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Genetics Home Reference: your guide to understanding genetic conditions
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X-linked lissencephaly with abnormal genitalia

Reviewed August 2013

What is X-linked lissencephaly with abnormal genitalia?

X-linked lissencephaly with abnormal genitalia (XLAG) is a condition that affects the development of the brain and genitalia. It occurs most often in males.

XLAG is characterized by abnormal brain development that results in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. Individuals without any folds in the brain (agyria) typically have more severe symptoms than people with reduced folds and grooves (pachygyria). Individuals with XLAG may also have a lack of development (agenesis) of the tissue connecting the left and right halves of the brain (corpus callosum). The brain abnormalities can cause severe intellectual disability and developmental delay, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties. Starting soon after birth, babies with XLAG have frequent and recurrent seizures (epilepsy). Most children with XLAG do not survive past early childhood.

Another key feature of XLAG in males is abnormal genitalia that can include an unusually small penis (micropenis), undescended testes (cryptorchidism), or external genitalia that do not look clearly male or clearly female (ambiguous genitalia).

Additional signs and symptoms of XLAG include chronic diarrhea, periods of increased blood sugar (transient hyperglycemia), and problems with body temperature regulation.

How common is X-linked lissencephaly with abnormal genitalia?

The incidence of XLAG is unknown; approximately 30 affected families have been described in the medical literature.

What genes are related to X-linked lissencephaly with abnormal genitalia?

Mutations in the ARX gene cause XLAG. The ARX gene provides instructions for producing a protein that is involved in the development of several organs, including the brain, testes, and pancreas. In the developing brain, the ARX protein is involved with movement and communication in nerve cells (neurons). The ARX protein regulates genes that play a role in the migration of specialized neurons (interneurons) to their proper location. Interneurons relay signals between neurons. In the pancreas and testes, the ARX protein helps to regulate the process by which cells mature to carry out specific functions (differentiation).

ARX gene mutations lead to the production of a nonfunctional ARX protein or to the complete absence of ARX protein. As a result, the ARX protein cannot perform its role regulating the activity of genes important for interneuron migration. In addition to impairing normal brain development, a lack of functional ARX protein disrupts cell differentiation during the formation of the testes, leading to abnormal genitalia. It is thought that the disruption of ARX protein function in the pancreas plays a role in the chronic diarrhea and hyperglycemia experienced by individuals with XLAG.

Related Gene(s)

Changes in this gene are associated with X-linked lissencephaly with abnormal genitalia.

  • ARX

How do people inherit X-linked lissencephaly with abnormal genitalia?

This condition 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 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 gene in each cell can lead to less severe brain malformations 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 X-linked lissencephaly with abnormal genitalia?

These resources address the diagnosis or management of X-linked lissencephaly with abnormal genitalia and may include treatment providers.

  • Genetic Testing Registry: X-linked lissencephaly 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1846171)

You might also find information on the diagnosis or management of X-linked lissencephaly with abnormal genitalia in Educational resources (http://www.ghr.nlm.nih.gov/condition/x-linked-lissencephaly-with-abnormal-genitalia/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/x-linked-lissencephaly-with-abnormal-genitalia/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 X-linked lissencephaly with abnormal genitalia?

You may find the following resources about X-linked lissencephaly with abnormal genitalia 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 X-linked lissencephaly with abnormal genitalia?

  • LISX2
  • XLAG
  • X-linked lissencephaly 2
  • X-linked lissencephaly with ambiguous genitalia
  • XLISG

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 X-linked lissencephaly with abnormal genitalia?

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

What glossary definitions help with understanding X-linked lissencephaly with abnormal genitalia?

agenesis ; cell ; chromosome ; chronic ; corpus callosum ; cryptorchidism ; developmental delay ; differentiation ; disability ; epilepsy ; gene ; genitalia ; hyperglycemia ; hypotonia ; incidence ; inheritance ; inherited ; micropenis ; muscle tone ; neuronal migration ; pancreas ; protein ; sex chromosomes ; spasticity ; testes ; tissue ; transient

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

References

  • Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber P, Barthez MA, Radi S, Biran-Mucignat V, Rodriguez D, Gélot A. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann Neurol. 2002 Mar;51(3):340-9. (http://www.ncbi.nlm.nih.gov/pubmed/11891829?dopt=Abstract)
  • Kato M, Dobyns WB. X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". J Child Neurol. 2005 Apr;20(4):392-7. (http://www.ncbi.nlm.nih.gov/pubmed/15921244?dopt=Abstract)
  • Miyata R, Hayashi M, Miyai K, Akashi T, Kato M, Kohyama J. Analysis of the hypothalamus in a case of X-linked lissencephaly with abnormal genitalia (XLAG). Brain Dev. 2009 Jun;31(6):456-60. doi: 10.1016/j.braindev.2008.08.008. Epub 2008 Oct 7. (http://www.ncbi.nlm.nih.gov/pubmed/18842366?dopt=Abstract)
  • Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat. 2010 Aug;31(8):889-900. doi: 10.1002/humu.21288. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20506206?dopt=Abstract)
  • Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-Schäfer H, Hehr U, Winkler J. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003 Jul 22;61(2):232-5. (http://www.ncbi.nlm.nih.gov/pubmed/12874405?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: August 2013
Published: October 20, 2014