What is Lissencephaly?
Lissencephaly, which literally means
"smooth brain," is a rare, gene-linked brain malformation characterized
by the absence
of normal convolutions (folds) in the
cerebral cortex and an abnormally small head (microcephaly). In the
usual condition
of lissencephaly, children usually have a
normal sized head at birth. In children with reduced head size at
birth, the condition
microlissencephaly is typically diagnosed.
Lissencephaly is caused by defective neuronal migration during
embryonic development,
the process in which nerve cells move
from their place of origin to their permanent location within teh
cerebral cortex gray
matter. Symptoms of the disorder may
include unusual facial appearance, difficulty swallowing, failure to
thrive, muscle spasms,
seizures, and severe psychomotor
retardation. Hands, fingers, or toes may be deformed. Lissencephaly may
be associated with
other diseases including isolated
lissencephaly sequence, Miller-Dieker syndrome, and Walker-Warburg
syndrome. Sometimes
it can be difficult to distinguish between
these conditions clinically so consultation with national experts is
recommended
to help ensure correct diagnosis and
possible molecular testing.
 |
| Our Rowan has the pattern on the right. DCX X Linked Lissencephaly |
Is there any treatment?
There
is no cure for lissencephaly, but children can show progress in their
development over time. Supportive care may be
needed to help with comfort,
feeding, and nursing needs. Seizures may be particularly problematic but
anticonvulsant medications
can help. Progressive
hydrocephalus (an excessive accumulation of cerebrospinal fluid in the
brain) is very rare, seen only
in the subtype of Walker-Warburg
syndrome, but may require shunting. If feeding becomes difficult, a
gastrostomy tube may
be considered.
What is the prognosis?
The
prognosis for children with lissencephaly depends on the degree of
brain malformation. Many will die before the age of
10 years. The cause of death is
usually aspiration of food or fluids, respiratory disease, or severe
seizures. Some will
survive, but show no significant
development -- usually not beyond a 3- to 5-month-old level. Others may
have near-normal
development and intelligence.
Because of this range, it is important to seek the opinion of
specialists in lissencephaly
and support from family groups
with connection to these specialists.
What is X-linked lissencephaly? (the type Rowan has)
X-linked lissencephaly is a condition of abnormal brain development
that mainly affects males, though females may be mildly affected.
Normally the exterior of the brain (cerebral cortex) is multi-layered
with folds and grooves. People with lissencephaly have an abnormally
smooth brain with fewer folds and grooves. This abnormality can cause
severe intellectual disability and developmental delay, seizures,
abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia),
and feeding difficulties. People without any folds in the brain
(agyria) typically have more severe symptoms.
There are at least two forms of X-linked lissencephaly. The first is characterized by lissencephaly only, and usually involves no other parts of the body. The second is lissencephaly with abnormal (ambiguous) genitalia. This form of X-linked lissencephaly is typically more severe, with seizures often beginning within the first day of life, and sometimes even before birth. In addition, affected males can have an unusually small penis (micropenis), undescended testes (cryptorchidism), or external genitalia that do not look clearly male or clearly female (ambiguous genitalia). Males with this form of X-linked lissencephaly also can show a lack of development (agenesis) of the tissue connecting the left and right halves of the brain (corpus callosum), low body temperature (hypothermia), and chronic diarrhea.
There are at least two forms of X-linked lissencephaly. The first is characterized by lissencephaly only, and usually involves no other parts of the body. The second is lissencephaly with abnormal (ambiguous) genitalia. This form of X-linked lissencephaly is typically more severe, with seizures often beginning within the first day of life, and sometimes even before birth. In addition, affected males can have an unusually small penis (micropenis), undescended testes (cryptorchidism), or external genitalia that do not look clearly male or clearly female (ambiguous genitalia). Males with this form of X-linked lissencephaly also can show a lack of development (agenesis) of the tissue connecting the left and right halves of the brain (corpus callosum), low body temperature (hypothermia), and chronic diarrhea.
How common is X-linked lissencephaly?
The overall incidence of lissencephaly is estimated to be 1 in 85,000
individuals. The incidence of males with X-linked lissencephaly is
unknown.
What genes are related to X-linked lissencephaly?
X-linked lissencephaly is caused by a mutation in either the DCX gene or the ARX gene. Mutations in the DCX gene cause isolated lissencephaly, which typically does not involve any other parts of the body. Mutations in the ARX
gene can cause X-linked lissencephaly with ambiguous genitalia and
other associated health issues. Both genes provide instructions for
producing proteins that play a role in the development of the brain.
The DCX protein, doublecortin, plays a role in the migration of nerve
cells (neurons) to their proper location in the developing brain. The
ARX protein is involved in the regulation of other genes that contribute
to brain development. The ARX protein is also found in the pancreas
and testes.
X-linked lissencephaly is seen primarily in males. Most females with a DCX mutation have a milder brain disorder called subcortical band heterotopia, or doublecortex. Females with an ARX mutation usually have some degree of intellectual disability, epilepsy, and agenesis of the corpus callosum.
Read more about the ARX and DCX genes.
X-linked lissencephaly is seen primarily in males. Most females with a DCX mutation have a milder brain disorder called subcortical band heterotopia, or doublecortex. Females with an ARX mutation usually have some degree of intellectual disability, epilepsy, and agenesis of the corpus callosum.
Read more about the ARX and DCX genes.
How do people inherit X-linked lissencephaly?
This condition is inherited in an X-linked dominant pattern. The
gene associated with this condition is located on the X chromosome,
which is one of the two sex chromosomes. In females (who have two X
chromosomes), a mutation in one of the two copies of the gene in each
cell is sufficient to cause the disorder. In males (who have only one X
chromosome), a mutation in the only copy of the gene in each cell
causes the disorder. In most cases, males experience more severe
symptoms of the disorder than females. A characteristic of X-linked
inheritance is that fathers cannot pass X-linked traits to their sons.
In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.
There are a number of subtypes of lissencephaly
that are distinguished by differences in the physical structure of the
brain. "Classical," or type 1, lissencephaly and cobblestone dysplasia, or type 2, lissencephaly are the most common subtypes.
Classical, or type 1, lissencephaly consists of a brain surface that is completely smooth except for a few shallow valleys (sulci). The cortex is thicker than normal and there are clumps of neurons found in areas outside the cortex (heterotopia). The corpus callosum, the band of tissue between the hemispheres of the brain, is often small and is sometimes absent. The posterior ventricles, the fluid-filled spaces in the center of the brain, are often larger than normal.
Type 1 lissencephaly can be seen in a number of genetic syndromes and can also occur by itself in a condition called Isolated Lissencephaly Sequence (ILS). The vast majority of cases of ILS is a result of mutations or deletions (missing sections) in one of two different genes involved in brain development.
The gene causing the majority of cases of ILS is called the LIS1 and is located on the short arm of chromosome 17. Between 40% and 64% of persons with ILS have a deletion of a portion of the LIS1 gene, and about 24% have a mutation that disrupts the normal function of the gene. Most deletions and mutations in the LIS1 gene are sporadic and are not present in other family members.
Another 12% of persons with ILS have a mutation in a gene called XLIS (or DCX), located on the long arm of the X chromosome. Mutations in XLIS cause X-linked lissencephaly in males and may or may not cause symptoms in the mothers who carry the mutation.
There are also a few cases of ILS that appear to be inherited in an autosomal recessive pattern. As of 2001, the mutated genes for this and other types of ILS have not been discovered.
An example of a genetic syndrome involving type 1 lissencephaly is Miller-Dieker syndrome (MDS). This disorder is caused by a deletion of part of the short arm of chromosome 17 (17p13) that includes the LIS1 gene. In addition to lissencephaly, children with MDS have distinctive facial features including a high forehead, short upturned nose, and thin lips. They also have narrowing at the temples and a small jaw, although these traits can also be seen in ILS and other lissencephaly syndromes. Children with MDS occasionally have other birth abnormalities of the heart, kidneys, or palate. Calcium deposits in the midline of the brain are common in MDS, but not in ILS or other syndromes.
Type 2 lissencephaly is also called cobblestone dysplasia because of the pebbled appearance to the surface of the cerebral cortex. Brains with cobblestone dysplasia often show abnormalities of the white matter, enlarged ventricles, underdeveloped brainstem and cerebellum, and absence of the corpus callosum. There are four known syndromes that include cobblestone dysplasia: cobblestone lissencephaly without other birth defects (CLO); Fukuyama congenital muscular dystrophy (FCMD); muscle-eye-brain disease (MEB); and Walker-Warburg syndrome (WWS). These disorders are quite rare and all are inherited in an autosomal recessive pattern. Diagnosis depends on MRI studies and clinical evaluations. As of 2001, there are no specific genetic tests available for clinical use for these conditions.
There are other rare syndromes involving lissencephaly and variants of lissencephaly, some of which are autosomal recessive and some X-linked. None of the genes responsible for these other conditions have been identified as of Spring 2001.
Other causes may include:
In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.
Genetic Profile
| Associated forms of Lissencephaly | ||||||
| Disorder | Inheritance | Gene location | Proportion of patients | Gene name | Protein product | Clinical test |
| MDS (Miller-Dieker syndrome) | AD | 17p13.3 | 100% | LIS1 | Platelet activating factor Acetylhydrolase 45K | Yes |
| ILS1 (Isolated lissencephaly sequence 1) | AD | 17p13.3 | >40% | LIS1 | Platelet activating factor acetylhydrolase 45K | Yes |
| X-linked lissencephaly and subcortical band heterotropia | X-linked | Xq22.3–q23 | Unknown | XLIS | Unknown | No |
| Cobblestone lissencephaly (lissencephaly type 2) | AR | Unknown | Unknown | Unknown | Unknown | No |
Classical, or type 1, lissencephaly consists of a brain surface that is completely smooth except for a few shallow valleys (sulci). The cortex is thicker than normal and there are clumps of neurons found in areas outside the cortex (heterotopia). The corpus callosum, the band of tissue between the hemispheres of the brain, is often small and is sometimes absent. The posterior ventricles, the fluid-filled spaces in the center of the brain, are often larger than normal.
Type 1 lissencephaly can be seen in a number of genetic syndromes and can also occur by itself in a condition called Isolated Lissencephaly Sequence (ILS). The vast majority of cases of ILS is a result of mutations or deletions (missing sections) in one of two different genes involved in brain development.
The gene causing the majority of cases of ILS is called the LIS1 and is located on the short arm of chromosome 17. Between 40% and 64% of persons with ILS have a deletion of a portion of the LIS1 gene, and about 24% have a mutation that disrupts the normal function of the gene. Most deletions and mutations in the LIS1 gene are sporadic and are not present in other family members.
Another 12% of persons with ILS have a mutation in a gene called XLIS (or DCX), located on the long arm of the X chromosome. Mutations in XLIS cause X-linked lissencephaly in males and may or may not cause symptoms in the mothers who carry the mutation.
There are also a few cases of ILS that appear to be inherited in an autosomal recessive pattern. As of 2001, the mutated genes for this and other types of ILS have not been discovered.
An example of a genetic syndrome involving type 1 lissencephaly is Miller-Dieker syndrome (MDS). This disorder is caused by a deletion of part of the short arm of chromosome 17 (17p13) that includes the LIS1 gene. In addition to lissencephaly, children with MDS have distinctive facial features including a high forehead, short upturned nose, and thin lips. They also have narrowing at the temples and a small jaw, although these traits can also be seen in ILS and other lissencephaly syndromes. Children with MDS occasionally have other birth abnormalities of the heart, kidneys, or palate. Calcium deposits in the midline of the brain are common in MDS, but not in ILS or other syndromes.
Type 2 lissencephaly is also called cobblestone dysplasia because of the pebbled appearance to the surface of the cerebral cortex. Brains with cobblestone dysplasia often show abnormalities of the white matter, enlarged ventricles, underdeveloped brainstem and cerebellum, and absence of the corpus callosum. There are four known syndromes that include cobblestone dysplasia: cobblestone lissencephaly without other birth defects (CLO); Fukuyama congenital muscular dystrophy (FCMD); muscle-eye-brain disease (MEB); and Walker-Warburg syndrome (WWS). These disorders are quite rare and all are inherited in an autosomal recessive pattern. Diagnosis depends on MRI studies and clinical evaluations. As of 2001, there are no specific genetic tests available for clinical use for these conditions.
There are other rare syndromes involving lissencephaly and variants of lissencephaly, some of which are autosomal recessive and some X-linked. None of the genes responsible for these other conditions have been identified as of Spring 2001.
Opisthotonos
For a while now Rowan has arched his back. I am still researching this, but here is what I found:
Opisthotonos is a condition in which the body is held in an abnormal position. The person is usually rigid and arches the back, with the head thrown backward. If a person with opisthotonos lies on his or her back, only the back of the head and the heels touch the supporting surface.
See: Abnormal posturing
Opisthotonos is a condition in which the body is held in an abnormal position. The person is usually rigid and arches the back, with the head thrown backward. If a person with opisthotonos lies on his or her back, only the back of the head and the heels touch the supporting surface.
See: Abnormal posturing
Considerations
Opisthotonos is much more common in infants and children than in adults. It is also more exaggerated in infants and children because of their less mature nervous systems.Causes
Opisthotonos may occur in infants with meningitis. It may also occur as a sign of reduced brain function or injury to the nervous system.Other causes may include:
- Arnold-Chiari syndrome (a problem with the structure of the brain)
- Brain tumor
- Gaucher disease
- Growth hormone deficiency (occasionally)
- Glutaric aciduria and organic acidemias (forms of chemical poisoning)
- Krabbe Disease
- Seizures
- Severe electrolyte imbalance
- Severe head injury
- Stiff-person syndrome (a condition that makes a person rigid and have spasms)
- Subarachnoid hemorrhage (bleeding in the brain)
- Tetanus
Lissencephaly Resources:
National Institute of Neurological Disorders and Stroke
P.O. Box 5801
Bethesda, MD 20824
Tel: (301)496-5751
Fax: (301)402-2186
Tel: (800)352-9424
TDD: (301)468-5981
Email: me20t@nih.gov
Internet: http://www.ninds.nih.gov/
MUMS National Parent-to-Parent Network
150 Custer Court
Green Bay, WI 54301-1243
USA
Tel: (920)336-5333
Fax: (920)339-0995
Tel: (877)336-5333
Email: mums@netnet.net
Internet: http://www.netnet.net/mums/
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
TDD: (888)205-3223
Email: http://rarediseases.info.nih.gov/GARD/EmailForm.aspx
Internet: http://rarediseases.info.nih.gov/GARD
Madisons Foundation
PO Box 241956
Los Angeles, CA 90024
Tel: (310)264-0826
Fax: (310)264-4766
Email: getinfo@madisonsfoundation.org
Internet: http://www.madisonsfoundation.org
NINDS Lissencephaly Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/lissencephaly.htm?format=printable>.
Lissencephaly Contact Group (UK). <http://www.lissencephaly.org.uk/index.htm>.
The Lissencephaly Research Project (University of Chicago) http://www.genes.uchicago.edu/ucgs/lissproj.html
P.O. Box 5801
Bethesda, MD 20824
Tel: (301)496-5751
Fax: (301)402-2186
Tel: (800)352-9424
TDD: (301)468-5981
Email: me20t@nih.gov
Internet: http://www.ninds.nih.gov/
MUMS National Parent-to-Parent Network
150 Custer Court
Green Bay, WI 54301-1243
USA
Tel: (920)336-5333
Fax: (920)339-0995
Tel: (877)336-5333
Email: mums@netnet.net
Internet: http://www.netnet.net/mums/
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Tel: (301)251-4925
Fax: (301)251-4911
Tel: (888)205-2311
TDD: (888)205-3223
Email: http://rarediseases.info.nih.gov/GARD/EmailForm.aspx
Internet: http://rarediseases.info.nih.gov/GARD
Madisons Foundation
PO Box 241956
Los Angeles, CA 90024
Tel: (310)264-0826
Fax: (310)264-4766
Email: getinfo@madisonsfoundation.org
Internet: http://www.madisonsfoundation.org
Websites:
Dobyns, William B. [1999]. "Lissencephaly Overview." GeneClinics: Lissencephaly Overview. University of Washington, Seattle. <http://www.geneclinics.org/profiles/lis-overview/>.NINDS Lissencephaly Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/lissencephaly.htm?format=printable>.
Lissencephaly Contact Group (UK). <http://www.lissencephaly.org.uk/index.htm>.
The Lissencephaly Research Project (University of Chicago) http://www.genes.uchicago.edu/ucgs/lissproj.html
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