THIS PROJECT AIM AT UNDERSTANDING THE NEURODEVLEOPMETAL DISORDERS IN CHILDREN AND APPLICATION OF THIS KNOWLEDGE IN TREATMENT OF THESE DISORDERS

1. MOTIVATION LETTER
Genetic and Molecular Basis of
Neurodevelopmental Disorders
Neurodevelopmental disorders are disabilities in the functioning of
the brain that affect a child’s behavior, memory or ability to learn e.g. mental
retardation, dyslexia, attention deficit hyperactivity disorder (ADHD),
learning deficits and autism [1,2].
FIG -1: Depicting normal embryological development. Red indicates sensitive stages
in development and yellow indicates stages that are less sensitive to teratogens[3].
Neurodevelopment begins in the early prenatal stage with a complex
neurological development that begins with proliferation of radial glia and
neurons. These continue to develop in the postnatal years. This process is

2. not complete until almost 3 years of age.
Migration of neurons, which occurs from the 2nd to the 6th month of
gestation, and again within the cerebellum postnatally, is a very important
and complex process. Synapse formation, which occurs essentially in the
last trimester as well as in the first 2 years of life, is critical to ongoing
functioning and development. Myelination is an important process that
begins in the second half of gestation and goes on to adolescence, with
different systems myelinating at different times, as shown in figure-2
Figure -2 depicting neuronal development at various stages [4].

3. Figure 3: The determinants of Neurodevelopmental process is
depending multiple factors [5].
Neurodevelopmental behavioral disorders occur most commonly in
industrialized countries. Nearly15% of children is described as having
learning disabilities, developmental delay, attention deficit hyperactivity
disorder, autism, reduced intelligence quotient and cerebral palsy.
Major subclasses of neurodevelopmental disorders:
 Intellectual disability Learning disabilities
 Communication disorders
 Autism spectrum disorders

4.  Neurobehavioral disorders
 Neurogenetic disorders Neurometabolic disorders
 Neuromuscular disorders Cerebral palsy
 Other neuromotor disorders Sensory impairments
 Disabilities associated with chronic diseases Traumatic brain injuries
Spinal cord injuries
The majority of children with neurodevelopmental disorders are delayed in
language milestones and many are later diagnosed with language
impairments.
Genetics play an important role in many neurodevelopmental
disorders. However, most neurodevelopmental disorders are multifactorial
in nature. These disorders likely result from a combination of genetic,
biological, psychosocial and environmental risk factors. A broad range of
environmental risk factors may affect neurodevelopment, which are
maternal use of alcohol, tobacco, or teratogenic drugs during pregnancy,
lower socioeconomic status, preterm birth, low birth weight and prenatal or
childhood exposure to certain environmental contaminants.
Lead, methylmercury, and PCBs are widespread environmental
contaminants associated with adverse effects on a child’s developing brain
and nervous system in multiple studies. The National Toxicology Program
(NTP) has concluded that childhood lead exposure is associated with

5. reduced cognitive function, including lower intelligence quotient (IQ) and
reduced academic achievement. The NTP has also concluded that childhood
lead exposure is associated with attention-related behavioral problems
(including inattention, hyperactivity, and diagnosed attention-
deficit/hyperactivity disorder) and increased incidence of problem
behaviors (including delinquent, criminal, or antisocial behavior).
Figure 4: depicting various environmental factors disturbing the
development of normal neurodevelopmental process [6].
Autism Spectrum Disorders:

6. Autism spectrum disorders (ASDs) are a group of developmental disabilities
characterized by significant deficits in social, communication, and
behavioral domains. Autistic disorder, Asperger syndrome, and pervasive
developmental disorder are the three ASDs. Persons who have autistic
disorder have significant language delays, social and communication
challenges, and unusual behaviors and interests Research on the genetic
contributions to complex disorders remained minimal until recent years.
The understanding of these neurobehavioral disorders has undergone a
remarkable shift in the past decade, with a surge of research exploring the
genetic basis of these traits and conditions. Momentous discoveries were
first made in heritability estimates and have progressed to the identification
of specific genetic linkages associated with language impairments across a
number of neurodevelopmental disorders.
The initial question of interest was to what degree language
impairment or ASD was due to environmental versus genetic factors. Twin
studies provided our first insights into understanding question, through the
comparison of concordance rates across monozygotic (MZ) and dizygotic
(DZ) twins. Several studies indicated that concordance rates for MZ twins
exceeded those for DZ twins across both Specific language impairment (SLI)
and ASD populations.

7. In SLI, concordance was found in 70–96% of MZ and 48–69% of DZ
twins. In studies of ASD, the most recent MZ concordance rates hover
between 50 and 77%, while DZ twins showed around 25– 36%
concordance.
From these studies, researchers concluded that both these conditions
are highly heritable, pointing to the role of genetic variation in
neurodevelopmental disorders characterized by language and
communication impairments. A study by Fisher et al., 1998, discovered that
FOXP2, a gene associated with severe speech impairment, on chromosome
7q31, created ripples through the genetic research community, which led to
more research on genetic basis of neurodevelopmental disorders [7]
Approximately 30% of children with epilepsy have autism and/or
intellectual or developmental disabilities. Epileptogenesis is a process that
proceeds over months to years in humans. After an initial precipitating
event such as a prolonged febrile seizure or head trauma, there are
processes that occur very rapidly including ion channel activation,
posttranslational changes, and immediate early genes.
Next, over a period of days to weeks, there are transcriptional events,
neuronal death, and inflammation. Sprouting, network reorganization,
neurogenesis, and gliosis occur over the ensuing weeks, months, and years.
These processes may lead to the development of the first spontaneous seizures,

8. and then be recapitulated with each seizure, resulting in perpetuation or
progression of epilepsy.
Table 5- some of the genes implicated in the epilepsy [8].

9. Table-6: The various routes to an epilepsy phenotype can result from gene
defects affecting multiple levels of neuronal function [9].

10. Table 7: Steps in finding and understanding a novel epilepsy gene which can
b targeted for anti epileptic treatment.[9]

11. CONCLUSION:
We have made great progress since last decade in targeting human
epilepsy genes that has been phenomenal. Many gene defects and
mechanisms can result in a single phenotype, whereas many differing
phenotypes may result from a single gene defect. Some gene defects alter
specific physiologic mechanisms involved in seizure production, such as
ionic-channel function or neurotransmission. Few Other gene defects
produce more diffuse alteration of neuronal function, such as abnormal

12. development of neuronal structure or synaptic connectivity, altered intra-
cellular signaling, failure of cytoprotective systems, mechanisms, or
disrupted cellular metabolism which resultant in neuronal degeneration.
Development of constructs for region-specific gene expression linking
genotype to the phenotype and at the same time clinically refining the spectrum
of the epilepsies will provide a neurobiologic basis and mechanistic
understanding of the human epilepsies. The challenge to clinicians and
neurobiologists is to unravel this tangled web and translate these advances into
practical applications for early diagnosis, genetic counseling, and innovative
therapies for persons with epilepsy.
References:
.1The diagnostic and statistical manual of mental disorders. 5th ed.
Washington, DC: The American Psychiatric Association; 2013.
2. Kliegman RM, Stanton B, St Geme J, Schor N, Behrman RE. Nelson
textbook of pediatrics. 19th ed. Philadelphia: Saunders Elsevier; 2011.
3.Reprinted from Moore. The developing human. Elsevier Inc., 1973.
4.Rice D, Barone Jr S. Critical periods of vulnerability for the developing
nervous system: evidence from humans and animal models. Environmental
Health Perspectives, 2000, 108(S3):511-533.

13. 5. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial
chemicals. Lancet, 2006, 368(9553):2167- 2178.
6. Rice D, Barone Jr S. Critical periods of vulnerability for the developing
nervous system: evidence from humans and animal models. Environ Health
Perspectives, 2000, 108(S3):511-533.
7.Pears KC, Fisher PA 2005 Emotion understanding and theory of mind
among maltreated children in foster care: evidence of deficits. Dev
Psychopathol 17:47– 65.
8. Ortrud K. Steinlein GENETIC MECHANISMS THAT UNDERLIE EPILEPSY
NEUROSCIENCE, VOLUME 5 | MAY 2004,400-408.
9. Asuri N. Prasad, Progress in Epilepsy Research;Recent Advances in the
Genetics of Epilepsy: Insights from Human and Animal Studies, epilepsia 40(
lO):I329-1352. 1999.