe LD, claw hand, dwar \201 sm, hypertrichosis, hearing lumbar joint stiffness. Beha vioral problems Restlessness, sleep vertebrae, problems, challenging behavior. Etiology Typ e A (most severe, most common) mapped to 17q25.3 (heparan sulfate sulphatase). Type B 17q21 (N-acetyl- -D-glucosaminidase). Type C on chromosome 14 or 21 (acetyl-CoA- -glucosaminid e-N-acetyltransferase). Type D 12q14 (N-acetyl-A-D-glucosamine-6-sulphatase). Prognosis Poo r, many die between 10 \200\22320yrs of respiratory tract infections. loss, hepatosplenomegaly, biconvex Hurler syndrome Due to de \201 ciency in A-L-iduronidase (4p16.3); incidence 1:76 000 \200 \223144 000. Clinical features Progressive LD (eventually severe/profound), skeletal abnorm alities (short stature, kyphosis, \202 exion deformities, claw hand, long head, character istic facial appearance), hearing loss, respiratory and cardiac problems, hepatosplenomegal y, umbilical/ inguinal hernia. Prognosis Poor, some survive to 20s; may bene \201 t from a llogenic bone transplantation. Laurence \200\223Moon syndrome Associated with multiple loci (11q13, 11q21, 15q22, 3p13); p revalence 1:125 000 \200\223160 000 (higher in Bedouins of Kuwait and Newfoundland). Also k nown as Laurence \200\223Moon \200\223Biedl syndrome (incorporating Bardet \200\223Biedl sy ndrome which shares clinical features, but additionally there is central obesity and polyda ctyly). Clinical features Mild \200\223 moderate LD, short stature, spastic paraparesis, hy pogenitalism (most males are infertile), night blindness (due to red cone dystrophy), non- insulin dependent diabetes mellitus (NIDDM), renal problems (diabetes insipidus, renal fail ure). 18_Semple_Chap18.indd 750 12/7/2012 3:52:14 PM AUTOSOMAL RECESSIVE SYNDROMES 751 Joubert syndrome Exceptionally rare, no loci identi \201 ed, but recessively inherited. Cl inical features Severe LD, characteristic hyperpnoea ( \200\230panting like a dog \200\231) , cerebellar dysgenesis, hypotonia, ataxia, tongue protrusion, facial spasm, abnormal eye m ovements, cystic kidneys, syndactyly/ polydactyly. Behavioral problems Self-injury. Prognos is Poor \200\224no speci \201 c treatments. Gaucher \200\231s disease Most common of the lysosomal storage diseases. Caused by de \201 ciency of glucocerebrosidase, leading to accumulation of glucosylceramide, most commonly i n spleen, liver, lung, bone, and brain. Type I \200\224brain is unaffected, onset later in adulthood. Types II and III associated with learning disability, type II being the most sev ere. Prognosis Type I \200\224close to normal, type II \200\224children usually die by age 2, type III \200\224adolescence \200\224adulthood. Treatment Enzyme replacement and bone ma rrow replacement both used in the treatment of types I and III. Unfortunately there is no t reatment for the neurological effects in types II and III. 18_Semple_Chap18.indd 751 12/7/2012 3:52:14 PM CHAPTER 18 Learning disability 752 X-linked dominant syndromes Fragile X syndrome A common inherited cause of LD, affecting 71 :4000 males and 1:8000 females, with X-linked dominant transmission. Penetrance is low, but greater in males than females (due to the \200\230protective \200\231 effects of the seco nd normal X chromosome in females). Gene sequence has been cloned1 and designated FMR-1. Th e syndrome is associated with a large sequence of triplet repeats (CGG)n at a fragile site on the X chromosome (Xq27.3). In affected males n >230 \200\2231000+, in transmitting males and obligate females n = 43 \200\223200, and in the general population n = 6 \200\22354 (m ean 30). Clinical features Variable, subtle, and often cannot be detected before adulthood. May incl ude: large testicles and ears, smooth skin, hyper- extensible \201 ngers, \202 at feet, mitral valve prolapse, inguinal and hiatus hernia, facial features (long, narrow face with underdevelopment of the mid-face, macrocephaly), epilepsy (725%), variable LD (borderline to profound); behavioral features appear to be similar to those seen in ADHD and autism: ha nd \202 apping/waving, repetitive mannerisms, shyness, gaze avoid- ance, poor peer relati onships, communication dif \201 culties (e.g. delayed language development, conversational rigidity, perseveration, echolalia, palilalia, cluttering, and over-detailed/circumstantia l speech), psychiatric problems (e.g. prominent depression/anxiety). Many of the features o f fragile X also overlap with those of autism, though debate is ongoing as to the exact nat ure of the relationship. Note: general domestic and daily living skills may be excellent. B rain imaging Reduced posterior cerebellar vermis, enlarged hippocampus and caudate nuclei, enlarged ventricles. Other disorders with \200\230fragile \200\231 sites Two other fragile sites have been foun d on the X chromosome. The origi- nal \200\230fragile X \200\231 site has hence been desig nated \200\230FRAX A \200\231. FRAX E, caused by FMR-2 mutation is also associated with mi ld LD, with an incidence of 1:100 000, and 200 \200\2231000 triplet repeats. FRAX F has not (yet) been associated with any disorder. Another fragile site has been located on chromoso me 16 (FRA 16) associated with a large GCC triplet expansion \200\224but no spe- ci \201 c clinical disorder. Rett \200\231s syndrome A pervasive developmental disorder (see b p. 758) almost exclusivel y affecting females with an incidence of 1:10 000 \200\22420 000. Initially described by Au strian physican Andreas Rett in 1966,2 but only fully recognized after a second paper in 19 83.3 Clinical features Initially normal development followed by 4 stages: (1) early onset/develo pmental arrest, (2) rapid destructive/regressive, (3) plateau (or pseudo-stationary) and (4 ) late motor deterioration: \200 Stage 1 Onset usually 6 \200\22318mths. May be delays in gross motor skills. Infants may sh ow d eye contact and d interest in toys. The typically described hand-wringing and d rate o f head growth may also be apparent. 18_Semple_Chap18.indd 752 12/7/2012 3:52:14 PM X-LINKED DOMINANT SYNDROMES 753 Stage 2 movements and spoken language are lost. Stereotypical hand movements including wrin ging, washing, clapping, or tapping are often seen. Emergence of some autistic symptoms and a worsening gait may be seen. Stage 3 Seizures and motor problems more prominent. Some imp rovement in behavior, with more interest in others and surroundings and some improvement in communication skills. Stage 4 This stage can last for decades and is typi \201 ed by grad ual worsening in mobility, with scoliosis, spasticity, and muscle weakness. Onset usually between 1 and 4yrs. Purposeful hand Onset usually before age 10, and can last for most of life. Etiology Mutations in the MECP2 gene on the X chromosome are present in the majority of gir ls with Rett \200\231s syndrome. Mutations on the CDKL5 gene have also been implicated in a variant of Rett \200\231s with notably early- onset of seizures. Prognosis The prognosis i s poor with continued motor deterioration and usually severe learning disability. Aicardi syndrome Rare (only 200 reported cases \200\224all female); dysgenesis of the corpu s callosum and cerebrum, with severe LD; prognosis poor (often death in infancy). Clinical features Microcephaly, facial asymmetry, low-set ears, eye lesions (chorioretinal lacunae), hypotonia, scoliosis, epilepsy. Behavioral problems 25% \200\224aggression, lack of commun ication, tiredness/sleep prob- lems, self-injurious behavior. 1 Verkerk AJ, Pieretti M, Sutcliffe JS, et al. (1991) Identi \201 cation of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length vari ation in fragile X syndrome. Cell 65: 905 \200\22314. 2 Rett A (1966) Ueber ein eigenartige s hirnatrophisches Syndrom bei Hyperammoniamie in Kindesalter. Wien Med Wschr 116: 723 \200 \2238. 3 Hagberg B, Aicardi J, Dias K, et al. (1983) A progressive syndrome of autism, deme ntia, ataxia, and loss of purposeful hand use in girls: Rett \200\231s syndrome: report of 35 cases. Ann Neurol 14: 471 \200\2239. 18_Semple_Chap18.indd 753 12/7/2012 3:52:14 PM CHAPTER 18 Learning disability 754 X-linked recessive syndromes These include other lysosomal storage diseases, e.g. mucopolys accaride storage \200\224Hunter syndrome; trihexosylceramide storage \200\224Fabry disease and other extremely rare conditions such as Lesch \200\223Nyhan syndrome and oculocerebrore nal syndrome of Lowe. Hunter syndrome Caused by iduronate sulphatase de \201 ciency (mapped to Xq27-28); inciden ce 1:132 000 \200\22328 0000 (more common in male Ashkenazi Jews: 1:34 000). Symptoms are c aused by build-up of glycosaminoglycans (GAG) in a variety of body tissues. Only 20% have c omplete depletion of iduronate sulphatase and two subtypes are recognized: Type A Progressi ve LD and physical disability, with death before age 15yrs. Type B Milder form, with minima l intellectual impairment and better prognosis. Clinical features Short stature, distinctiv e course, facies \200\230gargoylism \200\231, prominent forehead, enlarged tongue, \202 attened bridge of nose, enlarged head, degenerative hip disease, joint stiffness, claw hand , chest deformities (pes cavus or excavatum), cervical cord compression, hepatosplenomegaly , hearing loss, breathing obstruction, developmental delay, eye defects (retinitis pigmento sa, papilloedema, hypertrichosis), umbilical/inguinal hernia. Lesch \200\223Nyhan syndrome An extremely rare X-linked recessive condition, due to a mutat ion in the HPRT gene (hypoxanthinephosphoribosyl transferase) on the short arm of chromosom e Xq26-27, with a nearly total loss of the enzyme leading to hyperuricaemia. Prognosis is p oor and most affected individuals die in early adulthood. Clinical features Children appear healthy at birth, dystonias become apparent around 3 \200\2234mths with delayed developmen tal milestones, later there is development of spasticity, choreoform movements and transien t hemiparesis (which may be misdiagnosed as cerebral palsy), variable degree of LD (usually severe), microcephaly is common, 750% develop epilepsy. Behavioral problems Around age 2yr s (sometimes not until adolescence) self- mutilating behaviors may be seen (biting of lips, inside of mouth, \201 ngers). Sometimes there is an episodic pattern, and some may show a reduction in frequency and severity after age 10yrs. May be associated with verbal and ph ysical aggression. There is no clear cause for this behavior \200\224 CNS \201 ndings inc lude reduction in dopamine in the basal ganglia and at synaptic terminals (but not in the c ell bodies of the substantia nigra), with other monoaminergic systems apparently intact. Ma nagement Even treating hyperuricaemia does not appear to reduce behavioral problems; howeve r, there is some evidence for use of SSRIs. Oculocerebrorenal syndrome of Lowe Very rare X-linked recessive condition (Xq24-26); incide nce 1:200 000. Clinical features Moderate \200\223severe LD (up to 25% have normal IQ), sho rt stature, hypotonia, epilepsy (730%), eye problems (e.g. congenital cataracts), renal pro blems (tubular dysfunction). Behavioral problems Temper tantrums, hand-waving movements, se lf-injury (770% \200\224esp. in early adolescence). 18_Semple_Chap18.indd 754 12/7/2012 3:52:14 PM SEX CHROMOSOME DISORDERS 755 Sex chromosome disorders Turner \200\231s syndrome Sex chromosome monosomy; karyotype 45XO, female phenotype; generally normal IQ with LD rare though there may be speci \201 c de \201 cits of visuospatial learning. Trisomy X Sex chromosome trisomy; karyotype 47, XXX; 1:1000 female births. Clinical feature s Slight increase in height, 770% have learning dis- order (usually mild), some evidence of reduced fertility (children have normal karyotypes), possibly increased incidence of schiz ophrenia. Klinefelter \200\231s syndrome Sex chromosome trisomy; karyotype 47, XXY; 1:1000 male birth s (50% due to paternal and 50% maternal non-dysjunc- tion). Clinical features Variable degr ee of development of secondary sexual characteristics with hypogonadism, scant facial hair (90%), gynaecomastia (50%). Taller than average (74cm), asthenic body build, median IQ 790 with skewed distribution \200\224most in 60 \200\22370 range, uncertain association with ps y- chiatric disorders. XYY male Sex chromosome trisomy; karyotype 47, XYY; 1:1000 male births. Clinical features C ontroversial suggestion of higher incidence in prison populations, IQ may be slightly lower than average, behavioral problems commonly seen. 18_Semple_Chap18.indd 755 12/7/2012 3:52:14 PM CHAPTER 18 Learning disability 756