Neurodevelopmental Disorders (Autism)

Question 1

Overview of Brain
Development

Answer 1

• Neurodevelopmental disorders (NDDs) are
  common brain disorders, which arise when brain
  developmental processes are perturbed by
  various genetic and/or environmental factors.
• Historically, the NDD concept has been
  restricted to disorders in which perturbations are
  thought to occur during embryonic brain
  development, e.g., as for autism spectrum
  disorder, attention deficit hyperactivity disorder,
  and intellectual disability.
• However, with a better understanding of the
  maturational processes continuing up to early
  adulthood, disorders with a later age of onset,
  e.g., schizophrenia, are now also referred to as
  NDDs.
  Ref:10.1038/s41380-022-01876-1

Question 2

Overview

Answer 2

• Autism spectrum disorder (ASD)
  encompasses a group of neuro-
  developmental conditions diagnosed
  solely based on behavioral assessments
  that reveal social deficits.
• Broadly, ASDs have been classified into
  syndromic—Rett syndrome (RS), Fragile X
  syndrome (FXS), and tuberous sclerosis
  (TSC)—and nonsyndromic.
• Syndromic ASDs are typically associated
  with chromosomal abnormalities or
  mutations in a single gene and have
  clinical dysmorphic features.
• Patients diagnosed with ASD often
  present with other comorbidities such as
  intellectual disability (ID), epilepsy, and
  motor abnormalities

Question 3

ASD stats

Answer 3

• According to the CDC, around 1% of the world’s population has autism
  spectrum disorder – that is over 75,000,000 people.
• Prevalence of ASD among 8-year-old children has been estimated at 13–
  29 per 1000, and between 50–70 per 1000 in the general population.
• Prevalence is on the rise since 1970s.
• ASD is more prevalent in males than in females, with an overall male-
  female ratio of 4–5:1.

Question 4

Genetics of ASD

Answer 4

• The heritability of ASD is estimated to be approximately 80% (Bai
  et.al. 2019).
• ASDs have been typically classified into syndromic and nonsyndromic,
  a distinction that is exclusively based on clinical criteria.
• The term “syndromic” refers to conditions in which ASD occurs in
  conjunction with additional phenotypes and/or dysmorphic features.
• For these conditions, the etiology in most cases is known and can
  involve chromosomal abnormalities, submicroscopic copy number
  variations, and mutations in a single gene, such as in fragile X
  syndrome (FXS), Rett syndrome (RTT), MECP2 duplication syndrome
  (MDS), tuberous sclerosis complex (TSC), and PTEN macrocephaly
  syndrome.
• These monogenic syndromic disorders are rare, and none of these
  genes can explain more than 1–2% of ASD cases, but together they
  are estimated to represent ∼5% of ASD cases.
• The term “nonsyndromic” typically refers to ‘classic autism’ as it was
  described by Kanner, in which no additional symptoms are present.
• For most nonsyndromic ASD cases the etiology is unknown, and the
  term “idiopathic autism” has been used alternativel

Question 5

Fragile X Syndrome

Answer 5

• First described by Martin and Bell in 1943, FXS is the most
  frequent form of inherited intellectual disability in boys and the
  most common monogenic cause of syndromic ASD.
• The disorder is characterized by cognitive disability, delayed or
  absent speech, autistic features, attention deficit, hyperactivity,
  anxiety, a high incidence of epilepsy, and macroorchidism.
• FXS accounts for about 2% of all ASDs and about 30–60% of
  males with FXS meet the diagnostic criteria for ASD (FXS ASD).
• FXS is caused by an expansion of a CGG triplet repeat in the 5′
  UTR of the FMR1 gene, leading to hypermethylation of its
  promoter and a shutdown of its transcriptional product FMRP.
• FMRP is an RNA-binding protein that regulates the translation,
  stability, and transport of several mRNAs encoding proteins
  (e.g., SHANK3, PSD-95 ) that are essential for synaptic plasticity
  and have been associated with increased risk of ASD.
• The current model: total absence of FMRP causes upregulation
  of metabotropic glutamate receptor 5 (mGluR5) signaling (the
  so-called ‘mGluR theory of FXS’), a parallel inhibition of the
  GABAA receptor pathway, and dysregulation of proteins related
  to synaptic plasticity, together leading to excitation/inhibition
  imbalance and abnormal connectivity typical of ASD.

Question 6

Rett syndrome

Answer 6

• In 1966, Andreas Rett first reported on a series of 22
  young female patients with similar characteristics. The
  syndrome later came to bear his name.
• RTT is a progressive neurological disorder usually caused
  by loss-of-function mutations in the methyl-CpG-binding
  protein 2 (MECP2) gene.
• RTT affects ∼1 in 10,000 female live births and is
  characterized by 6–18 months of normal development
  followed by rapid regression, autistic features, loss of
  purposeful hand use and language skills, cognitive deficits,
  motor impairments, breathing abnormalities, seizures, and
  acquired microcephaly.
• The wide interest in RTT increased in 1999 when it became
  the first sporadic ASD with a defined genetic etiology.
• At the cellular level, in both RTT and classic autism the
  pathological deficit involves abnormal dendritic synaptic
  function, suggesting the possibility of common molecular
  and cellular mechanisms.
• Several deficits can be reversed upon reactivation of
  MeCP2 expression in adult Mecp2 knockout mice.

Question 7

Complex
Genetics of
Idiopathic ASD

Answer 7

• More than 400 high confidence genes have been
  associated with idiopathic ASD.
• Most of these gene products functionally cluster
  around synaptic regulation or chromatin remodeling
  and gene expression.

Question 8

Cell Biology
of Autism

Answer 8

• E/I imbalance is a long-favored hypothesis as an ASD etiology.
• Hypofunction of interneurons in the pathogenesis of autism: (1) the density
  of PV INs is reduced; (2) the expression levels of PV protein are lower; (3) the
  density of PNNs around INs is decreased; (4) the power of baseline gamma
  oscillations (regulated by PV and SST INs) is increased; and (5) the activity of
  PV INs is decreased.

Question 9

GxE in ASD

Answer 9

• The concordance rate of AD in monozygotic twins is
  incomplete, suggesting a contribution of environmental
  factors. Refer: 10.1001/archgenpsychiatry.2011.76
• Environmental factors could be prenatal, perinatal, or
  postnatal.
• Prenatal risks: advanced paternal and maternal age at
  birth, gestational diabetes, gestational alcohol
  consumption, recreational drugs, and in utero exposure
  to known teratogenic medications (thalidomide,
  valproate), acetaminophen and SSRIs. Additional risks
  from nutritional deficiency (e.g., folate).
• Perinatal risks: preterm birth
• Postnatal risks: air pollution in early life, environmental
  pollutants, endocrine disruptors (e.g., BPA) and
  neurotoxins, profound early social deprivation, etc.
  Ref: 10.3390/epigenomes6020015
  Below: Chemical–protein interaction
  network of ASD-associated cognitive
  phenotype genes that presents 904
  chemical–gene–ASD interactions for
  the 118 cognition-specific proteins
  (blue label) with 39 chemicals.
  Bisphenol A (BPA), valproic acid (VPA),
  acetaminophen, lead, and arsenic are
  the five high-degree chemicals