Neuronal migration disorder (NMD) refers to a heterogenous group of disorders that, it is supposed, share the same etiopathological mechanism: a variable degree of disruption in the migration of

neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...

s during

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs ...

. The

neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...

disorders are termed cerebral dysgenesis disorders, brain malformations caused by primary alterations during neurogenesis; on the other hand, brain malformations are highly diverse and refer to any insult to the brain during its formation and maturation due to intrinsic or extrinsic causes that ultimately will alter the normal brain anatomy. However, there is some controversy in the terminology because virtually any malformation will involve neuroblast migration, either primarily or secondarily.

Symptoms and signs

Symptoms vary according to the abnormality, but often feature poor muscle tone and motor function,

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, ...

mental retardation Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

, failure to grow and thrive, difficulties with feeding, swelling in the extremities, and a smaller than normal head. Most infants with an NMD appear normal, but some disorders have characteristic facial or skull features that can be recognized by a neurologist.

Cause

In the developing brain, neural stem cells must migrate from the areas where they are born to the areas where they will settle into their proper neural circuits. Neuronal migration, which occurs as early as the second month of

gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during preg ...

, is controlled by a complex assortment of chemical guides and signals. When these signals are absent or incorrect, neurons do not end up where they belong. This can result in structurally abnormal or missing areas of the brain in the

cerebral hemispheres The vertebrate cerebrum (brain) is formed by two cerebral hemispheres that are separated by a groove, the longitudinal fissure. The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres ...

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cere ...

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...

, or

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

. Several genetic abnormalities in children with NMDs have been identified. Defects in genes that are involved in neuronal migration have been associated with NMDs, but the role they play in the development of these disorders is not yet well understood. A study in Sweden investigated the impact of

environmental factors An environmental factor, ecological factor or eco factor is any factor, abiotic or biotic, that influences living organisms. Abiotic factors include ambient temperature, amount of sunlight, and pH of the water soil in which an organism lives. ...

on NMDs. The study indicated that there might be an impact of low or subnormal maternal BMI before and during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

, maternal infection, such as

rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...

, and maternal smoking on fetal brain development, including neuronal migration. The roles of maternal BMI and congenital infections should be tested in future analytical studies. NMDs occur in the instance that 1) neuroblasts do not migrate from all of the ventricles or migrate only part of the way, 2) only some of the neuroblasts reach the

cortical layer The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...

, 3) neuroblasts overshoot the appropriate cortical layer and protrude into the

subarachnoid space In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is locate ...

, or 4) the late stage organization of the neuronal layer in the cortex is disrupted. Abnormal migration ultimately results in abnormal gyral formation.

Diagnosis

Types of NMD syndromes

More than 25 syndromes resulting from abnormal neuronal migration have been described. Among them are syndromes with several different patterns of inheritance;

genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...

thus differs greatly between syndromes. *

Lissencephaly Lissencephaly (, meaning "smooth brain") is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in ...

* Microlissencephaly *

Schizencephaly Schizencephaly () is a rare birth defect characterized by abnormal clefts lined with grey matter that form the ependyma of the cerebral ventricles to the pia mater. These clefts can occur bilaterally or unilaterally. Common clinical features of ...

Porencephaly Porencephaly is an extremely rare cephalic disorder involving encephalomalacia. It is a neurological disorder of the central nervous system characterized by cysts or cavities within the cerebral hemisphere.Parker, J. (2004). The official pare ...

Pachygyria Pachygyria (from the Greek "pachy" meaning "thick" or "fat" gyri) is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, ...

Polymicrogyria Polymicrogyria (PMG) is a condition that affects the development of the human brain by multiple small gyri ( microgyri) creating excessive folding of the brain leading to an abnormally thick cortex. This abnormality can affect either one region ...

* Agyria *

Macrogyria Pachygyria (from the Greek "pachy" meaning "thick" or "fat" gyri) is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizu ...

Microgyria A microgyrus is an area of the cerebral cortex that includes only four cortical layers instead of six. Microgyria are believed by some to be part of the genetic lack of prenatal development which is a cause of, or one of the causes of, dyslexia. ...

* Micropolygyria *

Grey matter heterotopia MRI of a child experiencing seizures. There are small foci of grey matter heterotopia in the corpus callosum, deep to the Cortical dysplasia">dysplastic cortex. (double arrows)">Heterotopia (medicine)">heterotopia in the corpus callosum, deep ...

Agenesis of the corpus callosum Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres i ...

* Agenesis of the cranial nerves * Band heterotopias Focal

cortical dysplasia Focal cortical dysplasia (FCD) is a congenital abnormality of brain development where the neurons in an area of the brain failed to migrate in the proper formation in utero. ''Focal'' means that it is limited to a focal zone in any lobe. Focal cor ...

Miller–Dieker syndrome Miller–Dieker syndrome, Miller–Dieker lissencephaly syndrome (MDLS), and chromosome 17p13.3 deletion syndrome is a micro deletion syndrome characterized by congenital malformations. Congenital malformations are physical defects detectable in a ...

, , Fukuyama congenital muscular dystrophy and Walker–Warburg syndrome are genetic disorders associated with lissencephaly.

Treatment

Treatment is symptomatic and may include

anti-seizure medication Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

and special or supplemental education consisting of

physical Physical may refer to: *Physical examination In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally cons ...

occupational Employment is a relationship between two parties regulating the provision of paid labour services. Usually based on a contract, one party, the employer, which might be a corporation, a not-for-profit organization, a co-operative, or any other ...

and speech therapies.

Prognosis

The prognosis for children with NMDs varies depending on the specific disorder and the degree of brain abnormality and subsequent neurological signs and symptoms.

References

{{reflist, 2 Neurological disorders *