There are many different congenital and maternally derived abnormalities associated with the nervous system. There are potentially 1000's of neurological abnormalities that could be listed on this page, therefore I include only a very brief introduction to some neural abnormalities.
Abnormalities | Australian Statistics 1981-1992 | Neural Tube Closure | Maternally Derived | Folic Acid and Neural Tube Defects | Spina Bifida | Cephalic Disorders | Anencephaly | Hydrocephalus | Encephalocele | Trisomy 21 | Neural Tumours | Medulloblastoma | Lesch-Nyhan Syndrome | Agenesis of the Corpus Callosum | Fragile X Syndrome | Autism | Holoprosencephaly | Huntington's Disease | Dandy Walker Syndrome | Arnold-Chiari Malformation | Primary Microcephaly | Infections | Self Assessment Questions | OMIM Database | References | Glossary
This pie diagram shows the percentage of neural defects of all notifiable birth defects in Australia.
Dysraphism is the term often used to describe the defective fusion of the neural folds. The position and degree of failure of fusion will result in either embryonic death or a range of different neural defects. The way (mode) in which the human neural tube fuses has been a source of contention. In humans, fusion appears to initiate at multiple sites but the mode is different from that found in many animal species used in developmental studies.
Human Embryonic Death:
5 weeks with total failure of fusion.
6.5 weeks with opening over the rhombencephalon.
survive beyond 7 weeks with a defect at the frontal and parietal regions.
(Data: Nakatsu T, Uwabe C, Shiota K. Neural tube closure in humans initiates at multiple sites: evidence from human embryos and implications for the pathogenesis of neural tube defects. Anat Embryol (Berl). 2000 Jun;201(6):455-66.)
There are potentially many different causes of spina bifida and neural tube defects. The basis of the abnormality is a failure of the neural tube to close caudally. At least one known cause is a low maternal diet of folic acid (folate) containing foods. (see Neural Tube Defects and Low Folic Acid or Folic Acid below)
Neural tube defects from failure to close can be screened by amniocentesis or ultrasound.
Alpha-fetoproetin normally present in the CSF, leaks and can be detected in amniotic fluid.
Links: Folic Acid | Abnormal Development - Spina Bifida | Abnormal Development - Neural Tube Defects and Low Folic Acid | OMIM- Spina Bifida | OMIM- Anencephaly-Spina Bifida | Australian Spina Bifida and Hydrocephalus Association |
Cephalic (Greek, kephale = head) are a group of abnormalities that relate to a wide range of skeletal (skull) and neural (brain) associated defects including: Anencephaly, Hydrocephalus, Encephalocele, Colpocephaly (occipital horn enlargement), Lissencephaly (smooth brain), Porencephaly (cyst or cavity in cerebral hemisphere), Acephaly (absence of head), Exencephaly (brain outside skull), Macrocephaly (large head), Micrencephaly (small brain), Otocephaly (absence of lower jaw), Brachycephaly (premature fusion of coronal suture), Oxycephaly (premature fusion of coronal suture + other), Plagiocephaly (premature unilateral fusion of coronal or lambdoid sutures), Scaphocephaly (premature fusion of sagittal suture), Trigonocephaly.
Links: NINDS - Cephalic Disorders
This is a neural tube defect, the basis of the abnormality is a failure of the neural tube to close cranially. Also called exencephaly or craniorachischisis.
Hydrocephalus (historic image from Hess, 1922)
This is a defect of cerebrospinal fliud (CSF) flow, leading to enlarged ventricles and head, separated skull cranial sutures and fontanelles. Obstruction of CSF flow can occur at any time (prenatally or postnatally) and leads to accumulation of within the ventricles. The time of onset will have different effects and should be compared to the equilivant neurological events that are occuring.
Ventricular obstruction usually occurs at the level of the cerebral aqueduct (narrowest site), but can occur elsewhere, and can be caused by viral infection.
Links: Cerebrospinal fluid | Skull Development | Viral Infection | NINDS - Cephalic Disorders | OMIM- Hydrocephalus | | Search PubMed - Hydrocephalus Australian Spina Bifida and Hydrocephalus Association |
This defect is generally mesodermal in origin, leading to protrusion of brain and meninges outside the crainal cavity. The severity of the disorder can vary dependent upon the degree of mesodermal abnormality.
This abnormality occurs due to the presence of an additional chromosome 21 (trisomy 21) which must occur in early in the original zygote during the first division. The frequency of trisomy 21 in the population is 1 in 650 to 1,000 live births.
Trisomy 21 has severe and variable effects on neurological development and also effects development of other systems.
Note that other trisomies (18, 13) can also have severe to mild neurological effects.
Approximately 17% of all pediatric cancers arise in the central nervous system, of which 90% are located within the brain, these are the second most common malignancy in childhood and the most common form of solid tumour.
Pediatric CNS tumors have a relatively high rate of occurrence within the cerebellum and brain stem.
CNS Tumour Types: 52% astrocytomas, 21% medulloblastoma/primitive neuroectodermal tumor (PNET), 15% other gliomas, and 9% ependymomas.
CNS Tumour Incidence Facts: reportedly increasing over past several decades (partly due to improvements in diagnostic technology), higher in males than in females, higher in whites than in blacks.
(text modified from: Cancer Medicine 6 -Central nervous system tumors)
(Note spelling difference Aus/US of tumour/tumor when searching)
This cancer is the most common malignant brain tumor in children (15 to 30% of all pediatric brain tumors) and a leading cause of cancer-related death in children under 9 years of age. In adults it is less than 1% of CNS neoplasms.
Medulloblastoma is thought to result from the transformation of granule cell precursors in the developing cerebellum. Approximately 25% of medulloblastoma cases have mutations in components of the Sonic hedgehog - Patched signaling pathway.
Agenesis of the corpus callosum (modified from VCU Pathology)
Agenesis of the corpus callosum (ACC) is a rare congenital abnormality in which there is a partial or complete absence (agenesis) of the corpus callosum.
The corpus callosum is the area of the brain which connects the two cerebral hemispheres. In most patients, ACC is diagnosed within the first two years of life. It may occur as a severe syndrome in infancy or childhood, as a milder condition in young adults, or as an asymptomatic incidental finding. The first symptoms of ACC are usually seizures, which may be followed by feeding problems and delays in holding the head erect, sitting, standing, and walking.
(This text from National Institutes of Health)
Lesch-Nyhan Syndrome (LNS) is a rare genetic disorder discovered over 30 years ago as an inborn error of purine metabolism by Nyhan et al (J. Pediat. 67: 257-263, 1965).
LNS is characterized by self-mutilating behaviors such as lip and finger biting and/or head banging. The symptoms of LNS usually appear between the ages of 3 and 6 months.
LNS is caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase or HPRT. Many mutations have been identified in a gene on the long arm of the X chromosome in patients with Lesch-Nyhan disease, all lead to a virtually complete loss of function of the enzyme HPRT.
In 1996, researchers showed that brains of patients with LNS may have much fewer dopaminergic nerve endings. This study also may help researchers better understand the biological causes of a major behavioral problem of the severely mentally retarded.
Fragile X results in apparently normal neurological development, with the effects becoming apparent during early learning (age 3-5). This disease is one of several CAG expansion diseases. In the general poulation we all carry a limited copy of this nuceotide sequence, it is only when the copy number increases that the encoded protein (FRP, Fragile X Protein) is decreased in neuronal expression.
Autism, or autism spectrum disorder, is a neurological disorder in children (approx 13 in 10,000) showing deficiencies in communication and reciprocal social interactions, often accompanied by restricted or repetitive interests and behaviors. The cause(s) is still unidentified, at least 2 candidate genes MET and EN2 have been assciated with this condition, both are probably involved with features of prenatal or neonatal neural development. It has also been an identified that some patients suffering from Fragile X Syndrome show many autistic symptoms.
A recent study (PNAS, Oct2006) has identified MET (on chromosome 7q31) is a cell surface receptor tyrosine kinase receptor (usually for growth factors) involved in neurological development and has now been associated with Autism susceptibility. Met was originally identified as a protooncogene (a gene when mutated which is oncogenic/cancer forming) in the early 80's. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, Elia M, Schneider C, Melmed R, Sacco R, Persico AM, Levitt P. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci U S A. 2006 Oct 19 PNAS Abstract | OMIM - MET
A 2005 study (AJHG, Nov2005) shown a link between between autism and the Engrailed 2 (EN2) gene, which may contribute to up to 40% of autism cases in the general population. EN2 is involved in normal neural development. Support for the Homeobox Transcription Factor Gene ENGRAILED 2 as an Autism Spectrum Disorder Susceptibility Locus ".....Together, these data provide further genetic evidence that EN2 might act as an ASD susceptibility locus, and they suggest that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development." (Am. J. Hum. Genet., 77:851-868, November 2005) OMIM - EN2
There are both genetic and teratogenic causes of holoprosencephaly, which occurs in about 1 in 16,000 live births and approximately 1 in 200 spontaneous abortions.
Maternal diabetes (teratogen) is known to increase risk 200-fold.
"Dandy-Walker malformation is defined by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus." (text from OMIM)
Arnold-Chiari Malformation (modified from VCU Pathology)
Cerebellar tonsils elongate and herniate through foramen magnum into spinal canal, resulting in compression of parts of the brain and spinal cord, and disruption of cerebrospinal fluid flow. Causes of the malformation appears multifactorial (including inherited and acquired) and is thought to be fundamentally the same as anencephaly and spina bifida.
A protein (abnormal spindle-like microcephaly-associated protein, ASPM) associated in development with maintaining the symmetric division of neuroepithelial cells is implicated as a cause of primary microcephaly in humans. ASPM is concentrated at mitotic spindle poles in embryonic neuroepithelial cells (progenitor cells of the brain) and down-regulated when they switch from proliferative to neurogenic divisions.
Links: Fish JL, Kosodo Y, Enard W, Paabo S, Huttner WB. Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc Natl Acad Sci U S A. 2006 Jun 23)
"Huntington disease (HD) is inherited as an autosomal dominant disease that gives rise to progressive, selective (localized) neural cell death associated with choreic movements and dementia. The disease is associated with increases in the length of a CAG triplet repeat present in a gene called 'huntingtin' located on chromosome 4p16.3." (text from OMIM)
For more details see Abnormal Development - Huntington's Disease.
These are not congenital (inherited) abnormalities and relate to an environmental, trauma, infection or nutritional effects during embryonic development. There are specific additional notes available from the Abnormal Development page. The abnormalities listed below should be completely preventable.
See also notes Fetal Alcohol Syndrome. In Australia, females aged 20-24, are more likely to drink to excess than females in other age groups and NHMRC recommends additional neonatal follow up assessment for alcoholic mothers. Consuming alcohol during pregnancy is the cause of Fetal Alcohol Syndrome (FAS), a leading preventable cause of birth defects, alterations to facial appearance and mental retardation. Similar effects without the obvious alterations to appearance, but with nervous system effects, are sometimes typified as Fetal Alcohol Effects (FAE).
Also see the list of selected review articles from PubMed Medline.
Search Pubmed Now: neural+tube+defects[TITL]
Research over the last 20 years has suggested a relationship between maternal diet and the birth of an affected infant, and recent evidence has confirmed that folic acid, a water soluble vitamin, found in many fruits (particularly oranges, berries and bananas), leafy green vegetables, cereals and legumes, may prevent the majority of neural tube defects.
Excerpt from NHMRC Publication
Search Pubmed Now: neural+tube+defects[TITL]
Below is a list of some known maternal (then fetal) infections that impact upon neurological development.
Viral infection causes systemic infection and extensive brain damage and cell death by necrosis.
Viral infection causes systemic infection and extensive brain damage and cell death by necrosis.
NCBI Bookshelf (external link) Search Medical Microbiology "Herpes Simplex Virus"
Bacterial infection by E. coli or streptocci B. can cause vascular thrombosis involving choroid plexus which can effect CSF flow, and can cause hydrocephalus.
NCBI Bookshelf (external link) Search Medical Microbiology "Purulent Meningitus"
Causes severe microcephaly and necrosis.
NCBI Bookshelf (external link) Search Medical Microbiology "Rubella"
Toxoplasma infection causes random necrosis throughout the brain and can cause hydrocephalus.
NCBI Bookshelf (external link) Medical Microbiology: 84. Toxoplasma Gondii | Figure 84-1. Girl with hydrocephalus due to congenital toxoplasmosis. | Search Medical Microbiology "Toxoplasmosis"
Many of the links below are to external resources and require an internet connection.
Environmental Health Perspectives Critical Periods of Vulnerability for the Developing Nervous System: Evidence from Humans and Animal Models
Developmental Brain Research Content Listing
International Journal for Developmental Neuroscience Official Journal of the International Society for Developmental Neuroscience |
Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000 Jun;108 Suppl 3:511-33. Review. (Pubmed Central)
Goto M, Piper Hanley K, Marcos J, Wood PJ, Wright S, Postle AD, Cameron IT, Mason JI, Wilson DI, Hanley NA. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest. 2006 Apr;116(4):953-60.
Note: books are listed for educational and information purposes only and does not suggest a commercial product endorsement.
Search May 2007 "neural abnormalities" 13,558 reference articles of which 1970 were reviews.
Search PubMed: term= neural abnormalities