Abstracts & Commentary
Sources: Uyanik G, et al. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003;61:232-235; Kato M, et al. Polyalanine expansion of ARX associated with cryptogenic West syndrome. Neurology. 2003;61:267-276.
Homeobox genes comprise a family of highly conserved genes responsible for developmental patterning by regulating expression of target genes in a temporal, spatial, and tissue-specific fashion. ARX (Xp22.13) is the human ortholog of Aristaless, a Drosophila homeobox gene involved in the development of specific head segments. ARX codes for a transcriptional factor expressed in fetal brain and testes. Mutations of ARX have been implicated in various X-linked neurological disorders involving cerebral cortical dysgenesis, mental retardation, and seizures.1
While other mutations have been previously described,2 Uyanik and colleagues describe novel mutations in ARX that are involved in X-linked lissencephaly with abnormal genitalia (XLAG). The XLAG phenotype, as expressed in the 2 probands studied, consists of postnatal growth retardation with hypotonia, microcephalus, hypothalamic dysfunction (episodic hypothermia), and micropenis with cryptorchidism. Seizure-types included tonic, tonic-clonic, and multifocal myoclonic, resistant to 4 antiepileptic drugs used in combination. Brain MRI showed lissencephaly with a moderately thickened cortex, agenesis of the corpus callosum, cystic lesions in the subependymal zone (Case 1), and small basal ganglia. Case 1 had a frameshift mutation (790delC) that leads to premature truncation and loss of expression of the protein product. In Case 2 from a different family, the ARX mutation was a single point mutation (994CtoT), changing a highly conserved arginine to a cysteine residue within the homeodomain.
Kato and associates describe a boy with cryptogenic West syndrome with an expansion of a polyalanine repeat in ARX. This has been previously reported3 in other families with X-linked West syndrome. Polymerase chain reaction and sequencing of the proband’s ARX showed a 24-base-pair duplication, leading to expansion from 12 to 20 alanine residues in the second of 4 polyalanine tracts in this gene. Perhaps the lack of MRI-detectable brain abnormalities in this patient and others with the same mutation is due to the fact that the polyalanine expansion (in contrast to the XLAG alleles) allows conservation of some homeodomain function.
Commentary
A query for "epilepsy" in "Online Mendelian Inheritance in Man" in PubMed yields 264 entries as of the time of this writing. Eighteen months earlier 206 items relating to epilepsy were listed in this database, reflecting the rapid progress in investigating the molecular genetics of the epilepsies. These entries generally list a single gene map locus (chromosomal location) for specific syndromic epilepsies. In other instances, however, multiple loci are identified for a single epileptic phenotype. Conversely, depending upon the nature of the allelic mutation (eg, out of frame insertions or deletions, missense or nonsense polymorphisms), a single gene locus can give rise to several different phenotypes.
Where gene products have been identified, the causes of these genetic epilepsies can be broadly categorized into 3 groups: channelopathies, involving ion channel or receptor pathology (eg, potassium channels in benign familial neonatal convulsions); "enzymatic" (eg, cystatin B, a cysteine protease inhibitor, in Baltic myoclonus); and migrational disorders, involving either structural proteins (eg, filamin in periventricular heterotopias) or genes involved in signal transduction or transcriptional regulation, as reported by Kato et al.
In time, these details of molecular pathophysiology may be exploited for truly rational targeted drug design and to explore new treatment options for epilepsy. The practicing neurologist will soon find that knowledge of these developments will quickly become part of his or her routine stock-in-trade. As far as the agenda for the molecular neurogeneticist, the challenge in the longer term lies in the focal epilepsies. The majority of seizure patients have "idiopathic" focal epilepsy. Researchers have not even begun to scratch the surface in investigating the presumed polygenic determinants that give rise to a "tendency" toward seizures in this population. — Andy Dean
References
1. Wellington C. Clin Genet. 2003;63:177-179.
2. Kitamura K, et al. Nat Genet. 2002;32:359-369.
3. Stromme P, et al. Brain Dev. 2002;24:266-268.
Andy Dean is Assistant Professor of Neurology and Neuroscience, Director of the Epilepsy Monitoring Unit, Department of Neurology, New York Presbyterian Hospital—Cornell Campus.
Homeobox genes comprise a family of highly conserved genes responsible for developmental patterning by regulating expression of target genes in a temporal, spatial, and tissue-specific fashion.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content