by William B. Dobyns, M.D.

Copyright © 1994, William B. Dobyns, All Rights Reserved, Used by Permission

When the Lissencephaly Research Project began in 1982, genetic counseling for patients of affected children was simple. Lissencephaly was a genetic disease with autosomal recessive inheritance, so the recurrence risk in future full siblings was 1-in-4 or 25 percent. Now almost 20 different lissencephaly syndromes have been recognized with a wide range of recurrence risks. For some diseases, the recurrence risk is negligible. For others, the risk is 25 percent or greater. Most geneticist and genetic counselors are able to provide the correct counseling information based on the child's diagnosis. The problem is to make sure that the diagnosis is correct. This often requires the help of a pediatric neurologist or neuroradiologist.

For some lissencephaly syndromes, the correct diagnosis is all that is required for genetic counseling. For others, especially Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS), chromosome analysis and sometimes FISH testing is also needed. The most current information regarding genetic recurrence risks for most lissencephaly syndromes is shown in the table below.

The most common lissencephaly syndromes (at least in the Network) are MDS and ILS. If your child has MDS and one parent is the carrier of a "balanced: chromosome abnormality in which the short arm of chromosome 1 has been moved to a different place, the recurrence risk is high, possibly even greater than 25 percent. If your child has ILS and no deletion of the LIS 1 gene on chromosome 17 has been found, the recurrence risk is about 5 percent. If your child has MDS or ILS and a deletion of the LIS 1 gene was found, then it is important to check for the same deletion in both parents. When the test in the parents is normal, the recurrence risk for future children is very low, probably less than 1 percent.

While MDS and ILS are relatively common, there are many children with lissencephaly with other syndromes. Many of these other syndromes are autosomal recessive. The recurrence risk for these disorders is 25 percent, which is considered high by most parents.

What do most parents do when they learn of these risks but want more children? It varies from couple to couple. However, most parents consider a risk of 5 percent or less to be low and most consider a risk of 10 percent or greater to be high. Parents given a "low" recurrence risk are more likely to try to have more children than parents given a "high" recurrence risk. If you are given a "high" recurrence risk and you still want children, artificial insemination by donor may be an option. This would need to be discussed with a genetic counselor on an individual basis.

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Table. Recurrence Risks in Different Lissencephaly Syndromes
Disorder				Inheritance	Recurrence Risk (%)
Classical Lissencephaly
	Isolated Lissencephaly Sequence			AD/mutation
		LIS 1 Gene Deletion			1
		No Deletion Found			5
	Miller-Dieker Syndrome
		LIS 1 Gene Deletion
			Parent is Carrier	AD/chromosomal	25 - ?
			Parent is Not a Carrier	AD/mutation	1
	X-Linked Lissencephaly and Sub-cortical Band Heterotopia (SBH)			XL
			Sons (with lissencephaly)		50
			Daughters (with SBH)		50
Cobblestone Lissencephaly
	Fukuyama Congenital Muscular Dystrophy			AR	25
	Muscle-Eye-Brain Disease			AR	25
	Walker-Warburg Syndrome			AR	25
	Cobblestone Lissencephaly Only			AR	25
Partial Lissencephaly or Polymicrogyria (PMG)
	Bilateral Frontal Pachygyria/PMG			AR	25
	Bilateral Frontal Pachygyria/PMG with Eye Malformations			AR	25
	Bilateral Opercular Polymicrogyria			AR	25
	Bilateral Opercular Pachygyria			AR	25
	Other Polymicrogyria
		Known Intra-uterine Virus		-	0
		Cause Unknown		??	low-?
Diffuse Heterotopia
	Bilateral Periventricular Nodular Heterotopia (females)			XL
		Daughters (with BPNH)			50-?
		Sons (with ??)			??
	Bilateral Periventricular Nodular Heterotopia (males)			??	??
	Sub-cortical Band Heterotopia			XL	see above
Rare Lissencephaly Syndromes
	Lissencephaly with Cerebellar Hypoplasia			AR-?	25-?
	Lissencephaly with Neonatal Death			AR	25
	Shallow Orbits-Ptosis-Colobomas- Trigonocephaly-Lissencephaly Syndrome			??	??
	Winter-Tsukuhara Syndrome			AR	25

The codes used in the table require some explanation. AD/chromosomal refers to an autosomal dominant disorder which is caused by a chromosome abnormality for which one parent is the carrier. The most common type of chromosome abnormality which causes MDS is known as a reciprocal translocation. AD/mutation refers to an autosomal dominant disorder caused by a new mutation that neither parent is a carrier. AR refers to autosomal recessive inheritance in which each parent is normal, but carries one copy of the disease gene. The recurrence risk for AR disorders is 25 percent. XL refers to X-linked inheritance in which males have severe expression of the disease and females no symptoms or milder symptoms than in males. The risk to sons is 50 percent. The risk to daughters may be negligible or may be as high as 50 percent for less severe abnormalities.

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