Fragile x Syndrome

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FRAGILE X SYNDROME Most frequent form of inherited intellectual disability 1 in 4000 in 6000 in males Prevalence in females is half of that in males X-linked disorder FMRP Clinical features vary Physical, cognitive and behavioural Associated Conditions Autism25% + 20% PDD NOS Epilepsy10-20% M & 5% F

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Fragile X

Transcript of Fragile x Syndrome

FRAGILE X SYNDROME

FRAGILE X SYNDROMEMost frequent form of inherited intellectual disability1 in 4000 in 6000 in malesPrevalence in females is half of that in malesX-linked disorderFMRP Clinical features vary Physical, cognitive and behaviouralAssociated ConditionsAutism25% + 20% PDD NOSEpilepsy10-20% M & 5% FDecreased or absent levels of fragile X mental retardation protein (FMRP) In more than 99 percent of cases, loss of function is caused by an unstable expansion of a trinucleotide (cytosine-guanine-guanine, CGG) repeat The clinical features of fragile X syndrome (FXS) vary depending upon the mutation state (full mutation versus premutation), degree of methylation, sex

1Clinical FeaturesMalesFull Mutation Significant impairmentPhysicalCraniofacialMitral valve prolapse (50%)Hypotonia, joint hyperlaxityTesticular enlargement (>8yrs)CognitiveGlobal developmental delayIntellectual disabilityLearning disabilitiesBehaviouralADHD/ Anxiety/ ASD

FemalesFull Mutation Variable ImpairmentMilder phenotype than male counterpartslyonisation50% have normal intellectSome characteristic physical featuresPremature ovarian failure (20% with premutation)Macrocephaly, strabismus, sunken eyes, arched palateThumb, finger, wrist joints. Flexible feet.Typically moderate intellectual disability range. Cognitive level and adaptive behaviour skills decline after early childhood (early intervention). Expressive language skills are achieved more slowly than receptive language skills (10% nonverbal)Hyperactivity, inattention, gaze aversion, and stereotypic movements, such as hand flapping, hyperarousal, social anxiety, unusual speech patternsRandom process by which one of the two copies of the X chromosome present in female mammals is inactivated50yrs with ataxia and intention tremor

4ManagementEducational InterventionsSpeech and language therapyOccupational therapyPhamacotherapyStimulantsSSRIsAntipsychoticsAnticonvulsantNormal life expectancyGenetic Counselling

Tailored to symptoms and degree of disability

5Rett SyndromeNeurodevelopmental disorder that occurs almost exclusively in femalesMECP2 gene>99% are sporadic mutationsKlinefelters syndrome/ mosaicism

Neurodevelopmental disorder that occurs almost exclusively in femalesMECP2 de novo mutation. Expressed in all tissues but most abundant in the brainLyonization allows survival in females but does not protect from neurodevelopmental abnormalities

Each girl develops her own distinctive unique hand pattern

6Clinical FeaturesDevelopmentally normal for 1st 6 months!Deceleration of head growth 12-18 months regression appears:Fine motor, communicative and intellectual declineStereotypiesInconsolable screamingRapid/ insidiousPeriod of partial recovery/ stabilization

1st sign = microcephalyInitial regression stabilization insidious deterioration

7Slow DeteriorationDecline in gross motor function (ataxic gait)Growth failure (severe in 33%)Scoliosis (70% by 16)Epilepsy (80% by 15)Respiratory dysfunction (70%)ANS dysfunction (cardiac electrical instability)

Ataxic gait, bruxism, dystonia, rigidityWorsened by malnutrition & feeding impairment swallow, chewing, refluxEpilepsy prevalence increases with age, up to 80% after 15yrs Hyperventilation followed by apnoea, up to 2mins, while awake0.3% sudden cardiac death

8DiagnosisTYPICAL RETT SYNDROMERegression followed by stabilizationAll of:Loss of purposeful hand movementsLoss of speechImpaired gaitStereotypiesNone of:Organic brain injuryAbnormal psychomotor development in 1st 6/12VariantsAtypical2/4 main criteria + 5/11 supportivePreserved speechless severe variantEarly seizure epilepsy before 5 monthsCongenital onset in 1st 6 months

Supportive = typical symptoms (apnoea, bruxism, scoliosis, growth failure etc.)

10ManagementMDT approachPharmacotherapy for associated conditions e.g. antiepilepticNutritionECGHigh calorie diet + treat refluxProlonged QT syndrome

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