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). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...

. 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 field ...

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 A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

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

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

, 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 pregn ...

, 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 (: cerebella or cerebellums; 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 it or eve ...

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 conti ...

, or

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

. 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, air, soil, water and pH of the water soil in which an ...

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 gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

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

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 are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...

Microlissencephaly Microlissencephaly (MLIS) is a rare congenital brain disorder that combines severe microcephaly (small head) with lissencephaly (smooth brain surface due to absent Sulcus (neuroanatomy), sulci and gyri). Microlissencephaly is a heterogeneous disor ...

Schizencephaly Schizencephaly () is a rare birth defect of the Human brain, brain, 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. C ...

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

Pachygyria Pachygyria ( 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, the onset and severity depending on the seve ...

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 of ...

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

* Macrogyria *

Microgyria In neuroanatomy, 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 cau ...

* Micropolygyria * Grey matter heterotopia *

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 ...

* Agenesis of the cranial nerves * Band heterotopias Focal cortical dysplasia,

Miller–Dieker syndrome Miller–Dieker syndrome, also called Miller–Dieker lissencephaly syndrome (MDLS) or chromosome 17p13.3 deletion syndrome, is a micro deletion syndrome characterized by congenital malformations. Congenital malformations are physical defects det ...

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

Treatment

Treatment is symptomatic and may include anti-seizure medication and special or supplemental education consisting of physical, occupational 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 *