X-linked Lissencephaly : a Smooth Brain and a Rough Journey for a 15-Year-Old-Patient

1 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2 Department of Pediatric Neurology, „Dr. Victor Gomoiu” Children’s Hospital, Bucharest, Romania 3 Regional Centre of Medical Genetics Dolj, Emergency County Clinical Hospital, Human Genomics Laboratory, University of Medicine and Pharmacy, Craiova, Romania Corresponding author: Zaharia Marius, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania. E-mail: zahariamarius16@gmail.com Abstract

Recent neurological exam showed spastic tetraparesis.She had severe mental retardation (IQ less than 20) and motor stereotypes characterized by hand movements on the median line of the body.
Th e genetic testing through MLPA showed that there were no deletions or duplications in the genes involved in lissencephaly (PAFAH1B1, DCX, POMT1, POMGnT1 or FLNA).Further genetic investigations need to be done.MRI evaluation detected bilateral bands of heteretopic gray matter located between the ventricular walls and cortex (double cortex aspect) and ventriculomegaly.Th ose bands were separated from the cortical mantle by a thin layer of white matter (Figure 2 and 3).
Based on the evidence previous presented, the diagnostic was clear: heterotopia in the subcortical band, also known as X-linked lissencephaly or double cortex syndrome.

CONCLUSIONS
X-linked lissencephaly is a rare congenital anomaly of the brain, aff ecting mostly women, characterized by specifi c clinical and imagistic signs.Although there are distinctive clinical signs, performing brain MRI is required to establish the diagnosis.Paraclinical investigations are extremely important in order to fi nd the optimal therapeutic scheme, to obtain seizure control and

INTRODUCTION
Th e cerebral cortex shows a precise layering of multiple neuronal types with distinct form and function, essential for the cognitive functions that defi ne us as humans.Remarkably, cortical neurons are not formed in the cortex itself but in specialized proliferative regions deep in the brain, so that postmitotic neurons must migrate as far as 1000 cell body-lenghts to reach their fi nal destination 1 .Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with defi cient neuronal migration and abnormal formation of cerebral convolutions or gyri.Th e LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia 2 .Recently, a gene located on chromosome X was identifi ed, that causes lissencephaly in carrier women of heterozygous mutations 1 .
Th e overall incidence of lissencephaly is estimated around 1.2/100,000 births 3 .Although once thought to be rare, malformations of the cerebral cortex represent a major cause of recurrent seizures in children and adults.Magnetic resonance imaging (MRI) has detected focal cortical dysplasia in 25% of children with intractable focal onset seizures 4 .
Th is severe developmental disorder leads to a thickened cerebral cortex whose normally folded contour is simplifi ed and smooth.X-linked lissencephaly also known as subcortical band heterotopia is characterized through bilateral bands of disorganized gray matter located just beneath the cortex and separated by a thin band of white matter.Th e most common clinical manifestation in patients with subcortical band heterotopia is epilepsy with polymorphic seizures 5 .Th e relative thickness of the band often correlates with the severity of mental retardation and seizures 6 .By far the greatest number of individuals diagnosed are females 7 .Th e gold standard of diagnosis for this pathology is represented by MRI or anatomopathological examination of the brain.

CLINICAL REPORT
We report the case of a 15-year-old girl diagnosed with lissencephaly, mental retardation and focal seizu res.Th e patient was born from young, healthy and unrelated parents.Family history revealed that her cousin had Menkes disease.She showed signs of developmental delay since she was 3 months old.Th e fi rst seizures occurred at 6 months.Computerized tomography, performed immediately after the fi rst seizures, identifi ed a very thin gray matter aspect and ventriculomegaly, es- an effi cient long term management, thus increasing quality of life.Despite the fact that a CT was performed right after the fi rst seizures occured, its limitations regarding resolution did not allow the detection of anomalies like subcortical band heterotopia.Also, the importance of the MRI is greater in certain cases such as this one, considering the fact that genetic testing did not detect any alteration in the genes associated with subcortical band heterotopia.

Compliance with ethics requirements:
Th e authors declare no confl ict of interest regarding this article.
Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law.Informed consent was obtained from all the patients included in the study.

Figure 2 .
Figure 2. Cerebral MRI T1 Axial View.Ventriculomegaly (arrows).Figure 3. Cerebral MRI T2 Axial View.Ventriculomegaly (arrows).Disorganized gray matter located just beneath the cortex and separated from it by a thin band of white matter (triangles).

Figure 3 .
Figure 2. Cerebral MRI T1 Axial View.Ventriculomegaly (arrows).Figure 3. Cerebral MRI T2 Axial View.Ventriculomegaly (arrows).Disorganized gray matter located just beneath the cortex and separated from it by a thin band of white matter (triangles).