Leukodystrophies: Indian Scenario
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《美国医学杂志》
Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, India
Abstract
The leukodystrophies are familial disorders with onset usually in infancy or childhood. The clinical features consist of motor dysfunction with varying degree of cognitive decline. Magnetic Resonance Imaging (MRI) has helped to identify and characterize these disorders. In some leukodystrophies, biochemical enzymatic and genetic defects have been identified. The commonest leukodystrophy seen in India is Megalencephalic Leukodystrophy with subcortical cysts. The essential features consist of large head, mild pyramidal and cerebellar dysfunction, and occasional seizures. MRI studies show extensive white matter changes with temporal cysts. It is common in the Agarwal community in India. An identical mutation in exon 2 of the MLC 1 gene has been identified in this community suggesting a founder effect.
Keywords: Leukodystrophy; Megalencephalic leukodystrophy; Temporal cysts; Agarwal community
The leukodystrophies form a heterogeneous group of disorders. The common denominator is an abnormality of the myelin of the central nervous system (CNS). In some varieties, the peripheral nervous system also gets affected. The defect in the formation of the myelin is due to an underlying genetically transmitted defect. The onset is usually in infancy or childhood. As these diseases are familial, a history of consanguinity and/or involvement of other siblings may be available. The clinical features consist of progressive intellectual deterioration with varying degrees of pyramidal and cerebellar dysfunction. Seizures, though infrequent, may occur. Enlargement of the head is a feature in some varieties. The course is usually progressive.
Recent years have witnessed significant advances in these disorders. Imaging techniques namely computerized tomography (CT) and especially magnetic resonance (MR) imaging reveal the changes in the CNS white matter. The distribution and characteristics of the changes in the white matter help to distinguish different varieties of leukodystrophies. Newer techniques like MR spectroscopy also identify the underlying biochemical changes in these disorders.
Electrophysiological procedures like electromyography and nerve conduction studies help to detect involvement (even sub-clinical) of the peripheral nervous system. Detection of the underlying biochemical and enzymatic defect has been possible in some conditions. Identification of the genetic defect has further helped genetic counseling and prenatal diagnosis.
Besides the well known leukodystrophies such as metachromatic leukodystrophy, adrenoleukodystrophy, Alexander's disease, Canavan disease and globoid cell leukodystrophy (Krabbe's disease), newer leukodystrophies have been described such as megalencephalic leukodystrophy with subcortical cysts and vanishing white-matter disease/childhood ataxia with CNS hypomyelination (CACH). In the coming years, an increasing number of primary white matter disorders are likely to be recognized as more genetic defects get identified.
There has been a paucity of reports of leukodystrophies from India. There are only a handful of pediatric neurologists in India. So far, adult neurologists and general pediatricians have been trying to deal with neurological disorders of childhood. Besides, there have been poor facilities for metabolic work-ups and genetic studies. In recent years, the availability of imaging techniques and international collaboration has made it possible to identify these disorders.
There are few reports of metachromatic leukodystrophy from India.[1]-[6] X-linked adrenoleukodystrophy cases have been identified. Atypical cases and patients with adrenomyeloneuropathy can be missed unless there is a high index of suspicion. We saw an adult patient with adrenomyeloneuropathy who presented with paraparesis and peripheral neuropathy where the diagnosis was not suspected till his nephew turned up ten years later with adrenoleukodystrophy. It is important to remember that occasionally leukodystrophies may present in adolescence or adult life. We reported adult Krabbe's disease in a brother and sister who presented with slowly progressive weakness in the lower limbs due to pyramidal deficits at the age of 23 years. Both patients had white matter changes on brain MRI and absence or severe reduction of the lysosomal enzyme galactocerebrosidase (GALC). Both had the same GALC mutation namely 30 kb deletion of exons 11 through 17 on one allele and A to G transition at nucleotide 908 (changing tyrosine 303 to cysteine) on the other allele.[7]
Megalencephalic Leukodystrophy with Subcortical Cysts
The commonest form of leukodystrophy described from India is the megalencephalic leukodystrophy with subcortical cysts (MLC). It has an autosomal recessive inheritance. The essential features include large head noted in infancy, motor disability in the form of spasticity and ataxia, and imaging evidence of extensive symmetrical white matter changes with subcortical cysts. Singhal et al described 18 patients with megalencephalic leukodystrophy from India in a meeting in Japan in 1991[8] but it was first well documented in a landmark paper by van der Knaap et al in 1995.[9] There have been several reports since. Singhal et al described this condition in a specific Indian community, namely Agarwals from India.[10] The other large series was reported by Topcu et al from Turkey.[11] There are reports of similar cases from several regions of the world.[12],[13]
Singhal et al recently reported the clinical presentation in 70 patients with MLC from India.[14] There were 42 males and 28 females. The age at onset of symptoms varied from birth to 25 years. The median age at onset was 6 months. The first presenting symptom was a large head in 45 patients, developmental delay (usually delayed motor mile stones) in 10 patients, seizures in 9 patients and motor disability in 6 patients. Many children were able to complete schooling. Of the 46 who could go to school, 6 completed college graduation, 22 had an average school performance and 18 were found to be below average.
Seizures are not uncommon. They were reported in 50% of the patients.[14] These can be tonic-clonic, focal or secondarily generalized. Seizures usually respond well to commonly used anticonvulsants like carbamazepine and valproate. An important precipitating factor is minor head trauma. Some patients may have seizures only on trauma (reported as impact seizure) while others have both spontaneous and provoked seizures. Occasionally this minor head trauma may result in an unconscious state lasting for several days. It is important to emphasize that falls should be avoided (which are likely to occur because of motor disability) and, if need be, protective head-gear should be used.
The patients with MLC generally have spastic ataxia due to pyramidal and cerebellar involvement. The upper limbs are relatively less affected. Some patients may have mild finger-nose-finger incoordination. Mild dysarthria may be seen, but is infrequent. Nystagmus is generally not seen. The progress is usually mild and slow. Van der Knaap[9] stressed on a discrepantly mild clinical course. Even in the study reported by Singhal et al[14], six patients had completed college graduation and were pursuing their careers. The patients in MLC do not have any dysmorphism, visceromegaly, peripheral neuropathy or retinopathy.
Electrophysiological studies such as nerve conduction studies, visual evoked potentials and brainstem auditory evoked responses generally do not show any abnormality. Somato-sensory evoked potential studies, however, may show delay at the cortical level. Inter-ictal EEG studies may be normal, or show abnormalities in the form of spike wave discharges or bilateral nonspecific slow potentials.
The characteristic changes seen on imaging studies help to identify this condition. Both CT and MRI show these changes but they are better appreciated on MRI. They show extensive white matter changes in the brain with relative sparing of the deeper structures. There is generally only mild involvement of the cerebellum. Cystic changes, seen in both temporal lobes, are a unique feature of MLC Figure1. Additional cystic changes may be seen in the frontal or occasionally more extensively in frontal, parietal and occipital regions. The patients with more extensive changes are usually more severely affected.
A positive family history of similar affection may be present in the sibs. As it has autosomal recessive inheritance, the parents show no abnormality. In the series reported by Singhal et al[14], of the 70 patients, 63 belonged to a special ethnic community namely Agarwals. The Agarwals hail from north India, a region close to Delhi, the Indian capital. They belong to an enterprising business community and are now scattered all over India and have also emigrated to many regions of the world. They marry within the community but are supposed to avoid the same lineage for seven or more generations. Of late, the mother's lineage is often forgotten, resulting in marriages in a closed group with greater chances of autosomal recessive disorders in their offspring.
MLC will need to be distinguished from other conditions with megalencephaly, cognitive decline and motor disability such as infantile form of Alexander's disease, Canavan-van Bogaert-Bertrand disease and glutaric aciduria type I. These can be distinguished by the differences in the clinical picture, changes on MRI imaging and biochemical changes. Lysosomal disorders such as mucopolysaccharidoses and GM2 gangliosidosis may also present with megalencephaly and leukoencephalopathy. However, the clinical and radiological features are distinct from those of MLC. White matter changes on imaging have also been described with congenital muscular dystrophy but patients with MLC do not have myopathy or dysmorphic features.
To date, no biochemical defect has been identified in patients with MLC, but the gene defect has been identified. Topcu et al[15] mapped the gene to chromosome 22 q tel. Leegwater et al[16] were able to narrow down the critical region to one gene K1AA0027 which they renamed as MLC 1. The transcription start site and the promoter regions have not been characterized so far. Several different mutations (frame-shifts, splice-acceptor mutations, splice-donor mutations and aminoacid substitutions) have been described by Leegwater et al[17]. They also noted an identical gene defect in three Indian children and suggested the possibility of a founder effect. In the Agarwal community, Gorospe et al[18] demonstrated homozygous insertion of cytosine between nucleotides 250 and 251 in exon 2. This resulted in a frame shift in proteins starting at aminoacid position 45 (P45 frame shift) with formation of a premature stop codon 100 nucleotides down stream. The same defect was found in 31 children belonging to this community confirming a founder effect. In about 40% of the patients, Leegwater et al[17] were unable to find a mutation in MLC 1 gene suggesting that there may be yet another gene associated with this disease. The diagnosis therefore should rest on clinical data and imaging findings. The absence of mutations in MLC 1 gene does not exclude the diagnosis.
The results of genetic studies have important implications. The finding of several mutations by Leegwater et al[17] resulting in a similar phenotypic expression suggests that there is genetic heterogeneity. Therefore in a given family it will be necessary to know the exact type of genetic mutation before counseling parents about subsequent pregnancies. This should however not be the case if a child belonging to the Agarwal community presents with he clinical syndrome of MLC. The finding of a founder effect suggests that the same gene defect is likely even if the family has moved to any other part of the world.
Besides the genetic heterogeneity there appears to be considerable phenotypic variation. In the Agarwal community, with the same gene defect, the severity of the illness may vary. This has happened even in the same family with one child getting severely affected and the other child being only mildly affected. These considerable phenotypic variations may be due to the effect of modifier genes or environmental factors.
To conclude, MLC is commonly seen in India especially in the Agarwal community. The gene defect has been identified with a founder effect. With the development of pediatric neurology and availability of diagnostic facilities it is hoped that all types of leukodystrophies will be easily identified in India. Ongoing researches in the genetic and metabolic fields bring the hope of treatment for these children.
References
1. Bharucha BA, Naik G, Savliwala AS, Joshi RM, Kumta NB. Siblings with the Austin variant of metachromatic leukodystrophy multiple sulfatidosis. Indian J Pediatr (India) 1984; 51: 477-480.
2. Nigam GK, Anand RK. Metachromatic leukodystrophy. Indian J Pediatr 1987; 24 (6), 518-519.
3. Jayakumar PN, Aroor SR, Jha RK, Arya BY. Computed tomography (CT) in late infantile metachromatic leukodystrophy. Acta Neurol Scand 1989; 79 (1): 23-26.
4. Pandit L, Kapadia R, Kini P, Rao S. Metachromatic leukodystrophy presenting with extrapyramidal disturbances. Indian J Pediatr 1994; 31 (6): 690-694.
5. Oak S, Rao S, Karmarkar S, Kulkarni B, Kalgutkar A, Malde A et al. Papillomatosis of the gallbladder in metachromatic leukodystrophy. Pediatr Surg Int 1997; 12 (5-6): 424-425.
6. Bindu P S, Mahadevan Anita, Desai Sunaili, Cristopher Rita, Jayakumar PN. Metachromatic leukodystrophy - A heterogenous disease with and without aryl sulfatase A deficiency: A cliniopathological reappraisal.
Abstract. Indian J Pediatr (Suppl) 2004; SS-1: 86.
7. Farina L, Bizzi A, Flnocchiaro G, Pareyson D, Sghirlanzon A, Bertagnolio B et al. MR imaging and proton MR spectroscopy in Adult Krabbe Disease. AJNR 2000; 21: 1478-82.
8. Singhal BS, Gursahani RD, Biniwale AA, Udani VP. Megalencephalic leukodystrophy in India.
Abstract. 8th Asian and Oceanian Congress of Neurology, Tokyo, Japan, 1991.
9. van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts FM, Hoogenraad F et al. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37:324-334.
10. Singhal BS, Gursahani RD, Udani VP, Binivale AA. Megalencephalic leukodystrophy in an Asian Indian ethnic group. Pediatr Neurol 1996; 14: 291-296.
11. Topcu M, Saatci I, Topcuoglu MA, Kose G, Kunak B. Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases. Brain & Development 1998; 20: 142-153.
12. Goutieres F, Boulloche J, Bourgeois M, Aicardi J. Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases. J Child Neurol 1996; 11:439-444.
13. Koeda T, Takeshita K. Slowly progressive cystic leukoencephalopathy with megalencephaly in a Japanese boy. Brain & Development 1998; 20 : 245-249.
14. Singhal BS, Gorospe JR, Naidu S. Megalencephalic leukoencephalopathy with subcortical cysts. J Child Neurol 2003; 18 : 646-653.
15. Tpocu M, Gartioux C, Ribierre F, Yalcinkaya C, Tokus E, Oztekin N et al. Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet 2000; 66 : 733-739.
16. Leegwater PAJ, Yuan BQ, van der Steen J et al. Mutations of MLC1 (KIAA0027) encoding a putative memebrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001; 68 : 831-838.
17. Leegwater PAJ, Boor PK,Yuan BQ et al. Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. Hum Genet 2002; 110 : 279-283.
18. Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J et al. Indian Agarwal megalencephalic leukodystrophy with cysts by common MLC I mutation. Neurology 2004; 62 : 878-882.(Singhal BS)
Abstract
The leukodystrophies are familial disorders with onset usually in infancy or childhood. The clinical features consist of motor dysfunction with varying degree of cognitive decline. Magnetic Resonance Imaging (MRI) has helped to identify and characterize these disorders. In some leukodystrophies, biochemical enzymatic and genetic defects have been identified. The commonest leukodystrophy seen in India is Megalencephalic Leukodystrophy with subcortical cysts. The essential features consist of large head, mild pyramidal and cerebellar dysfunction, and occasional seizures. MRI studies show extensive white matter changes with temporal cysts. It is common in the Agarwal community in India. An identical mutation in exon 2 of the MLC 1 gene has been identified in this community suggesting a founder effect.
Keywords: Leukodystrophy; Megalencephalic leukodystrophy; Temporal cysts; Agarwal community
The leukodystrophies form a heterogeneous group of disorders. The common denominator is an abnormality of the myelin of the central nervous system (CNS). In some varieties, the peripheral nervous system also gets affected. The defect in the formation of the myelin is due to an underlying genetically transmitted defect. The onset is usually in infancy or childhood. As these diseases are familial, a history of consanguinity and/or involvement of other siblings may be available. The clinical features consist of progressive intellectual deterioration with varying degrees of pyramidal and cerebellar dysfunction. Seizures, though infrequent, may occur. Enlargement of the head is a feature in some varieties. The course is usually progressive.
Recent years have witnessed significant advances in these disorders. Imaging techniques namely computerized tomography (CT) and especially magnetic resonance (MR) imaging reveal the changes in the CNS white matter. The distribution and characteristics of the changes in the white matter help to distinguish different varieties of leukodystrophies. Newer techniques like MR spectroscopy also identify the underlying biochemical changes in these disorders.
Electrophysiological procedures like electromyography and nerve conduction studies help to detect involvement (even sub-clinical) of the peripheral nervous system. Detection of the underlying biochemical and enzymatic defect has been possible in some conditions. Identification of the genetic defect has further helped genetic counseling and prenatal diagnosis.
Besides the well known leukodystrophies such as metachromatic leukodystrophy, adrenoleukodystrophy, Alexander's disease, Canavan disease and globoid cell leukodystrophy (Krabbe's disease), newer leukodystrophies have been described such as megalencephalic leukodystrophy with subcortical cysts and vanishing white-matter disease/childhood ataxia with CNS hypomyelination (CACH). In the coming years, an increasing number of primary white matter disorders are likely to be recognized as more genetic defects get identified.
There has been a paucity of reports of leukodystrophies from India. There are only a handful of pediatric neurologists in India. So far, adult neurologists and general pediatricians have been trying to deal with neurological disorders of childhood. Besides, there have been poor facilities for metabolic work-ups and genetic studies. In recent years, the availability of imaging techniques and international collaboration has made it possible to identify these disorders.
There are few reports of metachromatic leukodystrophy from India.[1]-[6] X-linked adrenoleukodystrophy cases have been identified. Atypical cases and patients with adrenomyeloneuropathy can be missed unless there is a high index of suspicion. We saw an adult patient with adrenomyeloneuropathy who presented with paraparesis and peripheral neuropathy where the diagnosis was not suspected till his nephew turned up ten years later with adrenoleukodystrophy. It is important to remember that occasionally leukodystrophies may present in adolescence or adult life. We reported adult Krabbe's disease in a brother and sister who presented with slowly progressive weakness in the lower limbs due to pyramidal deficits at the age of 23 years. Both patients had white matter changes on brain MRI and absence or severe reduction of the lysosomal enzyme galactocerebrosidase (GALC). Both had the same GALC mutation namely 30 kb deletion of exons 11 through 17 on one allele and A to G transition at nucleotide 908 (changing tyrosine 303 to cysteine) on the other allele.[7]
Megalencephalic Leukodystrophy with Subcortical Cysts
The commonest form of leukodystrophy described from India is the megalencephalic leukodystrophy with subcortical cysts (MLC). It has an autosomal recessive inheritance. The essential features include large head noted in infancy, motor disability in the form of spasticity and ataxia, and imaging evidence of extensive symmetrical white matter changes with subcortical cysts. Singhal et al described 18 patients with megalencephalic leukodystrophy from India in a meeting in Japan in 1991[8] but it was first well documented in a landmark paper by van der Knaap et al in 1995.[9] There have been several reports since. Singhal et al described this condition in a specific Indian community, namely Agarwals from India.[10] The other large series was reported by Topcu et al from Turkey.[11] There are reports of similar cases from several regions of the world.[12],[13]
Singhal et al recently reported the clinical presentation in 70 patients with MLC from India.[14] There were 42 males and 28 females. The age at onset of symptoms varied from birth to 25 years. The median age at onset was 6 months. The first presenting symptom was a large head in 45 patients, developmental delay (usually delayed motor mile stones) in 10 patients, seizures in 9 patients and motor disability in 6 patients. Many children were able to complete schooling. Of the 46 who could go to school, 6 completed college graduation, 22 had an average school performance and 18 were found to be below average.
Seizures are not uncommon. They were reported in 50% of the patients.[14] These can be tonic-clonic, focal or secondarily generalized. Seizures usually respond well to commonly used anticonvulsants like carbamazepine and valproate. An important precipitating factor is minor head trauma. Some patients may have seizures only on trauma (reported as impact seizure) while others have both spontaneous and provoked seizures. Occasionally this minor head trauma may result in an unconscious state lasting for several days. It is important to emphasize that falls should be avoided (which are likely to occur because of motor disability) and, if need be, protective head-gear should be used.
The patients with MLC generally have spastic ataxia due to pyramidal and cerebellar involvement. The upper limbs are relatively less affected. Some patients may have mild finger-nose-finger incoordination. Mild dysarthria may be seen, but is infrequent. Nystagmus is generally not seen. The progress is usually mild and slow. Van der Knaap[9] stressed on a discrepantly mild clinical course. Even in the study reported by Singhal et al[14], six patients had completed college graduation and were pursuing their careers. The patients in MLC do not have any dysmorphism, visceromegaly, peripheral neuropathy or retinopathy.
Electrophysiological studies such as nerve conduction studies, visual evoked potentials and brainstem auditory evoked responses generally do not show any abnormality. Somato-sensory evoked potential studies, however, may show delay at the cortical level. Inter-ictal EEG studies may be normal, or show abnormalities in the form of spike wave discharges or bilateral nonspecific slow potentials.
The characteristic changes seen on imaging studies help to identify this condition. Both CT and MRI show these changes but they are better appreciated on MRI. They show extensive white matter changes in the brain with relative sparing of the deeper structures. There is generally only mild involvement of the cerebellum. Cystic changes, seen in both temporal lobes, are a unique feature of MLC Figure1. Additional cystic changes may be seen in the frontal or occasionally more extensively in frontal, parietal and occipital regions. The patients with more extensive changes are usually more severely affected.
A positive family history of similar affection may be present in the sibs. As it has autosomal recessive inheritance, the parents show no abnormality. In the series reported by Singhal et al[14], of the 70 patients, 63 belonged to a special ethnic community namely Agarwals. The Agarwals hail from north India, a region close to Delhi, the Indian capital. They belong to an enterprising business community and are now scattered all over India and have also emigrated to many regions of the world. They marry within the community but are supposed to avoid the same lineage for seven or more generations. Of late, the mother's lineage is often forgotten, resulting in marriages in a closed group with greater chances of autosomal recessive disorders in their offspring.
MLC will need to be distinguished from other conditions with megalencephaly, cognitive decline and motor disability such as infantile form of Alexander's disease, Canavan-van Bogaert-Bertrand disease and glutaric aciduria type I. These can be distinguished by the differences in the clinical picture, changes on MRI imaging and biochemical changes. Lysosomal disorders such as mucopolysaccharidoses and GM2 gangliosidosis may also present with megalencephaly and leukoencephalopathy. However, the clinical and radiological features are distinct from those of MLC. White matter changes on imaging have also been described with congenital muscular dystrophy but patients with MLC do not have myopathy or dysmorphic features.
To date, no biochemical defect has been identified in patients with MLC, but the gene defect has been identified. Topcu et al[15] mapped the gene to chromosome 22 q tel. Leegwater et al[16] were able to narrow down the critical region to one gene K1AA0027 which they renamed as MLC 1. The transcription start site and the promoter regions have not been characterized so far. Several different mutations (frame-shifts, splice-acceptor mutations, splice-donor mutations and aminoacid substitutions) have been described by Leegwater et al[17]. They also noted an identical gene defect in three Indian children and suggested the possibility of a founder effect. In the Agarwal community, Gorospe et al[18] demonstrated homozygous insertion of cytosine between nucleotides 250 and 251 in exon 2. This resulted in a frame shift in proteins starting at aminoacid position 45 (P45 frame shift) with formation of a premature stop codon 100 nucleotides down stream. The same defect was found in 31 children belonging to this community confirming a founder effect. In about 40% of the patients, Leegwater et al[17] were unable to find a mutation in MLC 1 gene suggesting that there may be yet another gene associated with this disease. The diagnosis therefore should rest on clinical data and imaging findings. The absence of mutations in MLC 1 gene does not exclude the diagnosis.
The results of genetic studies have important implications. The finding of several mutations by Leegwater et al[17] resulting in a similar phenotypic expression suggests that there is genetic heterogeneity. Therefore in a given family it will be necessary to know the exact type of genetic mutation before counseling parents about subsequent pregnancies. This should however not be the case if a child belonging to the Agarwal community presents with he clinical syndrome of MLC. The finding of a founder effect suggests that the same gene defect is likely even if the family has moved to any other part of the world.
Besides the genetic heterogeneity there appears to be considerable phenotypic variation. In the Agarwal community, with the same gene defect, the severity of the illness may vary. This has happened even in the same family with one child getting severely affected and the other child being only mildly affected. These considerable phenotypic variations may be due to the effect of modifier genes or environmental factors.
To conclude, MLC is commonly seen in India especially in the Agarwal community. The gene defect has been identified with a founder effect. With the development of pediatric neurology and availability of diagnostic facilities it is hoped that all types of leukodystrophies will be easily identified in India. Ongoing researches in the genetic and metabolic fields bring the hope of treatment for these children.
References
1. Bharucha BA, Naik G, Savliwala AS, Joshi RM, Kumta NB. Siblings with the Austin variant of metachromatic leukodystrophy multiple sulfatidosis. Indian J Pediatr (India) 1984; 51: 477-480.
2. Nigam GK, Anand RK. Metachromatic leukodystrophy. Indian J Pediatr 1987; 24 (6), 518-519.
3. Jayakumar PN, Aroor SR, Jha RK, Arya BY. Computed tomography (CT) in late infantile metachromatic leukodystrophy. Acta Neurol Scand 1989; 79 (1): 23-26.
4. Pandit L, Kapadia R, Kini P, Rao S. Metachromatic leukodystrophy presenting with extrapyramidal disturbances. Indian J Pediatr 1994; 31 (6): 690-694.
5. Oak S, Rao S, Karmarkar S, Kulkarni B, Kalgutkar A, Malde A et al. Papillomatosis of the gallbladder in metachromatic leukodystrophy. Pediatr Surg Int 1997; 12 (5-6): 424-425.
6. Bindu P S, Mahadevan Anita, Desai Sunaili, Cristopher Rita, Jayakumar PN. Metachromatic leukodystrophy - A heterogenous disease with and without aryl sulfatase A deficiency: A cliniopathological reappraisal.
Abstract. Indian J Pediatr (Suppl) 2004; SS-1: 86.
7. Farina L, Bizzi A, Flnocchiaro G, Pareyson D, Sghirlanzon A, Bertagnolio B et al. MR imaging and proton MR spectroscopy in Adult Krabbe Disease. AJNR 2000; 21: 1478-82.
8. Singhal BS, Gursahani RD, Biniwale AA, Udani VP. Megalencephalic leukodystrophy in India.
Abstract. 8th Asian and Oceanian Congress of Neurology, Tokyo, Japan, 1991.
9. van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts FM, Hoogenraad F et al. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37:324-334.
10. Singhal BS, Gursahani RD, Udani VP, Binivale AA. Megalencephalic leukodystrophy in an Asian Indian ethnic group. Pediatr Neurol 1996; 14: 291-296.
11. Topcu M, Saatci I, Topcuoglu MA, Kose G, Kunak B. Megalencephaly and leukodystrophy with mild clinical course: a report on 12 new cases. Brain & Development 1998; 20: 142-153.
12. Goutieres F, Boulloche J, Bourgeois M, Aicardi J. Leukoencephalopathy, megalencephaly, and mild clinical course. A recently individualized familial leukodystrophy. Report on five new cases. J Child Neurol 1996; 11:439-444.
13. Koeda T, Takeshita K. Slowly progressive cystic leukoencephalopathy with megalencephaly in a Japanese boy. Brain & Development 1998; 20 : 245-249.
14. Singhal BS, Gorospe JR, Naidu S. Megalencephalic leukoencephalopathy with subcortical cysts. J Child Neurol 2003; 18 : 646-653.
15. Tpocu M, Gartioux C, Ribierre F, Yalcinkaya C, Tokus E, Oztekin N et al. Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel. Am J Hum Genet 2000; 66 : 733-739.
16. Leegwater PAJ, Yuan BQ, van der Steen J et al. Mutations of MLC1 (KIAA0027) encoding a putative memebrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001; 68 : 831-838.
17. Leegwater PAJ, Boor PK,Yuan BQ et al. Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. Hum Genet 2002; 110 : 279-283.
18. Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J et al. Indian Agarwal megalencephalic leukodystrophy with cysts by common MLC I mutation. Neurology 2004; 62 : 878-882.(Singhal BS)