Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886
Vol. 51, Num. 3, 2003, pp. 392-393
Untitled Document

Neurology India, Vol. 51, No. 3, July, 2003, pp. 392-393

X-linked lissencephaly in an Indian family


Departments of Neurology, All India Institute of Medical Sciences, New Delhi - 110 029

Correspondence Address:
Department of Neurology, Room No.705, C. N. Centre, A.I.I.M.S., New Delhi - 110 029
mantrips@ hotmail.co

Code Number: ni03128

ABSTRACT

Neuronal migration disorders are an important differential diagnosis to be considered in the evaluation of intractable epilepsy. Though the underlying causative factors which govern their development are many and varied, genetic factors have been found to be contributory in a few forms of these disorders. An X–linked association with lissencephaly has recently been discovered and there are a few families described till now with this entity.

INTRODUCTION

Neuronal migration disorders are often found as the underlying cause of intractable epilepsy and mental retardation. Though the genetic basis of these malformations has been established in some forms of these disorders, X- linked lissencephaly and its associations have only recently been documented. We report here a family with lissencephaly, probably X-linked, and briefly review the literature.

CASE REPORT

A 2-and-a-half-year-old boy presented with a history of intractable epilepsy. The boy was born of a full term normal delivery with no significant perinatal events. The parents had noticed that the child had a small head since birth. Since the age of 2-and-a-half months, the child had recurrent seizures, 2-3 times a day, characterized by tonic posturing of the body with uprolling of the eyes lasting for 1-2 minutes. The child also had sudden episodic flexion of his limbs suggesting a myoclonus, up to 10-15 times per day, lasting for less than a second. He had a weak cry, difficulty in sucking, and stiffness of limbs. He was unable to turn in bed, was unable to sit, stand and talk appropriately for his age. His head circumference was 43 cm. He had a peculiar facial appearance characterized by an elongated face with a small chin, micrognathia and hypertelorism. The fundus was normal. The child could not follow simple commands but would follow sound and light. He had poor neck control. He made non-purposive movements of all four limbs while lying in bed but could not sit or stand independently. The tone in the limbs was increased with brisk reflexes and the planters were bilaterally extensor.

The boy had two brothers and one sister. Both his male siblings had a history of similar small head. Both brothers were asymptomatic and normal. The sister was normal. There was no history of seizures in the family. The patient was treated with multiple antiepileptic drugs and ACTH with slight reduction in seizure frequency.

Neuroimaging studies were done for the patient and his younger male sibling. Plain CT head of the patient revealed prominence of lateral ventricles with no obvious parenchymal abnormality. The MRI brain showed normal myelination for age with evidence of poor sulcation and thickened cortex and associated ventriculomegaly, which was suggestive of pachygyria [Figure-1]. The MRI brain of the younger brother showed smooth cortical surface with pachygyria [Figure-2]. Imaging could not be done for the rest of the siblings and parents. Cerebrospinal fluid (CSF) titers for toxoplasma, rubella, cytomegalovirus and herpes (TORCH) were negative in the index case.

DISCUSSION

Neuronal migration disorders commonly present in childhood as intractable epilepsy and mental subnormality. The proliferation and differentiation of the neuronal precursors in the periventricular germinal matrix and their migration to the cortical mantle begins in the sixth gestational week. The radial glial fibers form the framework on which the nerve cells migrate.[1] The migrating neuroblasts which initially maintain affinity with the radial glial fibers through specific glycoproteins, detach themselves on approaching the cortex. They subsequently interact with the dendrites and axon terminals of other neuroblasts and engage in layer formation. The migration of the neuroblasts occurs in an 'inside-out' fashion in that the last cells migrate to the superficial layers of the cortex.[2]

Abnormalities of neuronal migration at any stage give rise to a group of congenital malformations comprising lissencephaly (agyria-pachygyria), pachygyria, schizencephaly, heterotopia and polymicrogyria. Cytoarchitectonic analysis of the agyric cortex suggests a disorder of neuronal migration between the 11th and 13th fetal week while the pachygyric cortex shows attenuated and later disorder acting in the Rakic and Sidman stage IV after the 13th fetal week. Therefore, there is a gradient from the agyric to the normal six-layered cortex. Polymicrogyria presumably results from events after the 16th fetal week when the migration has terminated.[3] When the layer of misplaced neurons is thinner, the later migrating neuroblasts pass through it to reach the cortex and form the double cortex. Sometimes when there is arrest of migration right at the place of origin, diffuse periventricular heterotopias occur. The latter two conditions are often associated with normal gyri.

The possible causes of neuronal migration disorders may be acquired or genetic. The acquired etiologies include cytomegalovirus and toxoplasmosis infections, exposure to toxins such as ethanol, carbon monoxide, isotretinoic acid and cytotoxic drugs, effects of ionizing radiation and intrauterine circulatory disturbances.[4] Classical lissencephaly occurring either as an isolated lissencephaly sequence or in association with the Miller-Dieker syndrome (MDS), has been found to be associated with visible or submicroscopic deletions of chromosome 17p 13.3 (in upto 90% of MDS patients).[4],[5],[6] The identification of unbalanced translocations and inversions is of particular importance because of the risk of recurrence, while deletions and ring chromosomes are mainly sporadic. Syndromes featuring lissencephaly type II are most probably autosomal recessively inherited though the location of the gene and the nature of the mutations are not known.

Recently, two distinct X-linked malformations of neuronal migration have been described, namely X-linked lissencephaly (XLIS) and subcortical band heterotopia (SBH) localized to chromosome Xq22.3, and bilateral periventricular nodular heterotopia which is mapped to chromosome Xq28. XLIS has been delineated as a specific genetic syndrome with manifestations in males as lissencephaly and in females as SBH. The clinical features of XLIS are similar to the classical form of lissencephaly. Patients with SBH are mostly females and manifest with mental retardation, behavior problems and epilepsy. This skew towards females reflects the potential lethality of the mutation in the affected males. XLIS has so far been documented in only 7 families.[7],[8],[9],[10],[11],[12] The existence of XLIS has been supported by chromosomal studies which show an apparently balanced denovo X - autosomal translocation in the gene at Xq22.3.[13] Though the nature of the product of the XLIS gene is not known, the phenotypic variability in the different sexes could be based on the complete absence of the gene product in males and functional mosaicism in females.

The family described by us comprised three brothers, all of whom had microcephaly. The mother and sister were not evaluated by MRI brain and therefore comment regarding any association with SBH cannot be made. Chromosomal analysis was not possible. However, on the basis of the phenotypic and imaging correlations, it is appropriate to propose that there exists a definite X-linked association between the presentations of lissencephaly in the male siblings.

X-linked lissencephaly is a rare syndrome and needs documentation by clinical and molecular biological tools. Awareness and detection of this entity prenatally is important for preventive neurology and genetic counseling.

REFERENCES

1. Barkovich AJ, Gressens P, Evrard P. Formation, maturation and disorders of brain neocortex. AJNR Am J Neuroradiol 1992;13:423-46.  
2. Rakic P. Specification of cerebral cortical areas. Science 1988;241:170-6. 
3. Jellinger K, Rett A. Agyria - pachygyria (lissencephaly syndrome). Neuropaediatrics 1976;7:66-91. 
4. Barth PG. Disorders of neuronal migration. Can J Neurol Sci 1987;14:1-16. 
5. Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development: 1995 update. Neuropaediatrics 1995;26:132-47.
6. Dobyns WB, Reimer O, Carazzo R, et al. Lissencephaly: a human brain malformation associated with deletion of the L1S1 gene located at chromosome 17p13. J Am Med Asso 1993;270:2838-42.      
7. Pavone L, Gullotta F, Incorpora G, et al. Isolated lissencephaly: report of four patients from two unrelated families. J Child Neurol 1990;5:52-9.
8. Berry-Kravis E, Israel J. X-linked pachygyria and agenesis of corpus callosum: evidence for an X chromosome lissencephaly locus. Ann Neurol 1994;36:229-33. 
9. Pinard J-M, Motte J, Chiron C, et al. Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene. J Neurol Neurosurg Psychiatry 1994;57:914-20.      
10. Scheffer IE, Mitchell LA, Howell RA, et al. Familial band heterotopias; an X-linked dominant disorder with variable severity (abstract). Ann Neurol 1994;36:511. 
11. Puche A, Rodriguez T, Domingo R, et al. X-linked subcortical laminar heterotopia and lissencephaly: a new family. Neuropaediatrics 1998;29:276-8.   
12. Berg MJ, Sciffito G, Powers JM, et al. X-linked female band heterotopia - male lissencephaly syndrome. Neurology 1998;50:1143-6.      
13. Dobyns WB, Andermann E, Andermann F. et al. X-linked malformations of neuronal migration. Neurology 1996;47:331-9.       

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