Autosomal recessive type I lissencephaly
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《美国医学杂志》
1 Department of Neuroradiology, All India Institute of Medical Science, Ansari Nagar, New Delhi, India
2 Department of Pediatrics, All India Institute of Medical Science, Ansari Nagar, New Delhi, India
Lissencephaly (LIS) is a brain malformation manifested by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration, excluding polymicrogyria and other cortical dysplasias. It is important to consider LIS in the diagnosis of developmental delay as many patients may be diagnosed as cerebral palsy. It may have familial occurrence and can occur in sibs of same family often leading to a diagnostic problem. Several lissencephaly syndromes have been described. Here a familial syndrome of lissencephaly is reported. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation cannot be excluded.
Keywords: Lissencephaly; Neuronal migration; Disorder; Brain malformation
Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. It manifests along with various syndromes and there are various types. There are many reports and case series in Western literature. To authors knowledge there are no case reports or care series reported in Indian subcontinent except for a recent report from India.[1] They reported two cases of lissencephaly; brother and sister from a same family.
Case reports
Case 1
One-year-old boy, presented to Pediatric Neurology Clinic of a tertiary care hospital with myoclonic seizures from 4-month of age, 10-40 episodes/day with gross developmental delay, hearing impairment and excessive weight gain. He was born at full term by a cesarean section; indication being cephalopelvic disproportion, though antenatal history was normal. The perinatal period was uneventful. His birth weight was 3.25 Kg and there was history of consistent weight gain; 9.2 Kg at 6 months, 12 Kg at 12 months (> 95th percentile for age). There was no history of hypothyroidism, inborn error of metabolism, (recurrent episodes of poor feeding, lethargy, sensorial alterations and tone abnormalities), or congenital malformation. There was no family history of seizures at the time of presentation to us initially. On examination his facial features were normal. There were no skeletal deformities or neurocutaneous markers. Head circumference was 44 cm (< 5th percentile) and length 76 cm (50th percentile), both being normal. Neurological examination was normal except for gross developmental delay. Other systemic examination including ophthalmologic evaluation were normal. For seizure control child was on valproate 25 mg/Kg/day, clobazam 0.2mg/Kg/day and seizures were well-controlled.
Magnetic resonance imaging of brain revealed thickened agyric cortex with diminished thickness of white matter suggestive of lissencephaly [Figure - 1]. There was associated agenesis of corpus callosum, white matter hypoplasia and ventriculomegaly. 99Tc brain SPECT revealed grossly decreased radio uptake in both temporal lobes and basal ganglia. EEG was abnormal with paroxysm of generalized spike and sharp waves throughout the record. Brain stem auditory evoked potential response revealed increased hearing threshold. Lipid profile, thyroid profile, renal and liver function tests, 24 hour urinary free cortisol was normal.
Case 2
His elder sister, 7-year-old girl, presented with seizure and headache for one-year duration. She was asymptomatic at the time of initial presentation of the younger child. Seizure type was generalized tonic-clonic, around 3-episodes had occurred. She was on carbamazepine 10 mg/Kg/day and presently seizures were controlled. She also had developmental delay. Antenatal period was uneventful and she was born by an emergency cesarean section, indication being delayed labour and malpresentation. Baby cried immediately after birth and had no perinatal complications.
On examination facial features, spine, skeletal system was normal. Her weight was 20 Kg (25th percentile), height 120 cm( 50th per entile) and head circumference 49cm ((between 50% and -2SD). There were no neuro-cutaneous markers. Neurologic examination was normal except for IQ: 70. Other systemic examination was also normal including ophthalmologic evaluation. Contrast enhanced tomography of brain revealed thick cortical mantle, dilated ventricles. Magnetic resonance imaging revealed features of lissencephaly, white matter hypoplasia and ventriculomegaly [Figure - 2]. The corpus callosum was normal. EEG was abnormal with focal seizure discharges with generalized seizure discharges. Discharges were more prominent from right hemisphere. Intelligence quotient was borderline and hearing was normal.
Discussion
Lissencephaly (LIS) and agyria-pachygyria are the terms used to describe brains with absent or poor sulcation. Complete lissencephaly is synonymous with agyria, whereas incomplete lissencephaly refers to brains with shallow sulci and a relatively smooth surface; incomplete lissencephaly is often used synonymously with agyria-pachygyria. Various types of LIS have been identified that are often associated with specific syndromes.[2],[3],[4] Significant causal heterogeneity has been proved: autosomal recessive disorders, chromosomal aneuploidies, recognized teratogens, and many sporadic causes suggesting extrinsic factors , new mutations and multi factorial determinations.
Classic lissencephaly (type I) is a brain malformation caused by abnormal neuronal migration at 9 to 13 weeks' gestation, resulting in a spectrum of agyria, mixed agyria/pachygyria, and pachygyria. It is characterized by an abnormally thick and poorly organized cortex with 4 primitive layers, diffuse neuronal heterotopia, enlarged and dysmorphic ventricles, and often hypoplasia of the corpus callosum. It is found in association with facial abnormalities in Miller-Dieker syndrome (MDLS) and Norman-Robert syndrome; and without other major anomalies in X-linked lissencephaly and isolated lissencephaly sequence (ILS).[5],[6] Two genes associated with LIS have recently been cloned: LIS1 and XLIS (also known as DCX). LIS1 maps to chromosome 17p13.3 and encodes the [beta] subunit of platelet activating factor acetylhydrolase, brain isoform Ib ([beta] LIS1). The gene name has therefore recently been modified to PAFAH1B1. XLIS is located on Xq22.3-q23 and encodes a protein named doublecortin. MDLS and up to 40% of cases of ILS result from a hemideletion or mutations of the LIS1 gene. Mutations in the X-linked gene cause classic lissencephaly in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The brain malformation due to LIS1 mutations are more severe over the parietal and occipital regions, whereas XLIS mutations are more severe over the frontal cortex, suggesting that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.[7] Both our patients were having normal facial features and had no associated congenital defects or characteristic features of MDS or Norman Robert Syndrome. They probably belong to pure isolated variety of LIS, which contributes to about 15-20% of patients[8] with probably autosomal recessive pattern of inheritance, as reported previously.[9]
Type II lissencephaly is a more complex malformation with agyria, pachygyria or even polymicrogyria with pebbled surface, thickened cortex, edematous or cystic white matter and often hydrocephalous. Cortex is severely disorganized, white matter poorly myelinated. Associated malformations include absent septum pellucidum, absent corpus callosum, vermis hypoplasia, Dandy -Walker malformation and brain stem hypoplasia. Syndromes associated with type II are Walker-Warburg syndrome More Details,[10] Muscle-eye-brain disease, Fukuyama muscle dystrophy; nothing was compatible with their patients.
Type 3 lissencephaly have primary CNS affection with severe fatal akinesia. It is characterized by agyric brain with hypoplastic brain stem and cerebellum, severe neuronal loss of the cortical plate, matrix zone, basal ganglia, brainstem nuclei and spinal cord with axonal swelling and microcalcification.[11]Mortality in this is very high.[8]
Both our patients represent LIS 1 as categorized by Dobyns et al[9] features being (a) variable type 1 LIS with normal cerebellum, (b) relatively normal facies and (c) no other consistent pattern of malformation. These patients have severe neurologic sequele, with profound mental retardation, non-specific malformation of cerebellum. Both patients had MR with normal facial features, normal eyes and normal antenatal events with no known risk factors of LIS like intra-uterine TORCH infection, perfusion failure during mid trimester (10-16 wks) or prolonged vaginal bleeding. There are literature reports for autosomal recessive inheritance of LIS with members of same family having affected.[9] But many non-genetic causes may be present. Patients with recessive LIS are known to be pure LIS. Mother's head circumference was 54 cm and had normal intelligence but they did not agree for a neuroimaging. In case of X-linked, the daughter should have had sub-cortical band heterotopia which was not present. Genetic studies were not possible and as familial affection in LIS is known, probably they represent autosomal recessive pattern of inheritance.
An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin ( RELN ).[12] X-linked LIS is a rare form of malformation reported in a recent past, including India.[1]
Younger sibling had obesity also, cause for which was not known and there are no associated syndromes which are associated with obesity in lissencephaly. Life span in children with LIS is probably much shorter than in normal children, the common cause of death being aspiration pneumonia.
A comprehensive approach and diagnosis of patients with LIS using clinical, computerized tomography and magnetic resonance imaging of brain and other laboratory data, allow a specific diagnosis in majority of patients. Familial inheritance should be kept in mind and to be considered in antenatal counseling. Patients with LIS detected by MRI should undergo cranial tomography to rule out intracranial calcification as these families have low risk of recurrence. It is important to consider LIS in the diagnosis of developmental delay as many patients may be diagnosed as cerebral palsy and parents are not counseled regarding recurrence and end up having more sibs with similar illness. The risk of recurrence in lissencephaly varies from 1 to 50% depending on its various types and associations. In isolated lissencephaly sequence the risk of recurrence is around 5% if no deletion is found but if LIS 1 gene deletion is found it is around 1%.
References
1.Panda S, Tripathi M, Jain S, Sharma P, 2003. X-linked lissencephaly in an Indian family. Neurology India 51 : 392-393.
2.Dobyns WB, Pagon RA, Armstrong D, Curry CJ, Greenberg F, Grix A, Holmes LB, Laxova R, Michels VV, Robinow M et al. 1989. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 32: 195-210.
3.Dobyns WB, Curry CJR, Hoyme HE, Turlington L, Ledbetter DH, 1991. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Human Genet 48 : 584-594.
4.Iannetti P, Schwartz CE, Dietz-Band J, Light E, Timmerman J, Chessa L, 1993. Norman-Roberts syndrome: Clinical and molecular studies. Am J Med Genet 47: 95-99.
5.Lo Nigro C, Chong SS, Smith ACM, Dobyns WB, Carrozzo R, Ledbetter DH, 1997. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Human Molecul Genet 6: 157-164.
6.Ledbetter SA, Kuwano A, Dobyns WB, Ledbetter DH, 1992. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am J Human Genet 50: 182-189.
7.Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, Walsh CA, Barkovich AJ, Dobyns WB, Ledbetter DH, Ross ME, 1998. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Human Molecul Genet 7: 2029-2037.
8.Norman MG, Roberts M, Sirois J, Tremblay LJM, 1976. Lissencephaly. Canadian Journal of Neurological Sciences 3: 39-46.
9.Dobyns WB, Truwit CL, 1995. Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 26 : 132-47.
10.Rodgers BL, Vanner LV, Pai GS, Sens MA, 1994. Walker-Warburg syndrome: Report of three affected sibs. American Journal of Medical Genetics 49: 198-201.
11.Attia-Sobol J, Encha-Razavi F, Hermier M, Vitrey D, Verloes A, Plauchu H, 2001. Lissencephaly type III, stippled epiphyses and loose, thick skin: A new recessively inherited syndrome. American Journal of Medical Genetics 99 : 14-20.
12.Hong SE, Shugart YY, Huang DT, Al Shahwan S, Grant PE, Hourihane JOB, Martin NDT, Walsh CA, 2000. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genetics 26 : 93-96.(Garg Ajay, Sridhar MR, Gulati Sheffali)
2 Department of Pediatrics, All India Institute of Medical Science, Ansari Nagar, New Delhi, India
Lissencephaly (LIS) is a brain malformation manifested by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration, excluding polymicrogyria and other cortical dysplasias. It is important to consider LIS in the diagnosis of developmental delay as many patients may be diagnosed as cerebral palsy. It may have familial occurrence and can occur in sibs of same family often leading to a diagnostic problem. Several lissencephaly syndromes have been described. Here a familial syndrome of lissencephaly is reported. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation cannot be excluded.
Keywords: Lissencephaly; Neuronal migration; Disorder; Brain malformation
Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. It manifests along with various syndromes and there are various types. There are many reports and case series in Western literature. To authors knowledge there are no case reports or care series reported in Indian subcontinent except for a recent report from India.[1] They reported two cases of lissencephaly; brother and sister from a same family.
Case reports
Case 1
One-year-old boy, presented to Pediatric Neurology Clinic of a tertiary care hospital with myoclonic seizures from 4-month of age, 10-40 episodes/day with gross developmental delay, hearing impairment and excessive weight gain. He was born at full term by a cesarean section; indication being cephalopelvic disproportion, though antenatal history was normal. The perinatal period was uneventful. His birth weight was 3.25 Kg and there was history of consistent weight gain; 9.2 Kg at 6 months, 12 Kg at 12 months (> 95th percentile for age). There was no history of hypothyroidism, inborn error of metabolism, (recurrent episodes of poor feeding, lethargy, sensorial alterations and tone abnormalities), or congenital malformation. There was no family history of seizures at the time of presentation to us initially. On examination his facial features were normal. There were no skeletal deformities or neurocutaneous markers. Head circumference was 44 cm (< 5th percentile) and length 76 cm (50th percentile), both being normal. Neurological examination was normal except for gross developmental delay. Other systemic examination including ophthalmologic evaluation were normal. For seizure control child was on valproate 25 mg/Kg/day, clobazam 0.2mg/Kg/day and seizures were well-controlled.
Magnetic resonance imaging of brain revealed thickened agyric cortex with diminished thickness of white matter suggestive of lissencephaly [Figure - 1]. There was associated agenesis of corpus callosum, white matter hypoplasia and ventriculomegaly. 99Tc brain SPECT revealed grossly decreased radio uptake in both temporal lobes and basal ganglia. EEG was abnormal with paroxysm of generalized spike and sharp waves throughout the record. Brain stem auditory evoked potential response revealed increased hearing threshold. Lipid profile, thyroid profile, renal and liver function tests, 24 hour urinary free cortisol was normal.
Case 2
His elder sister, 7-year-old girl, presented with seizure and headache for one-year duration. She was asymptomatic at the time of initial presentation of the younger child. Seizure type was generalized tonic-clonic, around 3-episodes had occurred. She was on carbamazepine 10 mg/Kg/day and presently seizures were controlled. She also had developmental delay. Antenatal period was uneventful and she was born by an emergency cesarean section, indication being delayed labour and malpresentation. Baby cried immediately after birth and had no perinatal complications.
On examination facial features, spine, skeletal system was normal. Her weight was 20 Kg (25th percentile), height 120 cm( 50th per entile) and head circumference 49cm ((between 50% and -2SD). There were no neuro-cutaneous markers. Neurologic examination was normal except for IQ: 70. Other systemic examination was also normal including ophthalmologic evaluation. Contrast enhanced tomography of brain revealed thick cortical mantle, dilated ventricles. Magnetic resonance imaging revealed features of lissencephaly, white matter hypoplasia and ventriculomegaly [Figure - 2]. The corpus callosum was normal. EEG was abnormal with focal seizure discharges with generalized seizure discharges. Discharges were more prominent from right hemisphere. Intelligence quotient was borderline and hearing was normal.
Discussion
Lissencephaly (LIS) and agyria-pachygyria are the terms used to describe brains with absent or poor sulcation. Complete lissencephaly is synonymous with agyria, whereas incomplete lissencephaly refers to brains with shallow sulci and a relatively smooth surface; incomplete lissencephaly is often used synonymously with agyria-pachygyria. Various types of LIS have been identified that are often associated with specific syndromes.[2],[3],[4] Significant causal heterogeneity has been proved: autosomal recessive disorders, chromosomal aneuploidies, recognized teratogens, and many sporadic causes suggesting extrinsic factors , new mutations and multi factorial determinations.
Classic lissencephaly (type I) is a brain malformation caused by abnormal neuronal migration at 9 to 13 weeks' gestation, resulting in a spectrum of agyria, mixed agyria/pachygyria, and pachygyria. It is characterized by an abnormally thick and poorly organized cortex with 4 primitive layers, diffuse neuronal heterotopia, enlarged and dysmorphic ventricles, and often hypoplasia of the corpus callosum. It is found in association with facial abnormalities in Miller-Dieker syndrome (MDLS) and Norman-Robert syndrome; and without other major anomalies in X-linked lissencephaly and isolated lissencephaly sequence (ILS).[5],[6] Two genes associated with LIS have recently been cloned: LIS1 and XLIS (also known as DCX). LIS1 maps to chromosome 17p13.3 and encodes the [beta] subunit of platelet activating factor acetylhydrolase, brain isoform Ib ([beta] LIS1). The gene name has therefore recently been modified to PAFAH1B1. XLIS is located on Xq22.3-q23 and encodes a protein named doublecortin. MDLS and up to 40% of cases of ILS result from a hemideletion or mutations of the LIS1 gene. Mutations in the X-linked gene cause classic lissencephaly in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The brain malformation due to LIS1 mutations are more severe over the parietal and occipital regions, whereas XLIS mutations are more severe over the frontal cortex, suggesting that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.[7] Both our patients were having normal facial features and had no associated congenital defects or characteristic features of MDS or Norman Robert Syndrome. They probably belong to pure isolated variety of LIS, which contributes to about 15-20% of patients[8] with probably autosomal recessive pattern of inheritance, as reported previously.[9]
Type II lissencephaly is a more complex malformation with agyria, pachygyria or even polymicrogyria with pebbled surface, thickened cortex, edematous or cystic white matter and often hydrocephalous. Cortex is severely disorganized, white matter poorly myelinated. Associated malformations include absent septum pellucidum, absent corpus callosum, vermis hypoplasia, Dandy -Walker malformation and brain stem hypoplasia. Syndromes associated with type II are Walker-Warburg syndrome More Details,[10] Muscle-eye-brain disease, Fukuyama muscle dystrophy; nothing was compatible with their patients.
Type 3 lissencephaly have primary CNS affection with severe fatal akinesia. It is characterized by agyric brain with hypoplastic brain stem and cerebellum, severe neuronal loss of the cortical plate, matrix zone, basal ganglia, brainstem nuclei and spinal cord with axonal swelling and microcalcification.[11]Mortality in this is very high.[8]
Both our patients represent LIS 1 as categorized by Dobyns et al[9] features being (a) variable type 1 LIS with normal cerebellum, (b) relatively normal facies and (c) no other consistent pattern of malformation. These patients have severe neurologic sequele, with profound mental retardation, non-specific malformation of cerebellum. Both patients had MR with normal facial features, normal eyes and normal antenatal events with no known risk factors of LIS like intra-uterine TORCH infection, perfusion failure during mid trimester (10-16 wks) or prolonged vaginal bleeding. There are literature reports for autosomal recessive inheritance of LIS with members of same family having affected.[9] But many non-genetic causes may be present. Patients with recessive LIS are known to be pure LIS. Mother's head circumference was 54 cm and had normal intelligence but they did not agree for a neuroimaging. In case of X-linked, the daughter should have had sub-cortical band heterotopia which was not present. Genetic studies were not possible and as familial affection in LIS is known, probably they represent autosomal recessive pattern of inheritance.
An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin ( RELN ).[12] X-linked LIS is a rare form of malformation reported in a recent past, including India.[1]
Younger sibling had obesity also, cause for which was not known and there are no associated syndromes which are associated with obesity in lissencephaly. Life span in children with LIS is probably much shorter than in normal children, the common cause of death being aspiration pneumonia.
A comprehensive approach and diagnosis of patients with LIS using clinical, computerized tomography and magnetic resonance imaging of brain and other laboratory data, allow a specific diagnosis in majority of patients. Familial inheritance should be kept in mind and to be considered in antenatal counseling. Patients with LIS detected by MRI should undergo cranial tomography to rule out intracranial calcification as these families have low risk of recurrence. It is important to consider LIS in the diagnosis of developmental delay as many patients may be diagnosed as cerebral palsy and parents are not counseled regarding recurrence and end up having more sibs with similar illness. The risk of recurrence in lissencephaly varies from 1 to 50% depending on its various types and associations. In isolated lissencephaly sequence the risk of recurrence is around 5% if no deletion is found but if LIS 1 gene deletion is found it is around 1%.
References
1.Panda S, Tripathi M, Jain S, Sharma P, 2003. X-linked lissencephaly in an Indian family. Neurology India 51 : 392-393.
2.Dobyns WB, Pagon RA, Armstrong D, Curry CJ, Greenberg F, Grix A, Holmes LB, Laxova R, Michels VV, Robinow M et al. 1989. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 32: 195-210.
3.Dobyns WB, Curry CJR, Hoyme HE, Turlington L, Ledbetter DH, 1991. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Human Genet 48 : 584-594.
4.Iannetti P, Schwartz CE, Dietz-Band J, Light E, Timmerman J, Chessa L, 1993. Norman-Roberts syndrome: Clinical and molecular studies. Am J Med Genet 47: 95-99.
5.Lo Nigro C, Chong SS, Smith ACM, Dobyns WB, Carrozzo R, Ledbetter DH, 1997. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Human Molecul Genet 6: 157-164.
6.Ledbetter SA, Kuwano A, Dobyns WB, Ledbetter DH, 1992. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am J Human Genet 50: 182-189.
7.Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, Walsh CA, Barkovich AJ, Dobyns WB, Ledbetter DH, Ross ME, 1998. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Human Molecul Genet 7: 2029-2037.
8.Norman MG, Roberts M, Sirois J, Tremblay LJM, 1976. Lissencephaly. Canadian Journal of Neurological Sciences 3: 39-46.
9.Dobyns WB, Truwit CL, 1995. Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 26 : 132-47.
10.Rodgers BL, Vanner LV, Pai GS, Sens MA, 1994. Walker-Warburg syndrome: Report of three affected sibs. American Journal of Medical Genetics 49: 198-201.
11.Attia-Sobol J, Encha-Razavi F, Hermier M, Vitrey D, Verloes A, Plauchu H, 2001. Lissencephaly type III, stippled epiphyses and loose, thick skin: A new recessively inherited syndrome. American Journal of Medical Genetics 99 : 14-20.
12.Hong SE, Shugart YY, Huang DT, Al Shahwan S, Grant PE, Hourihane JOB, Martin NDT, Walsh CA, 2000. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genetics 26 : 93-96.(Garg Ajay, Sridhar MR, Gulati Sheffali)