Main criteria

Selected syndromes every
neurologist should know
Myriam Srour, Pediatric Neurologist
September 25, 2013
Retts syndrome
Classical Retts- main clinical features
Initial normal development followed by regression (6-18 mo)
Deceleration of head growth
Loss of purposeful hand movements
Main criteria
Partial or complete loss of acquired purposeful hand
Partial or complete loss of acquired language skill
Gait abnormalities (dyspraxic or absence of ability)
Stereotypic hand movements including handwriting/squeezing, clapping/tapping, mouthing, and
washing/rubbing automatisms
Supportive criteria
Breathing disturbances when awake
Bruxism when awake
Impaired sleep pattern
Abnormal muscle tone
Peripheral vasomotor disturbances
Growth retardation
Small cold hands and feet
Inappropriate laughing/screaming spells
Diminished response to pain
Intense eye communication- “eye pointing”
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 variant
4. Forme fruste variant
5. Preserved speech variant
• Mutations in MECP2
– X-linked
– Lethal in males
• Neonatal encephalopathy in boys, severe, death <2
– 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
Hyperextensible joints
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
– 1.5-3%
• What do you counsel a male with Fragile X
– Risks to children
– Risks to grandchildren
– Risks to self
• Fragile X-related tremor/ataxia syndrome
Males with pre-mutation
Onset after 50 (usually early 60s)
Intension tremor and or/gait ataxia
Mild parkinsonism
• T2/FLAIR lesions in Middle cerebellar peduncle
• Also in periventricular white matter and brainstem
• Atrophy
• 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.
Table 4
FXTAS diagnostic criteria in FMR1 premutation carriers( 8)
Diagnostic Categories
Definite: Presence of one major radiological sign plus one major clinical symptom
Probable:Presence of either one major radiological sign plus one minor clinical symptom or has the two major clinical symptoms
Possible: Presence of one minor radiological sign plus one major clinical symptom
Symptom Types
MRI white matter lesions in MCPs and or brain stem
MRI white matter lesions in cerebral white matter
Moderate to severe generalized atrophy
Intention tremor
Gait ataxia
Moderate to severe short-term memory deficiency
Executive function deficit
MCP = middle cerebellar peduncle
• What do you counsel a female with Fragile X
– To children
– To self
– Premature Ovarian failure in 30%
Angelman Syndrome
• Protruding
• Widely spaced
• 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
• i.e. expression depends on whether it is
inherited from the mother or father
• e.g. deletion of 15q11
if maternal  Angelman syndrome
if paternal Prader-Willi syndrome
• due to deficient expression or function of
maternally-inherited UBE3A
• What are 4 genetic mechanisms underlying
Angelman syndrome?
Deletion 15q11 (65-70%)
Paternal uniparental disomy (2-5%)
Imprinting defect (2-5%)
UBE3A point mutation (10-15%)
Pick up on
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
• Type-2 diabetes + complications of obesity
• Behavior issues: temper tantrums, stubborn,
compulsive, autistic features, psychotic
Prader-Willi syndrome
• Main Clinical features
• Age dependent!
Birth – 2y
Hypotonia with poor suck
6-12 y
Global developmental delay,
hyperphagia begins
Hyperphagia, behaviour abnormalities
Mild MR, hypothalmalic
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
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
• 1-2% individuals
mosaic Down’s
• 2-3% due to
– Recurrence risk
• 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
• Obstructive sleep apnea

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