Angelman Syndrome
Maternal imprinting Clinical: happy, excitable demaner with frequent laughing -developmental delay -microcephaly -seizures (usually myoclonic) -hyperactive (hand flapping, waving) -ASD (autism)
Pradi Willy Syndrome
Paternal imprinting Clinical: hypotonia, hyperphagia and obesity (+++appetitie) -compulsive behaviour -hypogonadism -short-stature -seizures (focal more common)
Rett syndrome
X-linked (fatal in males)–> MECP2 mutation
- normal development upto 18 months, then rapid regression
- stereotypic movements–> hand wringing, repetitive blows to face
- inconsolable crying
- mircocephaly
- language regression
- gait ataxia
MAIN CRITERIA:
- ) loss of acquired hand skill
- ) loss of acquired SPOKEN language
- ) Gait abnormalities: impaired of absence ability
- ) Stererotypic hand movements; hand wringing, clapping/tapping, mouthing and washing/rubbing automatisms,
EXCLUSION CRITERIA:
- ) grossly abnormal psychomotor development in first 6 months
- ) secondary cause (i.e. structural, metabolic, etc)
Fragile X
X-linked; females may have milder symptoms
-CGG repeats >200 in fragile X gene; decreased levels of fragile X mental retardation protein
-clinical: post-puberty most obvious
-long face with prominent brow and jaw
-large ears, macroorchidism, hyperextensible skin and joints
-Neurological: intellectual disability, epilepsy, autism
**if presenting in adult life (>50), following clinical features: intention tremor, ataxia, parkinsonism, cognitive decline (dementia, decline in executive dysfunction), neuropathy, psychiatric features (anxiety, depression)
Adult females may have primary ovarian insufficiency (early menopause)
Imaging: T2/FLAIR middle cerebellar peduncles
-check for: SCOLIOSIS, GERD, sinusitis, otitis media, early childhood–> focus on dislocations, hypotonia, hernias
Ataxia Telangiectasia
AR Normal early development until gait and truncal ataxia become apparent Clinical: 1.) progressive ataxia -polyneuropathy 2.) choreoathetosis 3.) oculcutaneous telangiectatsia 4.) infections 5.) malignancies (leukemia/lymphoma) 6.) increased sensitivity to ionized radiation 7.) premature aging
- ) MRI: cerebellar atrophy
- ) decreased serum Ig levels
- ) elevated alpha feto-protein
Von Hippel-Lindau disease
AD -hemangioblastoma of cerebellum, kidneys, retina, spinal cord -median age 20-25 y Clinical features: 1.) angiomatosis 2.) hemangioblastomas (cerebellum and brainstem) 3.) pheochromocytoma 4.) renal cell carcinoma 5.) pancreatic cysts 6.) cafe-au lait macules
Management: surveillance!!
HARP pneumonic: hemangioblastoma, angiomatosis, renal cell carcinoma, pheochromocytoma
Sturge-Weber Syndrome
Somatic Mosaic mutation
Clinical:
1.) facial portwine cutaneous in distribution of trigeminal nerve (V1 and V2)
2.) ipsilateral glaucoma
3.) seizures
4.) ipsilateral leptomeningeal vascular lesions–> leads to cortical calcification
Management: symptomatic; hemispherectomy to control seizures when medical therapy fails; monitor for galucoma!!
Aicardi Syndrome
X-linked dominant disorder; lethal in affected male
- IS
- agenesis of the corpus callosum
- chorioretinopathy
- vertrebral anolomalies
- severe mental retardation
- EEG: asymmetric hypsarrthymia
Chiari I Malformation
-downward herniation of cerebellar tonsils through foramen magnum >5mm
Friedreich Ataxia
AR
- trineucleotide expansion >66 GAA
1. ) face: hearing loss, optic atrophy, nystagmus, dysarthria
2. ) heart: cardiomyopathy, dysrhythmia
3. ) endo: diabetes
4. ) MSK: scoliosis, pes cavus (high arch), talipes equinovarus
5. ) limb and head tremor
***ataxia, pyramidal signs, sensorimotor neuropathy, optic atrophy
Management:
- ) atrophy of spinal cord and medulla
- ) NCS: axonal neuropathy
Neurulation
3rd-4th week of gestation
Issues:
- )failure of rostral fusion=anencephaly, encephelocele
- )failure of caudal fusion=myelomeningocele (issues with ambulation, hydrocephalus, motor/sensory dysfunction depending on the level, spinchter function)
Myelomeningocele+displacement of cerebellar tonsils=Arnold-chiari malformation
Prosencephalic development
Begins 5th-6th week of gestation and continues…
Forebrain takes shape–>
3 stages: 1.) formation 2.) cleavage 3.) midline development
1.) Anomalies of formation stage are not viable and are rare
2.) rostral end expands and creates forebrain and prosencephalon–> after formation of prosencephalon, midline structure indents and cleaves into telencephalon
Issues: Holoprosencephaly (absence of hemipsheric seperation) ; thalamus and hypothalmus do not seperate properly; face–> cyclopia to single central incisor SHH gene (sonic hedgehog gene)
- )agenesis of corpus callosum and septooptic dysplasia
- Septooptic dysplasia–>optic nerve hypoplasia, pituitary dysfunction, absence of septum pellucidum
Neuronal Proliferation
Disorders of 1.) decreased proliferation 2.) disordered proliferation 3.) abnormal differentiation/maturation
- ) microcephaly: primary
- primary: genetic (decreased proliferation), destructive process (i.e. intrauterine infections, HIE) - ) Hemimegalencephaly: unilateral enlargement of one hemisphere; a/w TSC, hypomelanosis of Ito, linear nevus sebaceous syndrome
- ) Cortical dysplasia or cortical hamartoma in TSC
Stages of brain development
- ) neurulation
- ) prosencepahlic development
- ) neuronal proliferation
- )Neuronal migration
- ) Postmigrational cortical organization
Neuronal Migration
3-5 month of gestation–> neurons and glia migrate to cerebral cortex
- Heterotopia: ectopic neurons outside cortex
- Lissencephaly: paucity of normal gyri/sulci; “smooth brain”
- -> can get infantile spasms
- -> spastic quadriparesis
- -> intellectual disability
- -> epilepsy
- -> de novo mutation
- ) classic lissencepahly: agyria or pachygyria
- ) cobblestone: overmigration of neurons beyond disrupted basal membrane and pial surface (overlying subarachnoid tissue); associated with congenital muscular dystrophies
Postmigrational cortical organization
impairment of cortical organization after migration
1.) polymicrogyria: intrauterine CMV or genetic (focal but symmetric lesions such as bilateral perislyvian polymicrogyria or any other region)
- ) Schizencephaly: slit or clefts in the cerebral hemisphere
- ) post migrational microcephaly
Pompe’s disease
- AR
- ->mutation in GAA gene
- GAA deficiency (acid alpha-glucosidase)
- accumulation of glycogen within the lysosome in tissues
- )infantile form
- cardiomyopathy
- generalized hypotonia
- respiratory distress
- feeding difficulties
- TONGUE enlargement - ) juvenile and adult form
- progressive myopathy→ limb-girdle distribution, particularly hip flexors
- delayed gross-motor development
- early involvement of diaphragm
- camptocormia (severe anterior flexion of the spine)
3.) GI: dysphagia, GERD, diarrhea, constipation
Work-up
- Increase CK
- Increase LDH
- Increase AST
- GAA enzyme measured in WBC
Treatment:
-enzyme replacement therapy with alglucosidase alfa
Niemann-Pick Disease
- AR
- storage of lipids
- 3 types
- ) NPD-A
- Ashkenazai jews
- hepatosplenomegaly
- feeding difficulties
- loss of early motor skills
PNS: hypotonia, absent reflexes, peripheral neuropathy
Lungs: respiratory failure, interstitial lung disease, respiratory infections
Eye: MACULAR CHERRY RED SPOT
- ) NPD-B
- pan-ethnic
- less severe than A
Neurological signs: cerebellar involvement, nystagmus, extrapyramidal involvement, intellectual disability, peripheral neuropathy
Other: short stature, hyperlipidemia
MRI: cerebellar and supratentorial atrophy
- )NPD-C
- liver, spleen, lung
- Neurological: clumsiness, gait problems→ ataxia, slow cognitive deterioration, vertical supranuclear opthalmoplegia, seizures, progressive dystonia, dysarthria and dysphagia, hearing loss
Diagnosis of NPD-A and NPD-B and NPD-C
NPD-A
- hepatosplenomegaly
- interstitial lung disease
- macular cherry red spot
- developmental delay
NPD-B
- Hepatosplenomegaly
- thrombocytopenia
- interstitial lung disease
- hyperlipidemia
NPD-C
- newborns: ascites, abnormal LFTs
- childhood: hepatosplenomegaly, vertical supranuclear gaze palsy, ataxia, dystonia, seizures
- gelastic cataplexy
- adults: dementia, depression bipolar, schizophrenia
Treatment:
-Miglustat (decreases lipid storage)
Tay-Sachs disease
- AR
- HEXA mutation
- Lipid storage disease
1.) infantile form: startle reaction to sound, developmental regression, paralysis, dementia, blindness
- ) Juvenile:
- Psychiatric presentation
- Proximal muscle weakness
- Cerebellar: clumsiness, incoordination, ataxia, dysarthria, tremor, abnormal saccades
3.)Adult: progressive dystonia, spinocerebellar degeneration, motor neuron disease with muscle weakness and fasciculations, and/or psychosis
Other: Macular Cherry-Red spot
MRI: cerebellar atrophy
Labs: Elevated CPK, foamy leukocytes, deficient enzyme activity in leukocytes
Biopsy: liver/rectal accumulation of globosides and GM2 gangliosides
EMG: fasciculations
Dx: absent hexasaminidase A enzymatic activity in serum, genetic testing
