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Isolated lissencephaly sequence

Reviewed July 2013

What is isolated lissencephaly sequence?

Isolated lissencephaly sequence (ILS) is a condition that affects brain development before birth. Normally, the cells that make up the exterior of the brain (cerebral cortex) are well-organized, multi-layered, and arranged into many folds and grooves (gyri). In people with ILS, the cells of the cerebral cortex are disorganized, and the brain surface is abnormally smooth with an absence (agyria) or reduction (pachygyria) of folds and grooves. In most cases, these abnormalities impair brain growth, causing the brain to be smaller than normal (microcephaly). This underdevelopment of the brain causes severe intellectual disability, delayed development, and recurrent seizures (epilepsy) in individuals with ILS.

More than 90 percent of individuals with ILS develop epilepsy, often within the first year of life. Up to 80 percent of infants with ILS have a type of seizure called infantile spasms, these seizures can be severe enough to cause brain dysfunction (epileptic encephalopathy). After the first months of life, most children with ILS develop a variety of seizure types, including persisting infantile spasms, short periods of loss of consciousness (absence seizures); sudden episodes of weak muscle tone (drop attacks); rapid, uncontrolled muscle jerks (myoclonic seizures); and episodes of muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures).

Infants with ILS may have poor muscle tone (hypotonia) and difficulty feeding, which leads to poor growth overall. Hypotonia also affects the muscles used for breathing, which often causes breathing problems that can lead to a life-threatening bacterial lung infection known as aspiration pneumonia. Children with ILS often develop muscle stiffness (spasticity) in their arms and legs and an abnormal side-to-side curvature of the spine (scoliosis). Rarely, the muscle stiffness will progress to paralysis (spastic paraplegia). Individuals with ILS cannot walk and rarely crawl. Most children with ILS do not develop communication skills.

How common is isolated lissencephaly sequence?

ILS affects approximately 1 in 100,000 newborns.

What genes are related to isolated lissencephaly sequence?

Mutations in the PAFAH1B1, DCX, or TUBA1A gene can cause ILS. PAFAH1B1 gene mutations are responsible for over half of ILS cases; DCX gene mutations cause about 10 percent of cases; and TUBA1A gene mutations cause a small percentage of ILS. These genes provide instructions for making proteins that are involved in the movement (migration) of nerve cells (neurons) to their proper locations in the developing brain. Neuronal migration is dependent on cell structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules form scaffolding within the cell that elongates in a specific direction, altering the cytoskeleton and moving the neuron. The protein produced from the TUBA1A gene is a component of microtubules. The proteins produced from the DCX and PAFAH1B1 genes promote neuronal migration by interacting with microtubules.

Mutations in any of these three genes impair the function of microtubules and the normal migration of neurons during fetal development. As a result, the layers of the cerebral cortex are disorganized and the normal folds and grooves of the brain do not form. This impairment of brain development leads to the smooth brain appearance and the resulting neurological problems characteristic of ILS.

Some individuals with ILS do not have an identified mutation in any of these three genes; the cause of the condition in these individuals may be unidentified mutations in other genes that affect neuronal migration or other unknown factors.

Related Gene(s)

Changes in these genes are associated with isolated lissencephaly sequence.

  • DCX
  • PAFAH1B1
  • TUBA1A

How do people inherit isolated lissencephaly sequence?

The inheritance pattern of ILS depends on the gene involved.

When ILS is caused by mutations in the PAFAH1B1 or TUBA1A gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

When mutations in the DCX gene cause ILS, it is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the DCX gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the DCX gene in each cell can lead to a less severe condition in females called subcortical band heterotopia, or may cause no symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Where can I find information about diagnosis or management of isolated lissencephaly sequence?

These resources address the diagnosis or management of isolated lissencephaly sequence and may include treatment providers.

  • Gene Review: DCX-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK1185)
  • Gene Review: LIS1-Associated Lissencephaly/Subcortical Band Heterotopia (http://www.ncbi.nlm.nih.gov/books/NBK5189)
  • Genetic Testing Registry: Lissencephaly 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1843916)
  • Genetic Testing Registry: Lissencephaly 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1969029)
  • Genetic Testing Registry: X-linked lissencephaly (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1848199)

You might also find information on the diagnosis or management of isolated lissencephaly sequence in Educational resources (http://www.ghr.nlm.nih.gov/condition/isolated-lissencephaly-sequence/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/isolated-lissencephaly-sequence/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about isolated lissencephaly sequence?

You may find the following resources about isolated lissencephaly sequence helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for isolated lissencephaly sequence?

  • classical lissencephaly
  • ILS
  • LIS1
  • lissencephaly, classic
  • lissencephaly type 1
  • type 1 lissencephaly

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about isolated lissencephaly sequence?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding isolated lissencephaly sequence?

autosomal ; autosomal dominant ; cell ; cerebral cortex ; chromosome ; cytoskeleton ; disability ; encephalopathy ; epilepsy ; epileptic ; gene ; hypotonia ; infection ; inheritance ; inheritance pattern ; inherited ; microcephaly ; muscle tone ; mutation ; neurological ; neuron ; neuronal migration ; paraplegia ; pneumonia ; protein ; scoliosis ; seizure ; sex chromosomes ; spasticity ; subcortical

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • de Wit MC, de Rijk-van Andel J, Halley DJ, Poddighe PJ, Arts WF, de Coo IF, Mancini GM. Long-term follow-up of type 1 lissencephaly: survival is related to neuroimaging abnormalities. Dev Med Child Neurol. 2011 May;53(5):417-21. doi: 10.1111/j.1469-8749.2011.03937.x. Epub 2011 Mar 17. (http://www.ncbi.nlm.nih.gov/pubmed/21410694?dopt=Abstract)
  • Dobyns WB. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia. Epilepsia. 2010 Feb;51 Suppl 1:5-9. doi: 10.1111/j.1528-1167.2009.02433.x. (http://www.ncbi.nlm.nih.gov/pubmed/20331703?dopt=Abstract)
  • Friocourt G, Marcorelles P, Saugier-Veber P, Quille ML, Marret S, Laquerrière A. Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly. Acta Neuropathol. 2011 Feb;121(2):149-70. doi: 10.1007/s00401-010-0768-9. Epub 2010 Nov 3. Review. (http://www.ncbi.nlm.nih.gov/pubmed/21046408?dopt=Abstract)
  • Guerrini R, Parrini E. Neuronal migration disorders. Neurobiol Dis. 2010 May;38(2):154-66. doi: 10.1016/j.nbd.2009.02.008. Epub 2009 Feb 23. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19245832?dopt=Abstract)
  • Liu JS. Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep. 2011 Apr;11(2):171-8. doi: 10.1007/s11910-010-0176-5. Review. (http://www.ncbi.nlm.nih.gov/pubmed/21222180?dopt=Abstract)
  • Saillour Y, Carion N, Quelin C, Leger PL, Boddaert N, Elie C, Toutain A, Mercier S, Barthez MA, Milh M, Joriot S, des Portes V, Philip N, Broglin D, Roubertie A, Pitelet G, Moutard ML, Pinard JM, Cances C, Kaminska A, Chelly J, Beldjord C, Bahi-Buisson N. LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity. Arch Neurol. 2009 Aug;66(8):1007-15. doi: 10.1001/archneurol.2009.149. (http://www.ncbi.nlm.nih.gov/pubmed/19667223?dopt=Abstract)
  • Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatr. 2009 Mar;98(3):421-33. doi: 10.1111/j.1651-2227.2008.01160.x. Epub 2008 Dec 16. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19120042?dopt=Abstract)
  • Tian G, Jaglin XH, Keays DA, Francis F, Chelly J, Cowan NJ. Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway. Hum Mol Genet. 2010 Sep 15;19(18):3599-613. doi: 10.1093/hmg/ddq276. Epub 2010 Jul 5. (http://www.ncbi.nlm.nih.gov/pubmed/20603323?dopt=Abstract)
  • Verrotti A, Spalice A, Ursitti F, Papetti L, Mariani R, Castronovo A, Mastrangelo M, Iannetti P. New trends in neuronal migration disorders. Eur J Paediatr Neurol. 2010 Jan;14(1):1-12. doi: 10.1016/j.ejpn.2009.01.005. Epub 2009 Mar 4. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19264520?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: July 2013
Published: December 22, 2014