Selected syndromes every neurologist should know

Myriam Srour, Pediatric NeurologistSeptember 25, 2013

Retts syndrome

Classical Retts- main clinical features

1. Girls2. Initial normal development followed by regression (6-18 mo)3. Deceleration of head growth4. Loss of purposeful hand movements

Supportive criteria

• Breathing disturbances when awake• Bruxism when awake• Impaired sleep pattern• Abnormal muscle tone• Peripheral vasomotor disturbances• Scoliosis/kyphosis• Growth retardation• Small cold hands and feet• Inappropriate laughing/screaming spells• Diminished response to pain• Intense eye communication- “eye pointing”

Main criteria1. Partial or complete loss of acquired purposeful hand

skills2. Partial or complete loss of acquired language skill3. Gait abnormalities (dyspraxic or absence of ability)4. Stereotypic hand movements including

hand-writing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms

4 Stages

Other features• Epilepsy

– In 50-90%– All types– Onset usually between 2-5 years– Seizure frequency declines with age (late childhood/adolescence)

• Non-epileptic events– In one study, only 1/3 of reported seizures were correlated with

abnormal activity on EEG– Hand stereotopies, breath-holding, hyperventilation, dystonia,

dyskinesias, unusual eye movements• Bowel dysmotility• Gallbladder dysfunction, stones• Osteopenia• Prolonged QT interval

– Avoid medications that prolong QT

Different forms

• Classic Retts- typical Retts– Presence of all 4 major criteria

• Atypical Rett syndrome– Period of regression– 2 of 4 main criteria– 5 of 11 supportive criteria

Retts syndrome variants

1. Epileptic encephalopathy variant– Seizures predominate– Onset prior to 6 months– Think of CDKL5 mutations

2. Congenital variant– No regression– Think of FOXG1 mutations

3. Later onset variant4. Forme fruste variant5. Preserved speech variant

Genetics

• Mutations in MECP2– X-linked– Lethal in males

• Neonatal encephalopathy in boys, severe, death <2 years– Mutations are de-novo– Methyl-CpG-binding protein 2– Abundantly expressed nuclear protein– Mediates transcriptional silencing and epigenetic

regulation of methylated DNA

Key concept

Methylation usually mediates silencing MECP2 recruited to methylated sites

This leads to recruitment of proteins that

will de-acetylate histone tails

Chromatin compaction (inactive genes)

What are the main features?

Main clinical features of Fragile X?

• Dysmorphisms– More obvious in adults/post-pubertal

• Long face• Large ears• Prominent chin• Macroorchidism• Hyperextensible joints• strabismus

Main clinical features of Fragile X?

• Intellectual disability– Moderate to severe (IQ 30-50)– Variable

• ASD features– Impulse control problems, poor eye contact,

perseverative speech– 20-80% of males, 10—20% females

• Cardiac• Mitral valve prolapse• Aortic root dilatation

Fragile X genetics• X-linked, Dominant• Triplet repeat disorder

• FMR1 testing– Testing triplet repeats CGG in 5’UTR– PCR/Southern blot

– Why is it called fragile X?• Fragile site on X chromosome when cells grown in folate-deficient medium

• Triplet repeats decrease transcription of FMR1 (ie. Less mRNA) • What does FMRP do?

– Found in the cytoplasm of most cells, especially neurons– FMRP binds RNA and functions as a nucleocytoplasmic shuttling protein– Plays an important role in the structural and functional maturation of synapses by

suppressing translation of certain genes. – Disrupts glutamatergic neurotransmission.

Fragile X- genetics

• What is a pre-mutation? – 50-200 repeats

• How many repeats are in a full mutation?– >200

• What happens to the repeats with future progeny– In male carrier?– Female carrier?

• Increase in number of repeats if transmitted by female, but stable if transmitted by male

Fragile X

• How prevalent is Fragile X amongst patients with ID/ASD?– 1.5-3%

• What do you counsel a male with Fragile X premutation?– Risks to children– Risks to grandchildren– Risks to self

– FXTAS

FXTAS

• Fragile X-related tremor/ataxia syndrome– Males with pre-mutation– Onset after 50 (usually early 60s)– Intension tremor and or/gait ataxia– Mild parkinsonism– Neuropathy– MRI:

• T2/FLAIR lesions in Middle cerebellar peduncle• Also in periventricular white matter and brainstem• Atrophy

FXTAS• With pre-mutation, there is increased transcription of FMR1

(i.e. more mRNA).• Pathogenesis results from neural toxicity of FMR1 mRNA• Inclusion in neurons and astrocyes, spongiform white matter

changes in subcortical, periventricular and brainstem regions including middle cerebellar peduncle.

FXTAS

• What do you counsel a female with Fragile X premutation?– To children– To self

– Premature Ovarian failure in 30%

Angelman Syndrome

• Protruding tongue

• Widely spaced teeth

• Happy/smiling• Uplifted, flexed

armed position• Prognathia

Main clinical features• GDD/ Intellectual disability

– Severe range, best have 20 words– No regression

• Happy demeanor– “happy puppet”– Laughing, hand flapping

• Ataxic gait/tremulousness• Microcephaly• Seizures

– 90%, usually start <3 years• Sleep disturbances• Fascination with water

Characteristic EEG pattern- High amplitude sharp theta posteriorly

Genetics- key concept

What is genomic imprinting?- Genes are expressed in a parent-of origin

manner

• i.e. expression depends on whether it is inherited from the mother or father

• e.g. deletion of 15q11if maternal Angelman syndromeif paternal Prader-Willi syndrome

Genetics

• due to deficient expression or function of maternally-inherited UBE3A

• What are 4 genetic mechanisms underlying Angelman syndrome?1. Deletion 15q11 (65-70%)2. Paternal uniparental disomy (2-5%)3. Imprinting defect (2-5%)4. UBE3A point mutation (10-15%)

Pick up on methylation studies

What is uniparental disomy?

Inheritance of 2 copies of a chromosome/part of chromosome from the same parent and no copies from the other parent

Genetic mechanisms

What is function of UBE3A?

• Ubiquitin-protein ligase E3A– Involved in the ubiquitination pathway, which

targets slected protein for degradation

PWS- other clinical features

Hypothalamic dysfunction• Lack of satiety

– Low ghrelin levels– Hypogonadism in males and females

• Hypothyroidism• Adrenal insufficiency• Hypogonadism, infertility

PWS- Clinical features

• Characteristic facial features: almond-shaped eyes, blond, thin upper-lip, down-turned mouth

• Type-2 diabetes + complications of obesity• Behavior issues: temper tantrums, stubborn,

compulsive, autistic features, psychotic features

Prader-Willi syndrome

• Main Clinical features• Age dependent!

Birth – 2y Hypotonia with poor suck2-6y Global developmental delay,

hyperphagia begins6-12 y Hyperphagia, behaviour abnormalitiesTeens-adult

Mild MR, hypothalmalic hypogonadism

PWS- genetics

• Absence of Paternal 15q11contribution (PWCR)– Deletion- 70%– Maternal uniparental disomy- 20-30%– Imprinting defect- Mutation in methylation center– Same region as Angelman syndrome– Methylation testing identifies 99%

Down syndrome

Down syndrome• Upslanting palpebral fissures• Epicanthal folds• Flat profile• Folded, dysplastic ears• Low-set ears• Brachycephaly• Open mouth, protruding tongue• Excessive skin at nape• Transverse palmar crease• Incurved 5th finger• Sandal gap• Hypotonia and joint hyperlaxity

Trisomy 21

• 88% due to maternal non-dysjunction

• 1-2% individuals mosaic Down’s

• 2-3% due to Robertsonian (balanced translocation) – Recurrence risk

implications

Screening

• 1st trimester combined test:– Ultrasound for nuchal translucently– Serum markers (beta-hCG and PAPP-A)– 85% sensitive, 5% false positive

• Chorionic Villus sampling• > 35 years high-risk• Offered to all women

Clinical features• GDD/Intellectual disability

– Variable. Mainly mild-moderate• Cardiac defects (VSD, CAVSD)• Vision, hearing problems• Short stature• GI (duodenal atresia)• Endocrine disorders• Hematologic disorders (leukemias)• Atlantoaxial instability• Immune deficiencies

Neurologic features• Hypotonia• Ligamentous laxity

– Atlanto-axial instability– Signs and symptoms consistent with spinal injury

• Seizures– Bimodal distribution: infancy or after 3rd decade– Infantile spasms (usually more easily controlled)– Seizures >30 years associated with dementia

• Dementia– Alzheimers- typical neuropathology with senile plaques and tangles– Related to increased dosage of APP on chromosome 21 (amyloid precursor

protein)• Obstructive sleep apnea

QUESTIONS?