Copyright © 1991 William B. Dobyns, All Rights Reserved. Used by permission.
Copyright © 1991 William B. Dobyns, All Rights Reserved. Used by permission.
When parents first learn of a serious birth defect or other
developmental problem in their child, it can be
devastating. They may be surprised, especially if their
child has a normal appearance (see right). Their first
response is to ask questions, especially "What will
happen to our child?". Periods of sadness and often
denial follow. The greatest need at this time is for
compassionate counseling by physicians and other health
care professionals such as genetic counselors. Later,
many parents begin to seek out more information. If the
disorder is rare, finding a physician familiar with the
condition may be difficult. Important questions are
sometimes left unanswered.Over the past few years, I have been asked for information on lissencephaly by many parents. Most have wanted accurate and detailed information which they could not find elsewhere. In this article, I have tried to answer the most frequent questions asked in as much detail as I could. At the same time, I have tried to avoid use of complicated medical terms. This review is intended primarily for parents who have known about their child's diagnosis for some time. I suspect it will present an "information overload" for most parents of newly diagnosed children, so I suggest that it be read at a later date.
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Lissencephaly is a malformation of the brain in which the
brain surface is smooth rather than convoluted. The
name comes from the Greek words 'lissos' which means
smooth and 'enkephalos' which means brain.In man, the surface of the brain is formed by a complex series of ridges and valleys. The ridges are called gyri or convolutions, and the valleys are called sulci. In children with lissencephaly, the normal convolutions are absent or only partly formed, so the surface is smooth as shown in at right. Lissencephaly is usually diagnosed based on interpretation of either CT or MRI scan of the brain. It can be suspected based on ultrasound in newborn children. Several other brain abnormalities occur secondary to the lissencephaly.
Normally, a large majority of all nerve cells are located at or just under the surface in an area called the cortex. In lissencephaly, many of the nerve cells do not reach the surface. They are stuck in an abnormal position, and so cannot make their usual connections with other nerve cells.
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Each of these types may occur in several different syndromes. Type I lissencephaly occurs in isolated lissencephaly sequence, in Miller-Dieker syndrome and in a very rare condition called Norman-Roberts syndrome. Type II occurs in Fukuyama syndrome and Walker-Warburg syndrome. Fukuyama syndrome is usually known as Fukuyama congenital muscular dystropy.
Some of the problems parents are likely to notice first include failure to develop visual tracking, poor feeding and weight gain, and seizures. In most children, slow development is recognized between 2 and 6 months of age. In others, more obvious problems are recognized soon after birth such as very small head size, weak breathing efforts or other birth defects. Children with WWS may have large head size and several other types of birth defects.
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Development. About half of all children with ILS have profound mental retardation with abilities limited to brief and inconsistent visual tracking, brief smiling and reduced spontaneous movements. They are floppy and much less active than normal children. Head control is poor and they often arch their head and trunk backwards. If held by the chest, their head, arms and legs will droop. Most are never able to roll over. As they get older, some stiffness (spasticity) of the arms and legs occurs. I refer to this as 'developmental level 1'.
The other half also have severe mental retardation but do make limited developmental progress equivalent to perhaps 3-5 months. They are more alert, less floppy and have better (but not normal) visual tracking, social smiling and head control. Some arching postures are seen. Increased stiffness or spasticity occurs in these children also. Many eventually learn to roll over and reach toward but not grasp objects. A few may learn to sit. I refer to this as 'developmental level 2'. Only one child learned to walk, which I refer to as 'developmental level 3'. Some of these developmental abilities, such as rolling and reaching, may be lost during later childhood. This is most likely due to larger body size, more frequent seizures, higher doses of seizure medications and poor nutrition.
Appropriate treatment programs designed by physical and occupational therapists will help prevent some orthopedic problems, especially tightening or 'contractures' of the joints. Therapy may help hasten some developmental skills but it should not be expected to push the child's developmental skills past the levels described above.
Seizures. Most children with ILS have seizures which begin during the first year of life, although usually not during the first couple of months. Several different types of seizures may occur. Tonic seizures consist of sudden stiffening, usually of the whole body. They usually lasts only a few moments but can last over a minute. No further jerks are seen. However, brief tonic seizures (each lasting only a few seconds) may occur one after another over a period of many minutes. Tonic-clonic or "grand mal" seizures consist of stiffening of the body and rhythmic jerks of the head, arms and legs. These sometimes involve only part of the body. This type of seizure most often begins after the first year of life. Staring spells consist of open and unmoving eyes with a blank facial expression. These usually last only a few seconds although longer spells are possible. Small movements such as eyelid fluttering or chewing movements sometimes occur.
These seizures can usually be controlled with anti-seizure medications, although 100% control is not often achieved. Because of the mixed types of seizures which occur, certain medications are more likely to be effective than others. Effectiveness of any given medication may differ between children. In many children, the most effective medication is valproic acid (Depakene or Depakote). The second is often clonazepam (Klonopin). Other medicines such as phenobarbitol, phenytoin (Dilantin), carbamazepine (Tegretol) and ethosuximide (Zarontin) may be helpful in some children.
Some children have a severe seizure type known as infantile spasms or jackknife seizures which do not respond to the usual seizure medicines. This type of seizure occurs only in young children, usually between about 3 and 12 months of age. They consist of a cluster of very brief but hard jerks of the whole body. The direction may be either forward or backwards. That is, some children will jerk forward with their heads bent down and their legs pulled up. Others will arch their head and back backwards with the legs straightened. Each jerk lasts only a few seconds after which they relax till the next jerk. Clusters of infantile spasms may last from a few seconds to several minutes. They are most often seen just after awakening from sleep.
The most effective treatment is ACTH shots which stimulate the body to produce cortisone. Prednisone is a man-made drug which resembles cortisone. It may also be effective. Other medicines which may work are valproic acid and clonazepam. Other seizure medicines are much less likely to be effective. If left untreated, infantile spasms will increase in frequency and may result in loss of any developmental abilities. Eventually, they will change to other seizure types.
Feeding. Many children with ILS feed normally as newborns. Others have a weak suck and seem to tire easily while feeding. Weight gain may be poor. Feeding may improve after several days or weeks. More severe feeding problems begin or recur as spasticity becomes more prominent (usually 6 months to 3 years). Typical problems noticed by parents include choking and gagging while feeding, refusing feeding (turning their head away), spitting up and weight loss. The problems are most often caused by aspiration and reflux. Aspiration occurs when liquids or foods fall down the trachea or wind-pipe rather than the esophagus or swallowing tube. Reflux occurs when acid from the stomach shoots back up the esophagus. This is similar to heartburn. Such problems usually get worse over time.
These problems may be managed in several different ways. All require guidance by a physician experienced in treating children. Generally pediatricians will often refer the child to a specialist. The simplest methods are correct positioning of the child during and after feeding with the head up 20-30 degrees from horizontal. The feedings can be thickened. For example, rice cereal can be added to formula. Several medicines may help. If all of these fail and the child's nutrition is inadequate, an operation may be needed to tighten the muscle at the top of the stomach and place a tube directly into the stomach through a small hole in the wall of the abdomen. The tightening operation is called a 'fundal plication' or "Nissen fundal plication" after the Japanese surgeon who first developed the procedure. The opening into the stomach is called a gastrostomy or 'G-tube'.
Illnesses. Children with ILS are at high risk for repeated episodes of pneumonia. This risk is related to their feeding problems and poor coordination of swallowing. However, many do not have this problem. Careful management of the child's saliva and other secretions by chest physiotherapy and suctioning may help, as will quick attention to infections and other illnesses.
Lifespan. Most of the older medical literature concerning children with lissencephaly states that they usually die before age 2 years. In my experience, this is not true. Of the 60 ILS patients known to me, about 20 are 2 years or older and 6 are 5 years or older. The oldest is 19 years. Only 5 have died. However, lifespan is much shorter than normal. Medical studies of large numbers of children with severe mental retardation provide an estimate. For children with severe mental retardation who must be fed by tube, about half will die during any 7 year period of time. That is, about half of 3-year-old children will have died by 10 years, about half of 8-year-old children will have died by 15 years, and so on. The average lifespan is at least twice that for children able to feed themselves.
Cause. ILS may be caused by several different mechanisms, both genetic and non-genetic. The non-genetic causes are understandably hard to prove because they affect the unborn child long before birth, probably at 3-4 months gestation. The non-genetic causes which have the best support include (1) intra-uterine infection and (2) insufficient blood supply to the brain during early pregnancy. Supporting information for these proposed causes include specific abnormalities of pregnancy at 2-4 months gestation such as prolonged vaginal bleeding or viral illness, and signs of secondary damage to the brain such as atrophy and areas of calcium depositions. However, pregnancy history is normal in most mothers, even when infections or blood supply problems are suspected.
Known genetic causes include (3) autosomal recessive inheritance and (4) damage or mutation to genes on chromosome 17. Other genes causing lissencephaly may exist as well. A few children with ILS have had affected brothers or sisters. In these and probably some other families, ILS must be caused by a genetic disease which is inherited as a recessive trait. The risk of recurrence of ILS in siblings of these families is 25%. The reason for this is explained in more detail in the section below which discusses the cause of WWS. In several other children with ILS, a small missing piece of chromosome 17 has been found. This may be compared to a smudge on a Xerox copy. That is, the genetic material from either the mother or the father did not get copied correctly. The missing piece comes from the same region of chromosome 17 as in MDS, but is usually much smaller. The missing piece must contain some critical genes. Their absence somehow causes lissencephaly.
Genetic Counseling. In some children, a specific cause can be identified by testing. For example, areas of scaring may be identified because of calcium depositions on CT scans. Special genetic testing may show a small missing piece of chromosome 17. The recurrence risk for other siblings is very low for families in which either of these causes are identified. In other children with ILS, it is not possible to be sure what caused lissencephaly. However, my overall experience with ILS families suggests a relatively low risk in most families. Out of 42 brothers and sisters of ILS patients, 3 also had ILS. This gives a frequency of about 7%. However, there are subtypes in which the risk is much higher at 25%. Accurate genetic counseling requires evaluation of the particular child and family. In some instances, it will differ from the information given above.
Prenatal Diagnosis. Prenatal diagnosis is possible only for some of the families in which the affected child has a small missing piece of chromosome 17. Examination of the unborn child by ultrasound cannot identify lissencephaly.
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Development and Medical Problems. All Children with MDS have profound mental retardation with minimal developmental abilities as described for ILS patients with 'developmental level 1'. The problems with seizures, feeding and recurrent pneumonia are similar to ILS patients.
Lifespan. Many children with MDS die within the first 2 years of life, especially those with significant heart abnormalities. Others live well beyond 2 years. The oldest child known to me is now 10 years old. Lifespan is usually shorter in children with MDS compared to children with ILS.
Cause. MDS is caused by a 'deletion' or missing piece of one of the two number 17 chromosomes in each cell of the body. Some background will help you understand this. Each of us inherits two copies of almost all of our genes, one from our father and the other from our mother (the exception is the sex chromosomes in males). They are numbered in order of size. That is, chromosome 1 is the largest and chromosomes 21 and 22 are the smallest.
The deletion is large enough to see under the microscope in most children. It involves a specific part of chromosome 17 that is located on the shorter of the two arms of the chromosome. The formal name of the band involved is 17p13.3 (this is read as 'seventeen-p-one-three-point-three'). The location of the band is shown in Figure 4. In the remaining children, the deletion is too small to be seen under the microscope. The chromosomes are interpreted as "normal". These very small deletions can be detected with special tests using small pieces of DNA from this region of the chromosome.
In a few families, one of the parents has a complex rearrangement involving his or her chromosome 17. For example, the tip of chromosome 17 and the tip of some other chromosome can be switched. Although they themselves are normal, parents whose chromosomes have such a switch are said to be 'carriers' and can pass on an abnormal chromosome 17 to their children. Thus, more than one child could have MDS. However, this is uncommon. In most families, the deletion of chromosome 17 is due to a copy error. This can be compared to a smudge on a Xerox copy. That is, the 17p13.3 bands in all number 17 chromosomes from both parents are normal. When the parents chromosomes were copied to form the egg or sperm cell, one of the number 17 chromosomes did not get copied correctly. A small piece was missing. When this gene or group of genes is missing, it somehow results in lissencephaly.
Genetic Counseling. When one of the parents is a carrier, the risk of having other children with MDS is often high (25-50%). If neither parent is a carrier, the risk is very low, probably less than one percent.
Prenatal Diagnosis. Prenatal diagnosis is possible in most families. It is done by looking for the same deletion in the unborn child as was found in the child with MDS. Both examination of the chromosomes under the microscope and direct testing of pieces of DNA from chromosome 17 may be used. Examination of the unborn child by ultrasound is not reliable.
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Most children have had severe medical problems which lead to death during infancy. Many of the children with less severe birth defects and longer lifespan have come from Finland, but a few have been found in Germany and the United States. Finnish doctors use the term 'muscle-eye-brain disease' for these children.
Newborns. Children with severe WWS are often weak at birth and may need oxygen and use of a ventilator to help them breath. Some are stillborn and others die within the first few weeks of life, especially if they have hydrocephalus. Children with mild WWS are not ill a birth but usually do seem floppy and may not feed well.
Birth Defects. Several different types of birth defects occur which are usually recognized by the doctor soon after birth. The most severe of these involve the brain and eyes. A few children have an unusual facial appearance. A very few have cleft lip and palate or cleft palate alone.
Brain. Brain abnormalities are complex (see figures below). First, all children have a smooth brain surface, but it looks much different than the type of lissencephaly seen in children with ILS or MDS. It is called 'type II' lissencephaly for this reason. Most children also have abnormally large ventricles within the brain. This is called hydrocephalus but is also known as 'water on the brain'. Because of this, head size is often too large at birth. Others may have normal or small head size.
In addition, the cerebellum is smaller than normal and often associated with a fluid-filled sack which sits just behind it. This part of the brain is located beneath the back part of the brain and resembles a cauliflower. Sometimes, the sack will extend through a small hole in the skull and form a small fluid-filled sack on the back of their head. This is called a 'cephalocele'.
Eye.
Eye abnormalities are often severe and result in
poor vision (see figures at right). The outer covering of the eye, called the
cornea, may be cloudy or white rather than clear. Bands of
tissue may extend from the
back of the cornea to the front of the iris and lens. The
lens may have a cataract. The drainage system of the eye
sometimes does not work, so a few children will have
increased pressure inside the eye. This results in
glaucoma. A few children have a large mass of blood
vessels and other tissue which goes from the back of the
lens to the retina. This is called PHPV (persistent
hyperplastic primary vitreous). The blood vessels
involved are normal structures before birth which usually
stop growing and are eliminated before birth. PHPV
occurs when they fail to shrink away.
Photoreceptors are the small structures in the eye which detect light. They are located at the back of the eye in a part known as the retina. These receptors send out small nerve twigs which gather to form the optic nerve. The optic nerve then goes back to the brain. In all children with WWS, the retina does not develop properly and does not work well. If the problem is mild, the only visible abnormality may be small size of the optic nerve at the back of the eye. If severe, the entire retina may be pulled away from the back of the eye.
Muscle Disease. All children with WWS have a form of muscular dystrophy. In severe WWS, the brain problems are so severe that the muscle problems are usually not noticed unless special tests are done. In mild WWS, the muscle disease progresses so that the children get weaker during later childhood. There is insufficient experience to determine when this usually occurs. The simplest test for muscle disease is to check the level of 'creatine kinase' (also called CK or CPK) in the blood. It is usually elevated in children with WWS.
Development. Children with severe WWS have profound mental retardation with essentially no developmental gains. They are very inactive and floppy with poor head control. Arching spasms and stiffness (spasticity) may occur. They are also frequently blind because of a combination of eye and brain abnormalities. In those with mild WWS, developmental gains vary greatly. Some learn to roll and reach but little else, similar to ILS patients with 'developmental level 2'. Others, mostly reported from Finland, have learned to walk and even talk. The muscle disease in this group of children progresses noticeably.
Feeding Problems. Feeding problems are similar to those in ILS but may begin earlier and be even more severe. As would be expected, this is less of a problem in the milder WWS children.
Seizures. Seizure problems may not be noticed in children with severe WWS because other medical problems are so severe. This is especially true for those who live only a short time. In those who survive, seizure types and management are similar to ILS and MDS although I have less personal experience with them.
Lifespan. Most children with severe WWS survive less than a year, although a few have survived for several years. Those with mild WWS may survive much longer. Several patients from Finland have survived into young adulthood when the muscle disease begins to make them progressively weaker.
Cause.
WWS is a genetic disease which is inherited as
a recessive trait (refer to figure at right). It is not sex-linked. This
means that both the mother and the father of the child are
carriers of a WWS disease gene. That is, they have one
copy of the gene which has normal function and another
that does not work. Because one working copy is all that
is needed for normal function, both are normal
individuals. The child inherits one WWS disease gene
from the mother and another from the father. The child
thus has no working copies of the gene and develops the
disease.
Because the mother has two copies of the gene, each time she conceives a child, the risk is 1 out of 2 that she will pass on the WWS disease gene. The same is true for the father. Thus, the chance that the parents will each pass on a WWS disease gene is 1/2 x 1/2 = 1/4. To turn this around, the chance that another child will be normal is 3/4 or 75%.
Prenatal Diagnosis. Prenatal diagnosis is possible in most instances by performing a detailed examination of the unborn child by ultrasound. This should only be done by a doctor experienced in using ultrasound for prenatal diagnosis. Even when done by an expert, errors are possible. That is, a normal child could be considered affected or an affected child might be considered normal. Based on the limited experience available at this time, a large majority of unborn children at risk for WWS have been diagnosed correctly as either normal or affected.
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Many different causes of lissencephaly have been identified. Genetic counseling can be complicated. The risk of recurrence of lissencephaly in sibs varies from 0% to near 50% in different disorders. Parents should not rely on this summary to provide accurate genetic counseling for them because of the many different causes which may have very different recurrence risks.
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