Neurodevelopmental disorder (NDDs) is a term used for describing a range of disorders that involve injuries to the developing brain, such as cerebral palsy and genetic disorders, and also intellectual disability and other conditions that lead to functional limitations such as impaired cognition, motor performance, vision, hearing, speech, and behavior problems leading to impairments in personal, social, academic, or occupational functioning Rahman A et al. (2002); Behrman R (2007). This article explores various aspects of Neurodevelopmental Disorders (NDDs) in Nepal.

Neurodevelopmental disorders typically manifest early in life and persist into adulthood. This article explores the evolution of the term, the disorders classified under this category, their demographics, etiological factors, brain areas involved, and findings from neurological studies.

These include a range of disorders / conditions like Autism Spectrum Disorder (ASD), Attention Deficit/Hyperactivity Disorder (ADHD), Intellectual Disability, Specific Learning Disorders (SLD)s among others. These disorders typically manifest early in life and persist into adulthood. This article explores the evolution of the term, the disorders classified under this category, their demographics, etiological factors, brain areas involved, and findings from neurological studies.

There is a lack of epidemiological data on Neurodevelopmental Disorder (NDD) prevalence in low- and middle-income countries (LMIC) Bitta, M et al (2018), but it is estimated that between 93 and 150 million children suffer from some kind of disability, and most of these live in low-income countries WHO 2011; UNICEF 2020. Children with disabilities are often not represented in official statistics and as a result remain politically and socially “invisible” UNICEF, 2020. Overall, NDD conditions are likely to be more common in low- and middle-income countries (LMIC) because of the higher prevalence of recognized risk factors such as poor maternal and child healthcare in the prenatal and postnatal period, nutritional deficiencies, and neonatal infections.

Nepal has a difficult geography and infrastructure, and accessibility to roads is limited in many parts of the country. Eighty percent of the population lives in rural areas, and 40% of women are illiterate. It is among the poorest countries in the world, with about a quarter of its population living below the poverty line (Central Intelligence Agency, Nepal, 2021). Studies have shown that the prevalence of mental illness such as depression in Nepal is similar to the prevalence in the developed world (Wright, C, Nepal, MK, 1989;) (Simpson, P.L et al, 1996.)

Neurodevelopmental disorders include a variety of conditions, each with distinct features:

Autism Spectrum Disorder (ASD): Neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors

Attention-Deficit/Hyperactivity Disorder (ADHD): Involves inattention, hyperactivity, and impulsivity.

Specific Learning Disorders (SLDs): Difficulties in reading, writing, or mathematics.

Intellectual Disability:  A neurodevelopmental condition that affect cognitive adaptive functioning

Children born with Neurodevelopmental Disorders have difficulty in various domains of their life, mainly their impairment in cognitive abilities, deficiencies in language development and fluency, and their abilities in forming social bonding with peers and family members put a high level of distress grasping the fact that their children have the condition and then dealing with the repercussions of the disorders. This put a significant toll on the parents’ psychological wellbeing and daily life. In a country like Nepal where resources are scarce and poverty is prevalent, raising a child with neurodevelopmental disorder in Nepal is a daunting task.

There are studies showing that over 90% of parents report signs of psychological distress with half reporting severe anxiety and two-thirds reporting clinical depression (Bitsika & Sharpley, 2004).

In a systematic review conducted by Ilias et al. (2018), it was found that there are six major factors associated with parenting stress: financial challenges, concerns about the child’s future, social support, severity of autistic symptoms, and religious beliefs.

Adjusting to the demands of the child with these conditions is a daunting task and compromises and sacrifices having to be made in rearing these children puts a huge psychological, behavioral, financial and social toll on not only the parents but the schools where these children end up studying.

Raising a child with a neurodevelopmental disorder, the educational, social and financial challenges and burden parents have to go through results in burnout over the years, leading to higher rate of anxiety and depression, increased stress, and reduced quality of life. Desimpelaere et al. (2023); Maridal HK et al. (2021)

Most of the schools are not equipped to cater for the demands and needs of such children and put them in the average, regular lot where it becomes a burden on the children already suffering from a condition and then the demands of the scholastic tasks, roles and responsibilities. Adjusting to other “normal” children studying in the same class and school and fulfilling, often unrealistic and completely naive teachers who most of the time are not even aware of the conditions and the challenges faced by such students.

Etiologies

Neurodevelopmental disorders (NDDs) are thought to arise from multifactorial etiology. Disruptions in brain development leading to cortical malformations, disruptions in synaptic plasticity, imbalances in neurotransmitter such as dopamine and serotonin, and functional alterations in brain regions such as prefrontal cortex, amygdala and others are implicated. Genetic and environmental factors are also shown to play major roles in the development of these conditions. All of these factors play and intricate role leading in dysfunctions in the way brain develops and functions resulting in impairment of cognitive, behavioral and motor skills of children.

The number of children with Autism Spectrum Disorder (ASD) is reportedly increasing by 10,000 cases per year in Japan and similar rise of cases are seen in the US and Korea^{14,15,16,17,18}. Although exact data is scant, Nepal is also experiencing a net rise in the ASD cases reported to various health institutions around Kathmandu and elsewhere.

These sudden rise in the incidences and prevalences of ASD, a neurodevelopmental disorder, cannot be explained by genetic factors alone because there is no reason to suspect that mutation rates have suddenly increased in recent years. Rather, a more likely explanation is that environmental factors are involved¹⁹.

Role of Epigenetic principles in NDD

Epigenetic modifications offer one mechanism by which environmental factors might lead to changes in population health²⁰. This is partly supported by studies in twins showing that environmental factors contribute to the occurrence of autism^21,22,23. Epigenetic gene control is an essential mechanism for normal brain development. Abnormalities in the molecules associated with this process cause various congenital diseases.

It is notable that defects in epigenetic phenomena and epigenetic molecules involved in gene regulation result in congenital neurological features and mental retardation¹⁹.

Genes are believed to be expressed equally between the maternal and paternal chromosomes. However, an exceptional phenomenon, i.e., genomic imprinting, has been discovered that is the result of an epigenetic gene regulation mechanism. For an imprinted gene, one of the two parental alleles is active and the other is epigenetically inactivated

Therefore, a defect in the active allele of the imprinted gene results in the loss of expression. This has been found in some neurodevelopmental diseases, including Angelman syndrome, which is characterized by severe mental retardation and epilepsy, and Prader-Willi syndrome, which is characterized by neurocognitive deficits, excessive daytime sleepiness, muscle hypotonia, short stature, small hands and feet, hypogonadism, hyperphagia and obesity that leads to type 2 diabetes²⁴. The figure in the right is an illustration of the epigenetic principal in NDDs such as Intellectual Disabilities.

The nervous system in NDDs

NDDs comprise of a heterogenous group of disorders characterized by a plethora of clinical phenotypes such as cognitive impairments, communication deficits, impaired psychomotor skills, and inability to reach developmental milestones²⁶.

Malformation of development of the cerebral cortex are a common feature of most NDDs notably Autism Spectrum Disorder (ASD) and Attention Deficit and Hyperactivity Disorder (ADHD), Intellecutal Disability, Communication Disorders, Neurodevelopmental motor, learning and speech disorders.  Inter-comorbidity among these disorders are very common for example individuals with ASD aslo more likely to have comorbid ID. Also, importantly ASD and ID often exhibit MCDs (Microcephaly and macrocephaly) which are a wide spectrum of cortical abnormailities²⁷. MCDs clinical manifestations include epilepsy, autistic features, ID and developmental delay, coupling MCDs with neuropsychiatric disorders. For example, individuals with Rett Syndrome present microcephaly and ASD at the same time, while in Seckel and Angelman syndrome patients exhibit microcephaly and ID²⁸. Patients with Prader-Willi²⁹ and Timothy syndrome³⁰ suffer from both ID and ASD, while in Fragile X syndrome characteristics of ASD, ID, and ADHD are present simultaneously. Interestingly, while monogenic causes predominate in MCDs, NDDs usually exhibit polygenic pathophysiology³¹.

Autism Spectrum Disorder (ASD) remains one of the most heterogenous NDD with more than 800 associated genes³². Some of the most well-studied monogenic syndromes correlated with ASD in humans are: Fragile X syndrome (FXS) (mutation in FMR1) (Sitzmann et al., 2018), Rett syndrome (RTT) (mutation in MECP2) (Meloni et al., 2000), and tuberous sclerosis (mutations in TSC1 and TSC2) (Bjornsson et al., 1996) DEPDC5, CACNA1A, and SCN8A, highly vulnerable genes the mutations of which make the child highly vulnerable to develop NDDs36.

The development of the cerebral cortex  early in the first trimester of gestation when neuroepithelial cells (NEs), the founder neural progenitor population located in the most rostral part of the neural tube, divide symmetrically to expand the neuroepithelial area (Subramanian et al., 2017).

Centers in Nepal which offer diagnostic and professional help for NDDs

Psychiatric Department of Kanti Children’s Hospital is the government funded health facility which provides services for various mental health conditions including neurodevelopmental disorders at very affordable price. besides this there are NGOs such as CMC Nepal and CPH Nepal, TPO Nepal and PsychologyNepal where licensed mental health professionals are present to provide services which cater to different age groups and different mental health conditions. Institute of Medicine is another government funded hospital which provide mental health services.

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