Indian Agarwal community having megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation

Indian Agarwal community has a higher prevalence of megalencephalic leukodystrophy with cysts and is is caused by a common MLC1 mutation

DOI:10.1212/WNL.63.11.2197-a

Authors:

J R Gorospe

J R Gorospe

B S Singhal

B S Singhal

T Kainu

T Kainu

F Wu

F Wu

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Abstract

A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group (Agarwals) in India. This disorder is very similar to megalencephalic leukoencephalopathy with subcortical cysts (MLC), a newly characterized leukodystrophy whose molecular basis was recently shown to be mutations in a gene (KIAA0027) that has been renamed MLC1. To determine if this disorder among the Agarwals is due to mutations in MLC1 by a mutation screening study conducted on affected Agarwal patients. Genomic DNA from these Indian leukodystrophy patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the MLC1 gene. Thirty-three affected individuals whose clinical and imaging presentations were consistent with MLC were screened. All were from northern India and included 31 known Agarwals, 1 non-Agarwal, and 1 adopted patient whose ethnicity is unknown. All 31 Agarwal patients tested positive for a homozygous insertion of a cytosine in exon 2. The adopted patient was homozygous for A157E. No mutation in the coding region was found in the non-Agarwal patient. Indian patients with megalencephaly and MRI changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. Members of the Agarwal ethnic group affected with the disorder present with a mildly progressive course and show a common mutation (320insC) in the MLC1 gene, suggesting a founder effect.ResearchGate Logo

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Citations (69)

References (12)

… MLC is very rare and there have been no formal studies of its incidence, which seems to be highest in the Turkish population 1, 8 and Indian Agrawal community. 2, [9][10][11] As is the case for diseases with a low carrier frequency, consanguinity and inbreeding contribute to its occurrence. …

… The most common founder mutation is in the Indian Agrawal community, in which all patients share an insertion of one base-pair (c.135dupC), causing a frame shift and premature stop (p.Cys46LeufsX34). 11,33,34 Founder eff ects have also been described in Jewish, 35 Lebanese, 36 and Japanese 5,37 patients (appendix). There is no evidence of a genotype-phenotype correlation. …

… 32,33,38,39 The full phenotypic range is seen among patients from the Agrawal community, who are homozygous for the same founder mutation. 11 From the beginning, it was clear that MLC1 mutations were found in only 70-80% of patients with MLC. Several informative MLC families in whom no MLC1 mutations were found excluded linkage of the disease with the locus on chromosome 22q tel , 20,33,40 indicating that there had to be at least one other gene for MLC. …

Megalencephalic leukoencephalopathy with subcortical cysts: Chronic white matter oedema due to a defect in brain ion and water homoeostasis

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  • Nov 2012

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… 2,7 Brain magnetic resonance imaging (MRI) of diffuse swollen white matter with subcortical cysts in temporal or frontoparietal lobes are the diagnostic hallmarks of the disease. 1,[8][9][10] The clinical course and severity of the disease vary. 8,11 The first patients with MLC were described in India in 1991. …

… 1,[8][9][10] The clinical course and severity of the disease vary. 8,11 The first patients with MLC were described in India in 1991. 12 A subsequent run of patients was described by a Netherlands group, who reported the MRI findings. …

… Megalencephaly leukoencephalopathy with subcortical cysts is a rare neurological disorder with the highest incidence in Indian Agrawal community and the Turkish population. 1,2,7,8 Parental consanguinity and relative mating rather than random mating across successive familial generations are important contributors for the appearance of rare autosomal recessive disorders. However, few reports have described patients with MLC from Arab and Gulf populations, despite their having the highest rates of consanguineous marriage. …

Clinical, Neuroimaging, and Genetic Characteristics of Megalencephalic Leukoencephalopathy With Subcortical Cysts in Egyptian Patients

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  • Oct 2013

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… 6 Macrocephaly is the most important and obvious feature that has been documented in all previous genetically proven cases of MLC. 7 The other commonest initial feature is the delay in developmental milestones, developmental regression, difficulty in walking, and progressive deterioration in motor and mental function. 7 In previous studies, extrapyramidal abnormalities, such as dystonia and athetosis are reported in few patients. …

… 6 Macrocephaly is the most important and obvious feature that has been documented in all previous genetically proven cases of MLC. 7 The other commonest initial feature is the delay in developmental milestones, developmental regression, difficulty in walking, and progressive deterioration in motor and mental function. 7 In previous studies, extrapyramidal abnormalities, such as dystonia and athetosis are reported in few patients. 7 Megalencephaly is noted in infancy, as in our patient, and follows the normal growth pattern. …

… 7 In previous studies, extrapyramidal abnormalities, such as dystonia and athetosis are reported in few patients. 7 Megalencephaly is noted in infancy, as in our patient, and follows the normal growth pattern. Partial and/or generalised seizures have also been documented. …

Van der Knaap Disease

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… A first locus was mapped on chromosome 22q13.33 in Turkish families (Topcu et al., 2000). Mutations in MLC1 were later found to be the molecular basis for this disorder in families of different ethnicities (Leegwater et al., 2001;Ben-Zeev et al., 2002;Leegwater et al., 2002;Blattner et al., 2003;Saijo et al., 2003;Gorospe et al., 2004), including our own series from the Mediterranean area (Patrono et al., 2003). Additionally, families unlinked to the MLC1 locus have been reported (Leegwater et al., 2001) and the existence of at least another locus is hypothesized (Blattner et al., 2003;Patrono et al., 2003). …

… There is a wide array of mutations in MLC1, without a major common mutation. In some specific areas, ancestral mutations have been found consistent with a founder effect (Meyer et al., 2001;Ben-Zeev et al., 2002;Leegwater et al., 2002;Gorospe et al., 2004). Almost nothing is known about the pathogenic mechanism of these mutations, but recent heterologous expression studies proposed that gene mutations impair protein folding (Teijido et al., 2004). …

Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants inMLC1

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… Clinically it is characterised by early-onset macrocephaly with mild motor developmental delay, gradual ataxia and slow course of neurological deterioration. Macrocephaly is the consistent feature and the degree of macrocephaly is variable [1,2,3]. Though this disease bears the name of van der Knaap, it was first reported by Singhal et al. from India who presented a series of 18 patients at 8 th Asian and Oceanian Congress of Neurology at Tokyo in 1991. …

… It is characterized by early-onset macrocephaly with mild motor developmental delay, gradual onset ataxia, spasticity, seizures and usually late onset mild cognitive deterioration. The disease has a high incidence in populations in which consanguinity is common and in certain ethnic groups(Agarwal community in India, Jewish community) [1,2,3]. …

Megalencephalic leukoencephalopathy with subcortical cysts: A report of two cases with a brief review of literature

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  • Oct 2016

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… The patient who presented to us at 33 years of age was surprisingly well preserved. The most consistent feature is macrocephaly which has been demonstrated in all the genetically proven cases.[457] The macrocephaly is usually present at birth and after the first year follows the normal growth pattern. …

… A Turkish study of 12 patients[4] soon followed and established the genetic nature of the disease with autosomal recessive inheritance and a locus at 22q. From India, Gorospe, Singhal and co-workers did detailed genetic analysis and established this disease as a distinct clinicopathological entity with common locus at MLC 1 gene in all the 31 patients described in the Agarwal community.[5] …

Megalencephalic leukoencephalopathy with subcortical cysts: A report of four cases

Article

  • Apr 2011

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… This classical presentation is present in patients with autosomal recessive mutations in MLC1 and HEPACAM. 38,39,41,[43][44][45] A second improving clinical phenotype has been described in patients with an autosomal dominant (de novo or inherited from one parent) mutation in HEPACAM. Patients with this clinical phenotype also have macrocephaly in the first year of life, but demonstrate an improvement in motor function over time rather than deterioration. …

… MRI findings in patients with one mutation in the HEPACAM gene are initially milder and improve over time. 38,39,41,[43][44][45] There currently is no specific treatment for MLC. Supportive treatment for seizures and spasticity are indicated. …

Leukoencephalopathies Associated with Macrocephaly

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… Another child from the Agarwal community harbored a different c.112+1delG mutation in homozygous state. These findings led us to investigate the presence of a founder effect in the community, which is known to harbor other founder mutations (Gorospe et al. 2004;Bahl et al. 2005;Chabbria et al. 2007). …

… The Agarwal community is a large enterprising community consisting of affluent business-class North Indian population originating from a small town of Agroha, near Delhi and spreading all over the world (Singhal 2005). Genetic studies have suggested founder effect in Agarwals in some other genetic disorders like megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM #604004), spinocerebellar ataxia type 12 (OMIM #183090), and pantothenate kinase-associated neurodegeneration (PKAN, OMIM#234200) (Gorospe et al. 2004;Bahl et al. 2005;Chabbria et al. 2007). Recently, two mutations have been shown to have founder effect in Agarwals in calpain-3 gene (CAPN3, OMIM *114240) in patients of LGMD type 2A (OMIM #253600) (Ankala et al. 2013). …

Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India

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… Use of SNP microarray to identify regions of homozygosity and candidate genes in these regions is a strategy which can be successfully used in the consanguineous families (Stephen et al. 2015). Some conditions found to be relatively common have been Van Der Knaap disease with a founder mutation in the Agarwal community from north western India, calpainopahy, recessive forms of Osteogenesis imperfecta, Progressive pseudorheumatoid arthropthy of childhood and Handigodu disease from a specific community in South India (Gorospe et al. 2004;Pathak et al. 2010;Sachdeva et al. 2011Sachdeva et al. , 2012Shukla et al. 2011;Bashyam et al. 2012;Dalal et al. 2012;Bidchol et al. 2014;Ankala et al. 2015). However, the available data on monogenic malformation syndromes and metabolic disorders from India though extensive, represents only tip of the iceberg as a large population still does not have access to the clinical genetics services due to cost and limited number of genetic centers. …

… Recent years have seen publication of genetic and mutation profiles for large case series of osteogenesis imperfecta, skeletal dysplasias, and lysosomal storage disorders. These studies have revealed the unique molecular profile of patients from the India with identification of many novel mutations not previously reported in other populations (Gorospe et al. 2004;Pathak et al. 2010;Sachdeva et al. 2011Sachdeva et al. , 2012Shukla et al. 2011;Bashyam et al. 2012;Dalal et al. 2012;Mistri et al. 2012;Bidchol et al. 2014;Ankala et al. 2015;Stephen et al. 2015 Varawalla et al. (1991), Das et al. (2000), Agarwal et al. (2000), Colah et al. (2009), Sinha et al. (2011), Cao et al. (2000, …

Medical genetics and genomic medicine in India: current status and opportunities ahead

Article

Full-text available

  • May 2015

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… Another child from the Agarwal community harbored a different c.112+1delG mutation in homozygous state. These findings led us to investigate the presence of a founder effect in the community, which is known to harbor other founder mutations (Gorospe et al. 2004; Bahl et al. 2005; Chabbria et al. 2007). …

… The Agarwal community is a large enterprising community consisting of affluent business-class North Indian population originating from a small town of Agroha, near Delhi and spreading all over the world (Singhal 2005). Genetic studies have suggested founder effect in Agarwals in some other genetic disorders like megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM #604004), spinocerebellar ataxia type 12 (OMIM #183090), and pantothenate kinase-associated neurodegeneration (PKAN, OMIM#234200) (Gorospe et al. 2004; Bahl et al. 2005; Chabbria et al. 2007). Recently, two mutations have been shown to have founder effect in Agarwals in calpain-3 gene (CAPN3, OMIM *114240) in patients of LGMD type 2A (OMIM #253600) (Ankala et al. 2013). …

MOLECULAR DIAGNOSIS OF HEREDITARY FRUCTOSE INTOLERANCE SUGGESTION OF A FOUNDER MUTATION IN A COMMUNITY FROM INDIA?

Conference Paper

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  • Sep 2012

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… Gorospe et al. carried out detailed genetic analysis of these patients and identified a common locus on the MLC1 gene. [2] A 27-year-old male born from a nonconsanguineous marriage in a Sikh community in Haryana, India had experienced a history of seizures and ataxia since the age of eight. His seizures were well controlled by a single antiepileptic drug. …

… [1] Original cases were described by Alzheimer more than a century ago and later found to have tau-positive inclusions. [2] FTD can be classified into three clinical syndromes depending on the early and predominant symptoms. The more common syndrome is a behavioral variant (bvFTD) with two language variants namely semantic dementia and progressive nonfluent aphasia (PNFA), which is very rare compared to bvFTD. …

Van der Knaap Disease: Megalencephalic Leukoencephalopathy with Subcortical Cysts

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  • Sep 2016

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… [4,5] In India, majority of the patients belong to the Agarwal community. [6,7] Our patient however did not belong to this community. Indian patients with megalencephaly and MR changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. …

… Indian patients with megalencephaly and MR changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. [7] This disease has been assigned to the gene, MLC1, and is localized on chromosome 22qtel. [8] It has been reported that no basic biochemical defect was identified in patients with VML. …

UNUSUAL CASE OF VAN DER KNAAP’S DISEASE PRESENTING AT 2 YEARS OF AGE FOLLOWING HEAD TRAUMA

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… 20 Among neurologic diseases, limb-girdle muscular dystrophy and megalencephalic leukodystrophy with subcortical cysts are relatively more prevalent among the same ethnic group. [21][22][23] Depending on the geography of data collection, the prevalence of SCA has varied in different studies from India. SCA2 generally was the most common type in Northern, Eastern, and Western India. …

Clinical Characterization of Genetically Diagnosed Cases of Spinocerebellar Ataxia 12 from India

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… També és el cas de la població d’Agarwals de la Índia on pràcticament la totalitat d’individua presenten la inserció 135insC en homozigosi (Gorospe et al., 2004;. Un altre exemple és la mutació G59E dels jueus de Líbia , o la dels japonesos, que solen presentar la mutació puntual S93L . …

Avenços en la fisiopatologia de la Leucoencefalopatia Megalencefàlica amb Quists subcorticals

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… Other investigators and our group have identi ed a number of disorders with founder mutations among the Agarwal community [88,89]. Carriers for only two of these were identi ed in the current panel of genes -calpainopathy and megalencephalic leukodystrophy with cysts. …

NGS based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results – a pilot study.

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… In addition, many MLC1 mutations have been identified in the past years [3,[13][14][15][16][17][18][19]. Until now, there are around 70 MLC-related mutations of MLC1 have been reported in patients of various ethnic backgrounds (human gene mutation database, HGMD). …

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NGS based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results – a pilot study.

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… MLC with subcortical cysts is a form of Van der Knaap leukoencephalopathy with autosominal recessive inheritance resulting from gene mutations in the MLC 1 gene. It is typically described as occuring in the Agarwal community of India [19]. It generally presents in infancy with macrocephaly, often in combination with mild gross motor and cognitive decline, gradual onset of ataxia, spasticity and relatively late onset of mild mental deterioration. …

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… MLC has a significantly higher incidence in a population where consanguineous marriages are common as reported in Turkish series. [8] Gorospe et al. [9] in their series found that all Indian patients belonged to the ethnic group “Agarwal community of Haryana, India” and had the same mutation suggesting founder effect. [5] Incidence of MLC1 in Jews of Libya and Turkey, living thousands of miles apart, were studied and found to have the same mutation. …

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… Other investigators and our group have identi ed a number of disorders with founder mutations among the Agarwal community [88,89]. Carriers for only two of these were identi ed in the current panel of genes -calpainopathy and megalencephalic leukodystrophy with cysts. …

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… Currently, there are only 68 accredited centers in India offering genetic testing and/or counseling services (http://geneticsindia.org); most of these clinical laboratories only offer diagnostic assays that target either a single more recurrent mutation or a small set of Gorospe et al. (2004) a Founder effect of the mutation was established by haplotype studies and detection of the mutation in multiple affected individuals (personal communication by IC Verma). Allele count, number of alleles with mutation/number of alleles tested. …

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… Some patients die in their teens or twenties, whereas others stay alive into their forties [Pascual-Castroviejo et al., 2005;Saijo et al., 2003;Singhal et al., 1996;Singhal et al., 2003]. There are differences in disease severity among patients with the same mutation [Gorospe et al., 2004;Goutières et al., 1996;Singhal 2005;Singhal et al., 2003] and sibling patients [Pascual-Castroviejo et al., 2005;Patrono et al., 2003;Singhal 2005;Singhal et al., 2003]. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen white matter of the cerebral hemispheres and subcortical cysts in the anterior temporal and often also frontoparietal region. …

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… There are several reports that suggest founder effects. An ancestral mutation has also been described in Indian Agarwal [10], Jewish [11], Egyptian [12], and Japanese patients [13]. To date, there has been no study on the mutational spectrum of MLC1 in Korean MLC patients. …

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… This is rare entity and has been reported in Aggarwal community in India. 3 …

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… The disease is inherited by an autosomal recessive pattern and the regulator gene is MLC1 on chromosome 22q. 2 It is commonly seen in Agarwal community of north India. It is clinically characterized by macrocephaly, motor development delay, seizures, spasticity, ataxia, mild mental deterioration. 3 Magnetic resonance imaging(MRI) is the investigation of choice in which extensive, symmetrical white matter changes with subcortical cysts in the anterior temporal lobes and fronto-parietal subcortical area are. 4 This disease has a benign course with a survival rate upto the 4 th decade of life. …

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… A case report Discussion MLC or Van der Knaap disease is an autosomal recessive disorder, commonly seen though not restricted to members of a particular Agarwal community. [1] It was first described by Singhal et al. as early as 1991 [2] but was published in 1995 by Van der Knaap et al. and subsequently, the disease became recognized as Van der Knaap disease. [3] Singhal et al. published their case series in 1996. …

When the head is big, think this too: Megalencephalic leukoencephalopathy in a toddler with only a large head. A case report

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