Neurodevelopmental disorder

Neurodevelopmental disorders are impairments of the growth and development of the brain or central nervous system. A narrower use of the term refers to a disorder of brain function which affects emotion, learning ability, self-control and memory and which unfolds as the individual grows.

Definition

Neurodevelopmental disorders^[1] are impairments of the growth and development of the brain or central nervous system. A narrower use of the term refers to a disorder of brain function that affects emotion, learning ability, self-control and memory and that unfolds as an individual develops and grows.

The term is sometimes erroneously used as an exclusive synonym for autism spectrum disorders.

Types

Disorders considered neurodevelopmental in origin include:

1. Intellectual disability (ID) or intellectual and developmental disability (IDD), previously called mental retardation
2. Autism spectrum disorders, such as Asperger's syndrome or Kanner syndrome
3. Motor disorders including developmental coordination disorder and stereotypic movement disorder Tic disorders including Tourette's syndrome
4. Traumatic brain injury (including congenital injuries such as those that cause cerebral palsy^[2])
5. Communication, speech and language disorders
6. genetic disorders, such as fragile-X syndrome,Down syndrome^[3], attention deficit hyperactivity disorder, schizophrenia, schizotypal disorder, hypogonadotropic hypogonadal syndromes^[4]
7. disorders due to neurotoxicants like Fetal alcohol spectrum disorder, minamata disease caused by mercury, behavioral disorders including conduct disorder etc caused by other heavy metals, such as lead, chromium, platinum etc, hydrocarbons like dioxin, PBDE´s and PCB´s, medications and illegal drugs, like cocaine and others.

Causes

The development of the nervous system including the brain is orchestrated, tightly regulated, and genetically encoded process with clear influence from the environment. This suggests that any deviation from this program early in life can result in neurodevelopmental disorders and, depending on specific timing, might lead to distinct pathology later in life.^[5] Because of that, there are many causes of neurodevelopmental disorder, which can range from deprivation, genetic and metabolic diseases, immune disorders, infectious diseases, nutritional factors, physical trauma, and toxic and environmental factors.

Some neurodevelopmental disorders—such as autism and other pervasive developmental disorders—are considered multifactorial syndromes with many causes but more specific neurodevelopmental manifestation.^[6]

Deprivation

Deprivation from social and emotional care causes severe delays in brain and cognitive development. Studies with children growing up Romanian orphanages during Nicolae Ceauşescu's regime reveal profound effects of social deprivation and language deprivation on the developing brain. These effects are time dependent. The longer children stayed in negligent institutional care, the greater the consequences. By contrast, adoption at an early age mitigated some of the effects of earlier institutionalization (abnormal psychology).^[7]

Genetic disorders

A child with Down syndrome

A prominent example of a genetically determined neurodevelopmental disorder is Trisomy 21, also known as Down syndrome. This disorder usually results from an extra chromosome 21, although in uncommon instances it is related to other chromosomal abnormalities such as translocation of the genetic material. It is characterized by short stature, epicanthal (eyelid) folds, abnormal fingerprints, and palm prints, heart defects, poor muscle tone (delay of neurological development) and mental retardation (delay of intellectual development).^[3]

Less commonly known genetically determined neurodevelopmental disorders include Fragile X syndromeFragile X syndrome was first described in 1943 by J.P. Martin and J. Bell, studying persons with family history of sex-linked "mental defects".^[8] Rett syndrome, another X-linked disorder, produces severe functional limitations.^[9] Williams syndrome is caused by small deletions of genetic material from chromosome 7.^[10] The most common recurrent Copy Number Variannt disorder is 22q11.2 deletion syndrome (formerly DiGeorge or velocardiofacial syndrome), followed by Prader-Willi syndrome and Angelman syndrome.^[11]

Immune dysfunction

Immune reactions during pregnancy, both maternal and of the developing child, may produce neurodevelopmental disorders. One typical immune reaction in infants and children is PANDAS,^[12] or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection.^[13] Another disorder is Sydenham's chorea, which results in more abnormal movements of the body and fewer psychological sequellae. Both are immune reactions against brain tissue that follow infection by Streptococcus bacteria. Susceptibility to these immune diseases may be genetically determined,^[14] so sometimes several family members may suffer from one or both of them following an epidemic of Strep infection.

Infectious diseases

Systemic infections can result in neurodevelopmental consequences, when they occur in infancy and childhood of humans, but would not be called a primary neurodevelopmental disorder per se, as for exapmle HIV^[15] Infections of the head and brain , like brain abscesses , meningitis or encephalitis have a high risk of causing neurodevelopmental problems and eventually a disorder. For example Measles can progress to subacute sclerosing panencephalitis.

A number of infectious diseases can be transmitted either congenitally (before or at birth), and can cause serious neurodevelopmental problems, as for example the viruses HSV, CMV, rubella Congenital rubella syndrome, Zika virus, or bacteria like Treponema pallidum in congenital syphilis, which may progress to neurosyphilis if it remains untreated. Protozoa like PLasmodium ^[15] or Toxoplasma which can cause congenital toxoplasmosis with multiple cysts in the brain and other organs, leading to a variety of neurological deficits.

Some cases of schizophrenia may be related to congenital infections though the majority are of unknown causes.^[16]

Metabolic disorders

Metabolic disorders in either the mother or the child can cause neurodevelopmental disorders. Two examples are diabetes mellitus (a multifactorial disorder) and phenylketonuria (an inborn error of metabolism). Many such inherited diseases may directly affect the child's metabolism and neural development^[17] but less commonly they can indirectly affect the child during gestation. (See also teratology).

In a child, type 1 diabetes can produce neurodevelopmental damage by the effects of excess or insufficient glucose. The problems continue and may worsen throughout childhood if the diabetes is not well controlled.^[18] Type 2 diabetes may be preceded in its onset by impaired cognitive functioning.^[19]

A non-diabetic fetus can also be subjected to glucose effects if its mother has undetected gestational diabetes. Maternal diabetes causes excessive birth size, making it harder for the infant to pass through the birth canal without injury or it can directly produce early neurodevelopmental deficits. Usually the neurodevelopmental symptoms will decrease in later childhood.^[20]

Phenylketonuria, also known as PKU, can induce neurodevelopmental problems and children with PKU require a strict diet to prevent mental retardation and other disorders. In the maternal form of PKU, excessive maternal phenylalanine can be absorbed by the fetus even if the fetus has not inherited the disease. This can produce mental retardation and other disorders.^[21][22]

Nutrition

Nutrition disorders and nutritional deficits may cause neurodevelopmental disorders, such as spina bifida, and the rarely occurring anencephaly, both of which are neural tube defects with malformation and dysfunction of the nervous system and its supporting structures, leading to serious physical disability and emotional sequelae. The most common nutritional cause of neural tube defects is folic acid deficiency in the mother, a B vitamin usually found in fruits, vegetables, whole grains, and milk products.^[23][24] (Neural tube defects are also caused by medications and other environmental causes, many of which interfere with folate metabolism, thus they are considered to have multifactorial causes.)^[25][26] Another deficiency, iodine deficiency, produces a spectrum of neurodevelopmental disorders ranging from mild emotional disturbance to severe mental retardation. (see also cretinism)

Excesses in both maternal and infant diets may cause disorders as well, with foods or food supplements proving toxic in large amounts. For instance in 1973 K.L. Jones and D.W. Smith of the University of Washington Medical School in Seattle found a pattern of "craniofacial, limb, and cardiovascular defects associated with prenatal onset growth deficiency and developmental delay" in children of alcoholic mothers, now called fetal alcohol syndrome, It has significant symptom overlap with several other entirely unrelated neurodevelopmental disorders.^[27] It has been discovered that iron supplementation in baby formula can be linked to lowered I.Q. and other neurodevelopmental delays.^[28]

Physical trauma

CT scan showing epidural hematoma, a type of traumatic brain injury (upper left)

Brain trauma in the developing human is a common cause (over 400,000 injuries per year in the US alone, without clear information as to how many produce developmental sequellae)^[29] of neurodevelopmental syndromes. It may be subdivided into two major categories, congenital injury (including injury resulting from otherwise uncomplicated premature birth)^[2] and injury occurring in infancy or childhood. Common causes of congenital injury are asphyxia (obstruction of the trachea), hypoxia (lack of oxygen to the brain) and the mechanical trauma of the birth process itself.

Diagnosis

Traditionally, genetic abnormalities in neurodevelopmental disorders were detected using karyotype analysis, which found 5% of relevant disorders. As of 2017, chromosomal microarray analysis (CMA) has replaced karyotyping, because of its greater diagnostic yield in about 20% of cases, detecting smaller chromosome abnormalities. It is the first line genomic test.^[30]

New descriptions include the term Copy-number variants (CNVs), which are losses or gains of chromosomal regions greater than 1 kb in length.^[30] CNVs are mentioned with the chromosomal band(s) they involve and their genome sequence coordinates. CNVs can be nonrecurrent and recurrent.^[30]

With CMA costs of testing have increased from 800 US$ to 1500$. Guidelines from the American College of Medical Genetics and Genomics and the American Academy of Pediatrics recommend CMA as standard of care in the US.^[30]

Consequences

Neurodevelopmental disorders are in their multitude associated with widely varying degrees of difficulty, depending on which there are different degrees of mental, emotional, physical, and economic consequences for individuals, and in turn families, groups and society.

See also

Bibliography

• Tager-Flusberg, Helen (1999). Neurodevelopmental disorders. Cambridge, Mass: MIT Press. ISBN 0-262-20116-X. 
• Brooks, David R.; Walter Wolfgang Fleischhacker (2006). Neurodevelopmental Disorders. Berlin: Springer. ISBN 3-211-26291-1. 

Notes

External links

• Neurodevelopmental Disorders at DMOZ
• A Review of Neurodevelopmental Disorders - Medscape review