Medicine:Syndromic autism

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Syndromic autism (or syndromic autism spectrum disorders) denotes cases of autism spectrum disorder that are associated with a broader medical condition, generally a syndrome. Cases without such association, which account for the majority of total autism cases, are known as non-syndromic autism (or non-syndromic autism spectrum disorders).

Studying the differences and similarities (e.g. common pathways) between syndromic and non-syndromic cases can provide insights about the pathophysiology of autism and pave the way to new autism therapies.[1][2][3][4]

Syndromic autism

Autism spectrum disorder (ASD) is referred to as syndromic when it is one of the many characteristics associated with a broader medical condition, generally a syndrome.

Syndromic autism represents about 25% of the total ASD cases.[4][5] In most[quantify] cases, its etiology is known.[2][4]

Monogenic disorders are one of the causes of syndromic autism, which in this case are also known as monogenic autism spectrum disorders. They account for about 5% of the total ASD cases.


Non-syndromic autism

Non-syndromic autism, also called classic autism or idiopathic autism (as in most cases, the etiology is unknown), represents the majority of total autism cases.


Classification

A 2017 study[relevant? ] proposed to replace the classification "syndromic"/"non-syndromic" ASD into one based on the genetic etiology of the condition, specifying if the syndromic condition occurs in the context of a "phenotype first" clinically defined syndrome or from a "genotype first" molecularly defined syndrome.[4][clarification needed]

Following the proposal, ASD would be divided into three genetic categories:[4]

Clinically defined

Syndromes recognized by clinicians (depending on their experience), typically confirmed by a targeted genetic testing.

Molecularly defined

Syndromes recognized by genome-wide testing, not by hypothesis-driven testing (since clinical recognition is difficult).

  • Chromosomal (e.g.: isodicentric 15q)
  • ASD-risk genes (e.g.: ADNP, ARIDB1B, ANK2, SCN2A)
  • ASD-associated CNVs (e.g.: 16p11.2 deletion/duplication, exonic NRXN1 deletions)

Currently undefined

Currently undefined.[clarification needed]

Characteristics of syndromic ASD conditions
Condition Cause Chromosome(s) involved (if a mutation) ASD prevalence (95% CI) Clinically/Molecularly defined Other characteristics Template:Refh
Fragile X syndrome Monogenic disorder:
FMR1 (encodes FMRP)
X  30% (20.0–31.0) [male individuals only]
 22% (15.0–30.0) [mixed sex]
14% (13–18) [female individuals only]
Clinically defined [in some males] Long/narrow face, macroorchidism, long ears and philtrum, mild to moderate intellectual disability, hyperactivity, intellectual disability (ID), seizures [1][3][4][6]
Rett syndrome Monogenic disorder:
MECP2
X 61.0% (46.0–74.0) [female individuals only] Clinically defined Microcephaly, breathing irregularities, language deficits, repetitive/stereotyped hand movements, epilepsy, ID [1][3][4]
MECP2 duplication syndrome Monogenic disorder:
MECP2
X 100% [in a single study composed by 9 male participants] Clinically defined Brachycephaly, spasticity, recurrent respiratory infections, gastrointestinal hypermotility, genitourinary abnormalities, epilepsy, ID [1][4][7]
Tuberous sclerosis complex Monogenic disorder:
TSC1
TSC2
9
16
 36.0% (33.0–40.0) Clinically defined Benign tumours in multiple organs, epilepsy [1][3][4]
Angelman's syndrome Monogenic disorder:
UBE3A
15  34.0% (24.0–37.0) Cheerful demeanour, microcephaly, epilepsy, speech deficits, sleep disturbance, epilepsy, ID [1][3]
Phelan-McDermid Syndrome Monogenic disorder:
SHANK3
22  84% [in a single study composed by 32 participants] Molecularly defined [4][8]
Timothy syndrome Monogenic disorder:
CACNA1C
12  80% [in a single study composed by 17 participants] Clinically defined [4][9]
Smith-Lemli-Opitz syndrome Monogenic disorder:
DHCR7
11 55% [in a single study composed by 33 participants] [10]
Neurofibromatosis type I Monogenic disorder:
NF1
17  18% (9.0–29.0) Clinically defined [3][4]
PTEN hamartoma tumor syndrome Monogenic disorder:
PTEN
10  17% (8–27) Clinically defined [4][11]
Down syndrome Chromosomal disorder:
trisomy 21
21 16% (8.0–24.0) Clinically defined [3][4]
Cohen's syndrome Monogenic disorder:
VPS13B
8  54% (44.0–64.0) Clinically defined [3][4]
Cornelia de Lange syndrome Polygenic disorder  43% (32.0–53.0) Clinically defined [3][4]
CHARGE syndrome Monogenic disorder:
CHD7
8  28% (16–41) Clinically defined [4][12][13]
Noonan's syndrome Polygenic disorder  15% (7.0–26.0) [3]
William's syndrome Microdeletion syndrome:
7q11.23
7  12% (6.0–20.0) [3][14]
22q11.2 deletion syndrome Microdeletion syndrome:
22q11.2
22 11% (5.0–19.0) Clinically defined [3][4]
Fetal Valproate Spectrum Disorder Teratogen:
valproate
 8–15% [in VPA exposed children] Clinically defined [4][15][16]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 Benger, Matthew; Kinali, Maria; Mazarakis, Nicholas D. (December 2018). "Autism spectrum disorder: prospects for treatment using gene therapy". Molecular Autism 9 (1): 39. doi:10.1186/s13229-018-0222-8. PMID 29951185. PMC 6011246. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011246/. Retrieved 26 May 2023. 
  2. 2.0 2.1 Sztainberg, Yehezkel; Zoghbi, Huda Y (November 2016). "Lessons learned from studying syndromic autism spectrum disorders". Nature Neuroscience 19 (11): 1408–1417. doi:10.1038/nn.4420. PMID 27786181. https://www.nature.com/articles/nn.4420. Retrieved 4 June 2023. 
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Richards, Caroline; Jones, Christopher; Groves, Laura; Moss, Jo; Oliver, Chris (October 2015). "Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis". The Lancet Psychiatry 2 (10): 909–916. doi:10.1016/S2215-0366(15)00376-4. PMID 26341300. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00376-4/fulltext. Retrieved 27 May 2023. 
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 Fernandez, Bridget A.; Scherer, Stephen W. (31 December 2017). "Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach". Dialogues in Clinical Neuroscience 19 (4): 353–371. doi:10.31887/DCNS.2017.19.4/sscherer. PMID 29398931. PMC 5789213. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789213/. Retrieved 4 June 2023. 
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  9. Splawski, Igor; Timothy, Katherine W.; Sharpe, Leah M.; Decher, Niels; Kumar, Pradeep; Bloise, Raffaella; Napolitano, Carlo; Schwartz, Peter J. et al. (October 2004). "CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism". Cell 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078. https://linkinghub.elsevier.com/retrieve/pii/S0092867404008426. Retrieved 29 May 2023. 
  10. Thurm, Audrey; Tierney, Elaine; Farmer, Cristan; Albert, Phebe; Joseph, Lisa; Swedo, Susan; Bianconi, Simona; Bukelis, Irena et al. (December 2016). "Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update". Journal of Neurodevelopmental Disorders 8 (1): 12. doi:10.1186/s11689-016-9145-x. PMID 27053961. PMC 4822234. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822234/. Retrieved 31 May 2023. 
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  15. Bromley, Rebecca; Weston, Jennifer; Adab, Naghme; Greenhalgh, Janette; Sanniti, Anna; McKay, Andrew J; Tudur Smith, Catrin; Marson, Anthony G (30 October 2014). "Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child". Cochrane Database of Systematic Reviews 2020 (6). doi:10.1002/14651858.CD010236.pub2. PMID 25354543. PMC 7390020. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010236.pub2/full. Retrieved 29 May 2023. 
  16. Clayton-Smith, Jill; Bromley, Rebecca; Dean, John; Journel, Hubert; Odent, Sylvie; Wood, Amanda; Williams, Janet; Cuthbert, Verna et al. (December 2019). "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability". Orphanet Journal of Rare Diseases 14 (1): 180. doi:10.1186/s13023-019-1064-y. PMID 31324220. PMC 6642533. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642533/. Retrieved 27 May 2023.