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Deb K Pal

Publications and source records attributed to Deb K Pal.

11 recordsLinked to original sources
PubMed2006

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. METHODS: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. RESULTS: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. CONCLUSIONS: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

Chromosomes, Human, Pair 6↗
PubMed2006

Distinct phenotype of early childhood inflammatory bowel disease.

GOALS: Our goals were to answer 2 questions: (1) Is the presentation of early-onset inflammatory bowel disease (IBD) similar to typical adolescent-onset IBD? (2) Is there variability in familial aggregation in childhood IBD? BACKGROUND: The phenotype of IBD in children under 5 years of age (early-onset) is poorly defined. Clinical and genetic studies of IBD, however, generally assume the phenotype to be homogenous throughout childhood. STUDY: We analyzed data from 413 consecutive pediatric IBD outpatients attending our center between 1995 and 2000. Disease type, anatomic distribution, and family history were compared between children presenting before (early-onset) and after the age of five (5 to 15 y). RESULTS: Disease presentation was predominantly colonic in early-onset IBD, most patients presenting with ulcerative colitis (UC). Isolated colonic disease was most frequent in early-onset Crohn disease (colonic 76.5%, ileocolic 24%) compared with ileocolic disease (ileocolic 45.5%, colonic 26%, ileal 19.4%, proximal 6.3%) in the older age group. First-degree family history was highest in early-onset UC 26% versus 11% in the older UC group. CONCLUSIONS: We describe a distinct phenotype of early childhood onset IBD, with a strikingly high familial aggregation in UC and greater tendency to present with colonic disease. As more genetic heterogeneity is identified in IBD, careful definition of phenotype is required to identify further susceptibility genes. The early-onset form of UC presents an ideal group for further genetic analysis. These phenotype differences also suggest that treatment and outcome may vary in early-onset childhood IBD; prospective studies are required to confirm this.

Adolescent↗
PubMed2004

Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.

Adolescent↗
PubMed2003

BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy that starts in adolescence. A major JME susceptibility locus (EJM1) was mapped to chromosomal region 6p21 in three independent linkage studies, and association was reported between JME and a microsatellite marker in the 6p21 region. The critical region for EJM1 is delimited by obligate recombinants at HLA-DQ and HLA-DP. In the present study, we found highly significant linkage disequilibrium (LD) between JME and a core haplotype of five single-nucleotide-polymorphism (SNP) and microsatellite markers in this critical region, with LD peaking in the BRD2 (RING3) gene (odds ratio 6.45; 95% confidence interval 2.36-17.58). DNA sequencing revealed two JME-associated SNP variants in the BRD2 (RING3) promoter region but no other potentially causative coding mutations in 20 probands from families with positive LOD scores. BRD2 (RING3) is a putative nuclear transcriptional regulator from a family of genes that are expressed during development. Our findings strongly suggest that BRD2 (RING3) is EJM1, the first gene identified for a common idiopathic epilepsy. These findings also suggest that abnormalities of neural development may be a cause of common idiopathic epilepsy, and the findings have implications for the generalizability of proposed pathogenetic mechanisms, derived from diseases that show Mendelian transmission, to their complex counterparts.

Adolescent↗
PubMed2003

Phenotypic features of familial febrile seizures: case-control study.

OBJECTIVE: To identify phenotypic features of febrile seizures that can be used to reduce heterogeneity and thereby increase power in linkage analysis. BACKGROUND: Despite exciting discoveries in several rare pedigrees, the genetic basis of common febrile seizures remains a mystery. The major drawback of studying common febrile seizure disorder is etiologic and genetic heterogeneity. A linkage sample must therefore be classified a priori on phenotypic criteria likely to reflect genetically homogeneous subgroups. METHODS: Eighty-three cases (children with one or more febrile seizure plus first-degree family history of febrile seizures) and 101 controls (children with one or more febrile seizure but no first-degree family history of febrile seizures) were compared for association of phenotypic features in an unmatched case-control design. Odds ratios were calculated using univariate and multivariate methods. RESULTS: Recurrent febrile seizures was the only phenotypic feature significantly associated with first-degree family history of febrile seizures (OR 2.1, 95% CI 1.15 to 3.88). First-degree family history and later occurrence of afebrile seizures (OR 3.47, 95% CI 0.94 to 12.78) were independently associated with recurrent febrile seizures. Complex features did not show familial aggregation. CONCLUSIONS: The authors suggest recurrent and afebrile seizures as criteria on which to subgroup a linkage sample. These subgroups will not be evident at the time of the initial febrile seizure. Meticulous and prospective collection of phenotypic and family data are recommended.

Adolescent↗
PubMed2002

Social integration of children with epilepsy in rural India.

Only a small fraction of people with epilepsy in developing countries has access to medical facilities. Even with effective treatment, their psychosocial needs are often overlooked in the absence of obvious disability. In rural areas, community-based rehabilitation programmes assist in the integration of people with disabilities into employment and the community. However, the functional impairment associated with epilepsy is not well recognised in intervention programmes in developing countries. We report, for the first time, the social activities of children with epilepsy and their peers in rural India. We employed a cross-sectional design using a new age and sex-specific social activity questionnaire. Population screening in the context of a community-based rehabilitation programme identified 88 children with epilepsy and 250 randomly selected controls. A trained interviewer administered the questionnaire to mothers in Bengali. Girls' activities were principally domestic, whilst boys' were mostly outdoors and involved peers. All groups of children with epilepsy had significant social deficits, equally for boys and girls in the age range from 2 to 18 years (p < 0.05). Boys with epilepsy had limited peer group activities, and parents conferred fewer responsibilities to school age and adolescent children compared to controls. The nature and degree of deficits were beyond the constraints imposed by neurological impairment. Our findings in pre-schoolers were consistent with parental attitudes of overprotection found in previous research. We conclude that social integration needs active and early promotion among children with epilepsy. The assessment of remediable risk and protective factors in the family and community is an important practical area for research in community-based rehabilitation.

Activities of Daily Living↗
PubMed2002

Help-seeking patterns for children with epilepsy in rural India: implications for service delivery.

PURPOSE: Most people in the world with epilepsy are untreated with antiepileptic drugs (AEDs). In some developing countries, this is because treatment facilities are unavailable or difficult to access. It has even been suggested that indigenous health systems threaten the prospect of the global control of epilepsy with AEDs. We have investigated patterns and costs of help seeking for children with epilepsy in a region of rural India where only 12% of children with epilepsy were in treatment. Our objective was to find out (a) whom families had consulted; (b) if nonconsulting families differed in demographic or child medical factors; (c) if indigenous treatment was taken, exclusive of allopathic treatment; and (d) the direct and indirect cost of various providers. METHODS: We conducted a cross-sectional interview study in a community-based program for childhood epilepsy in rural West Bengal, India. We interviewed parents of 85 children aged 2 to 18 years with untreated epilepsy who had entered a clinical trial of AEDs during 1995 through 1996. RESULTS: Eighty percent of families had sought some help in the past: 62% with an allopathic practitioner, 44% with traditional practitioners. Primary health centres (PHCs) and quacks were not popular. Twenty-four percent of families never sought help of any kind, and this was unassociated with sex, income, maternal literacy, or medical variables. There was evidence of both exclusivity and pluralism: 42% of families first consulting allopathic practitioners also visited traditional practitioners, whereas 30% of families first consulting traditional practitioners also went to allopathic practitioners. One visit to a physician cost a median of 9-13% of monthly income and 5-12 person-hours; the cost of visiting indigenous providers was negligible. CONCLUSIONS: Most families sought some form of help and were motivated to spend large amounts of money and time for allopathic treatments from qualified practitioners. The typical cost of allopathic treatment was unsustainable in the long term. Medical pluralism is common and does not adversely influence use of allopathic treatment. The phenomenon of nonconsulting merits further study. Traditional practitioners play a complementary role and might become involved in community treatment programs. Low-cost, local treatment is essential to the public health control of epilepsy.

Adolescent↗
PubMed2002

Evaluating genetic heterogeneity in complex disorders.

OBJECTIVES: The Admixture test is routinely used in linkage analysis to take account of genetic heterogeneity, and yields an estimate of the proportion of families (alpha) segregating the linked disease gene. In complex disorders, the assumptions of the Admixture test are violated. We therefore explore how the estimate of alpha relates to the true proportion of linked families with a complex disorder in a population or dataset. METHODS: We simulated a two-locus heterogeneity model and varied genetic parameters, ascertainment scheme and phenocopy frequency. RESULTS: In this model, alpha is almost always overestimated, by as little as 5% to as much as 60%. The bias is largely attributable to (1). intrafamilial heterogeneity arising from ascertainment of families with many affected members or from analysis of dense pedigrees; (2). low informativeness, which occurs in the presence of reduced penetrance; and (3). differences in the evidence for linkage in linked and unlinked families. This bias is also affected by the analysis phenocopy frequency, but only if the linked locus is dominant and the unlinked locus is recessive. CONCLUSIONS: We conclude that, in complex diseases, the Admixture test has greater value in detecting linkage than in estimating the proportion of linked families in a dataset.

Family↗