Autism and Dev Delay Flashcards
Define the clinical definition of ASD
- clinically heterogeneous group
- complex behavior disorders that develop before 3yo
- char by imparitment sin social interaction, communication, and repetitive behaviors
- dx at age 2y –> reliable and stable
- median age dx = 3y10m
What is current prevalence of autism?
1/150 in 2000-2002
1/68 in 2010-2012
1/59 = latest CDC stat
–> boys = 4x more likely
more than doubling now –> bc earlier age dx + including milder cases; not know if true occurrence is up
What percentage of those with autism have ID?
31%
(25% borderline, 44% average -above average)
What are some maternal exposures that can increase risk for autism?
- maternal medications:
valproate (seizure med)
thalidomide (can treat leprosy or used in combo w other for mult myeloma)
misoprostol
What are some prenatal infections that can increase risk for autism?
TORCH
Rubella
What is the breakdown of known causes for autism?
> 70% unknown
7-20% CNVs
5-7% Single-gene disorders
<5% Metabolic disorders
The spectrum of autism is comprised of what classifications?
idiopathic/isolated
- essential = no phys abnorma –> 70% cases
- complex = syndromic w dysmorphic features, major malform, and/or microcephaly –> 20-30% cases
secondary = cases where we can identify chromo abnorm, single-gene disorders, or environ agent
Incidence of autism is highest in what 2 genetic syndromes?
- Down Syndrome –> 16.5%
- 22q11.2 del syndrome –> 20%
What is the prevalence of Fragile X?
1/1000 males
1/700 females
Fragile X accounts for what percentage of X-linked ID and what percentage of autism?
25-50% X-linked ID
1-5% autism
What is the cause of Fragile X?
expanded CGG trinuc repeat (>200) in FMR1 gene on Xq27.3
What are clinical features of Fragile X in males?
- slightly inc birth weight
- macrocephaly
- long face, large ears
- macro-orchidism - post pubertal (large testes)
- lax joints
- MVP/Aortic dilation - post pubertal
- DD/Autism –> 50-70%
- periventricular heterotopia + other neuroradiologic abnorm
(bc expressed in brain + soft tissue & can cause conn tissue + GI symp)
What are clinical features of Fragile X in females?
- prominent ears
- long, narrow face
- high arched palate
- hyperextenisble joints
- double-jointed thumbs
- single palmar crease
- flat feet
- murmur or systolic click
- milder dev symp
- POI
What are the breakdowns of Fragile X for CGG repeats?
6-50 = normal allele (30=peak # in gen pop)
50-200 = premutation
>200 = full mutation
full mut –> the FMR1 protein NOT produced at all bc full mut = fully methylated
What are ways to diagnosed Fragile X?
- order FX DNA test
- PCR w CGG probe
- Southern blot - digestion w EagI/EcoRI
What percent of autism is accounted for by Tub Scl?
1%
TS w SEGA (Subependymal giant cell astrocytoma (SEGA) brain tumor found in ~15% TS) have 2x risk of autism
What are main findings in Rett syndrome?
- normal dev from 6-12 months
- pd of regression
- loss hand movements
- sizures
- microcephaly
- ID
- Autistic features
- hand-wringing; bruxism
- hyperpnea; heart block
What percent of autism is accounted for by Tub Scl?
~1% autism cases/4% females
What is cause of Rett syndrome?
MeCP2 mut/del
CDKL5 –> atypical Rett
Males –> MeCP2 dup (otherwise lethal)
What percent of autism is accounted for by NF1?
rare
- common w ADHD and sometimes dev delay
What is Phelan-McDermid Syndrome + its rln to autism?
- microdel 22q13.3 (80%)
- intragenic del of SHANK3
- neonatal hypotonia
- normal - accel growth
- absent/v delayed speech
- global dd
- minor dysmorphic facial feat (Full brow, flat midface , ptosis, puffy eyelids, long eyelashes, wide nasal bridge, bulbous nose, puffy cheeks,
pointed chin, large/prominent ears) - Autistic behaviors
- mouthing non-food
- dec pain perception
What are some metabolic disorders associated with autism?
- PKU (if untreated)
- MPS III (Sanfilippo)
- Adenylosuccinase def
- Creatine def syndromes
- Mito disorders (more likely in pts w these feat: lactic acidosis, episodic regression, hypotonia, optic nerve atrophy, diabetes, hearing loss)
What percent of autism is accounted for by PTEN Hamartoma Tumor Syndrome?
1% autism cases
5% autism + macrocephaly
What percent of autism is accounted for by CNVs?
Recent CMA studies revealed copy number variants in 7-20% of ASD cases
What is the CMA diagnostic yield in patients w ASDs or ID?
15-20%
What is the most common del/dup that accounts for autism?
16p11.2 –> accounts for 1.1-1.2% cases
What was the main finding in “Rare CNV Variants in Autism Perturb Synaptogenesis”
they figured out that they can support hypoth that autism = mainly disease of synpatic + neuronal connectivity malfunction
What was the main finding in “Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder”
synaptic vesicle tranportation + cycling = imp in delivery of proteins to synapses in ASD
What are some epigenetic factors linked to autism?
(thinking about changes in chromatin state that reg gene exp w/o changing DNA OG seq)
- Rett syndrome –> MeCP2 gene binds to methylated DNA (so represses transcription of target genes)
- imprinted regions, sucha s mat 15q13.3 microdup
What is second tier w regard to testing autism according to ACMG?
- MECP2 seq –> for all females w ASDs
- MECP2 dup testing in males
- PTEN testing only if head circumf is >2.5 SD above mean
- Autism/ID panel (this is NOT pt of ACMG guidelines, but is realistic)
- Brain MRI only if certain indicators (like microcephaly, seizures, etc)
Among identical twins, if one child has ASD, then the other will be affected about ?% of the time
36-95%
In non-identical twins, if one child has ASD, then the other is affected about ?% of the time
0-31%
Parents who have a child with ASD have a ?% chance of having a second child who is also affected
10-15%
If there are two affected siblings, the recurrence risk is approximately ?% if the subsequent child is boy and ?% if the child is a girl.
50% for boy
12% for girl
