Week 4: ASD, ID & brain stuff

Question 1

Tell me all the things about autism

Answer 1

-Neurodevelopmental condition that is characterized by varying degrees of limitations in communication, social interaction, and atypical, repetitive behaviors with onset before age of 3
-Can be idiopathic (difficult to associate with single genetic cause) or multifactorial or a symptom of a known condition

Question 2

Define intellectual disability

Answer 2

-Condition characterized by significant limitations in intellectual functioning and adaptive behavior that originates before the age of 18
-Can be idiopathic (difficult to associate with single genetic cause) or multifactorial or a symptom of a known condition

Question 3

Tell me about Fragile X syndrome

Answer 3

-Most common inherited cause of ASD/ID
-Many clinics have discontinued testing as first tier and only doing if indicated

Question 4

Tell me about Rett syndrome/MECP2 disorders

Answer 4

-Classic Rett syndrome is a progressive neurodevelopmental disorder primarily affecting girls
-Characterized by apparently normal psychomotor development during first 6-18 months of life followed by developmental stagnation and then rapid regression then long term stability
-During the rapid regression phase, repetitive stereotypical hand movements are seen
-Features: fits of screaming and inconsolable crying, ASD, panic like attacks, bruxism, episodic apnea, gait ataxia, tremors/seizures, acquired microcephaly
-In males, usually neonatal onset encephalopathy followed by death before age 2
-X-linked: path variants in MECP2, more than 99% cases de novo (rarely inherited from mother with very favorable a inactivation)

Question 5

For ASD, what type of testing should be used for apparently isolated ASD vs syndromic ASD?

Answer 5

More isolated: CMA (maybe panel)

More symptoms/syndromic: WES

Question 6

Tell me about holoprosencephaly

Answer 6

-Incomplete cleavage of prosencephalon into L and R hemispheres
-Features: microcephaly, clefting, DD, pituitary dysgenesis, poor swallowing
-Broken down into alobar (most severe), semilobar, lobar, MIH (least severe)
-Causes: exposures (mat DM, statins, alc, retinoic acid) or heritable (chromosomal or syndromic/nonsyndromic single genes)
-Mortality high in newborns

Question 7

Tell me about septo-optic dysplasia

Answer 7

-Rare disorder of early brain development that affects the eyes, pituitary gland, and septum pellucidum, the thin membrane that separates the brain’s hemispheres
-SOD plus= addtl brain malformation (ie schizencephaly)

Criteria (2 or more):
-Optic nerve hypoplasia
-Pituitary hormone abnormalities
-Midline brain abnormalities: absent septum pellucidum, agenesis of corpus callosum

-Etiology: genetic abnormalities identified <1% of pts
-Genes: HESX1, SOX2
-Increased prevalence of prenatal drug and alcohol abuse, and younger maternal age

Question 8

Tell me about PTEN related disorders

Answer 8

-Cowden
-Hemimegalencephaly/FCD
-Megalencephaly/ASD
-Bannayan-Riley-Ruvalcaba syndrome

Clinical features:
-Macrocephaly (>2 SD)
-ASD/DD
-Dermatological findings including lipomas, trichillemmomas, oral papillomas, penile freckling
-Vascular findings including arteriovenous malformations or hemangiomas
-GI polyps
-Pediatric onset thyroid cancer and germ cell tumors are recognized associations of Cowden and should provoke testing

Question 9

Tell me about lissencephaly

Answer 9

-Abnormal gyration and lamination
-Defects due to abnormal neuronal migration or insult near the end of 3rd/4th month gestation
-Some genes: LIS1, DCX, TUBA1A, ARX, ACTB, ACTG1, RELN

-Isolated lissencpehaly: lissencephaly with no dysmorphic features
-Miller-Dieker syndrome, Walker-Warburg syndrome

Question 10

Tell me about Dandy Walker malformation

Answer 10

-Congenital brain malformation where two hemispheres of cerebellum don’t form correctly
-ID: 50%, associated CNS abnormalities, timing and adequacy of hydrocephalus treatment
-Presents with hydrocephalus, DD, ataxia
-Causes: many genetic/chromosome conditions, environmental exposures (prenatal rubella or alc, congenital infections)

Question 11

Tell me about Joubert syndrome

Answer 11

-Brain malformation syndrome, ciliopathy
-Hallmark feature is molar tooth sign
-Features: hypotonia, ataxia, ID, abnormal eye movement, abnormal breathing patterns
-AR, genetic heterogeneity
-Other features: retinal disease, colobomas, renal disease, hepatic fibrosis, polydactyly

Question 12

Tell me about Alzheimer’s disease

Answer 12

-Irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out simple tasks of everyday living
-Most individuals symptom onset in 60s
-Causes toxic deposits of proteins form abnormal beta amyloid plaques which impede neuron function
-Divided into familial, sporadic, early onset (<65yo) and late onset (>65yo)

-Most (75-85%) AD is sporadic
-Sporadic defined as an isolated case in the family or cases separated by more than 3 degrees of relationship
-15-25% familial: characterized by disease occuring in more than one individual and at least 2 affected individuals are third degree relatives or closer
-Overall <5% AD inherited in AD manner
-families with AD AD characterized by disease that occurs in at least 3 individuals in 2+ generations with two of the individuals being first degree relatives of the third person. These cases are almost exclusively early onset

-Genes: PSEN1, APP, PSEN2, unknown

APOE allele
-e4 allele associated with increased AD risk in dose dependent matter, single e4 allele increases lifetime risk 2-3X, two e4 increase risk 15X (however not everyone with AD has e4 allele)
-e2 allele thought to be protective

Genetic testing: panel, WES/WGS, other susceptibility genes not recommended

Question 13

Tell me about Parkinson’s disease

Answer 13

-Progressive neurological condition
-More common in Hispanic and white populations compared to Asian and Black
-Can be caused by mendelian (single gene) disorders but is more commonly non-Mendelian (combo of environment, genes, trauma, unknown)
-Most cases non-Mendelian
-Most individuals symptom onset 60yo, onset, onset <20yo considered juvenile onset, onset <50yo considered early onset, onset >50yo considered late onset

Clinical features:
T: tremor
R: rigidity
A: akinesia
P: postural instability

Juvenile cases typically due to AR inheritance, otherwise typically AD with reduced penetrance

Testing: panel typically

Question 14

Having a first degree relative with non-Mendelian Parkinson’s increases the lifetime risk to develop by approximately how much?

Answer 14

Increases lifetime risk 3-7%

Question 15

What percent of Parkinson’s is due to monogenic inheritance?

Answer 15

5-10%

Question 16

Tell me about ALS (amyotrophic lateral sclerosis)

Answer 16

-Nervous system disorder
-Categorized as either sporadic (most cases 90%) or familial (10% cases)
-Even in sporadic cases, increased risk for first degree relatives (8 fold risk increase compared to gen pop)
-Features: parkinsonism, chorea, issues w balance swallowing speech vision ovement, behavioral and cognition impairment, memory loss, frontotemporal dementia
-Muscle atrophy and weakness spread to other regions of pody, eventually become “locked in” as facial muscles and movement are paralyzed
-Wide variability in progression, survival, and presentation
-Mortality: weakness of respritory mnuscles, bleed/clot, arrhythmia

-Avg age onset 55 for males and 65 for females
-Early onset is <55-65yo

-AD inheritance most common, AR rare, X-linked very rare
-C9orf72 gene, hexanucleotide repeat expansion (other genes also)
-Testing should begin with C9orf72 unless known variant, WES/WGS considered if intial testing negative and highly sus

Question 17

About what percent of AD, PD, and ALS have a monogenic cause?

Answer 17

<5-10%

Question 18

AD, PD, ALS are all progressive disorders. Which of these generally progresses quickly and which generally progress slowly?

Answer 18

Quickly:
-ALS
-Some forms of PD

Slowly:
-AD
-Some forms of PD

Question 19

Tell me about epilepsy

Answer 19

Disorder defined by any of the following conditions:
-At least two unprovoked/reflex seizures occurring more than 24hrs apart
-One unprovoked seizure AND a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures occurring over the next 10yrs
-Diagnosis of an epilepsy syndrome

-Causes of epilepsy: genetic, structural (tumors, stroke, trauma, vascular malformations), metabolic, immune, infections, medication reactions

Syndromes associated with epilepsy:
-Rett
-Angelman
-TSC
-Lissencephaly (LIS1)
-Wolf-Hirschhorn
-Metabolic and mito disorders

-Monogenic seizure disorders caused by genes that affect ion channels or neurotransmitters, “channelopathies”
-Ex: SCN1A, SLC2A1, etc

-Can also be due to CNVs or structural malformations (hydrocephalus, holoprosencephaly, anencephaly, etc)

Question 20

Tell me a little bit about anencephaly and neural tube defects

Answer 20

-Complete etiology of most NTDs not understood
-Anencephaly and spina bifida are related genetically and in pathogenesis
-May occur as part of chromosome abnormality and other severe malformation syndromes (ex: Meckle Gruber)