Human Genetics

, Volume 126, Issue 5, pp 677–683 | Cite as

Familial autosomal dominant reflex epilepsy triggered by hot water maps to 4q24-q28

  • Rinki Ratnapriya
  • Parthasarthy Satishchandra
  • S. Dilip
  • Girish Gadre
  • Anuranjan Anand
Original Investigation


Hot water epilepsy is a reflex or sensory epilepsy in which seizures are triggered by the stimulus of bathing in hot water. Although there is evidence of a genetic basis to its etiology, no gene associated with this disorder has so far been found. In order to identify the genetic locus involved in the pathophysiology of hot water epilepsy, we performed a genome-wide linkage analysis in a four-generation family manifesting the disorder in an autosomal dominant manner. Significant linkage was detected on chromosome 4q24-q28, with the highest two-point LOD score of 3.50 at recombination value (θ) of 0 for the marker D4S402. Centromere-proximal and centromere-distal boundaries of this locus were defined by the markers D4S1572 and D4S2277, respectively. The critical genetic interval spans 22.5 cM and corresponds to about 24 megabases of DNA. The genes NEUROG2, ANK2, UGT8 and CAMK2D, which are known to be expressed in human brain, are strong positional candidates and we propose to examine these and other genes in the locus to identify the causative gene for this intriguing form of epilepsy.


Febrile Seizure Clobazam Audiogenic Seizure Genetic Interval Dravet Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all the family members for participation in the study. We thank Sharat Chandra and Prakash for critical reading and comments on the manuscript. RR acknowledges receipt of a research fellowship from CSIR, New Delhi. This work was supported by funds from DAE, Mumbai; ICMR, New Delhi and JNCASR, Bangalore.

Conflict of interest statement

All authors report no financial interests or potential conflicts of interests.

Supplementary material

439_2009_718_MOESM1_ESM.doc (66 kb)
Supplementary Table 1 (DOC 66 kb)
439_2009_718_MOESM2_ESM.doc (102 kb)
Supplementary Table 2 (DOC 102 kb)


  1. Allen IM (1945) Observations on cases of reflex epilepsy. NZ Med J 44:135–142Google Scholar
  2. Audenaert D, Van Broeckhoven C, De Jonghe P (2006) Genes and loci involved in febrile seizures and related epilepsy syndromes. Hum Mutat 27:391–401CrossRefPubMedGoogle Scholar
  3. Bebek N, Gürses C, Gokyigit A, Baykan B, Ozkara C, Dervent A (2001) Hot water epilepsy: clinical and electrophysiologic findings based on 21 cases. Epilepsia 42:1180–1184CrossRefPubMedGoogle Scholar
  4. Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH (1997) Sound-induced seizures in serotonin 5-HT2c receptor mice. Nat Genet 16:387–390CrossRefPubMedGoogle Scholar
  5. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL (1998) Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 63:861–869CrossRefPubMedGoogle Scholar
  6. Dravet C, Bureau M, Guerrini R, Giraud N, Roger J (1992) Severe myoclonic epilepsy in infants. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Perret A, Wolf P (eds) Epileptic syndromes in infancy, childhood and adolescence, 2nd edn. John Libbey, London, pp 75–88Google Scholar
  7. Engel J Jr (2001) ILAE Commission Report. A proposed diagnostic scheme for people with epileptic seizures and epilepsy. Report of the ILAE task force on classification and terminology. Epilepsia 42:796–803CrossRefPubMedGoogle Scholar
  8. Gachon F, Fonjallaz P, Damiola F, Gos P, Kodama T, Zakany J, Duboule D, Petit B, Tafti M, Schibler U (2004) The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev 18:1397–1412CrossRefPubMedGoogle Scholar
  9. International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945CrossRefGoogle Scholar
  10. Jackson FR, Wilson SD, Strichartz GR, Hall LM (1984) Two types of mutants affecting voltage-sensitive sodium channels in Drosophila melanogaster. Nature 308:189–191CrossRefPubMedGoogle Scholar
  11. Kawai H, Allende ML, Wada R, Kono M, Sango K, Deng C, Miyakawa T, Crawley JN, Werth N, Bierfreund U, Sandhoff K, Proia RL (2001) Mice expressing only monosialoganglioside GM3 exhibit lethal audiogenic seizures. J Biol Chem 276:6885–6888CrossRefPubMedGoogle Scholar
  12. Keipert JA (1969) Epilepsy precipitated by bathing: water-immersion epilepsy. Aust Paediatr J 5:244–247Google Scholar
  13. Klauenberg BJ, Sparber SB (1984) A kindling-like effect induced by repeated exposure to heated water in rats. Epilepsia 25:292–301CrossRefPubMedGoogle Scholar
  14. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247PubMedGoogle Scholar
  15. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363PubMedGoogle Scholar
  16. Kurata S (1979) Epilepsy precipitated by bathing: a follow-up study. Brain Dev (Domestic Ed) 11:400–405Google Scholar
  17. Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81:3443–3446CrossRefPubMedGoogle Scholar
  18. Lenoir P, Ramet J, De Meirleir L, D’Allest AM, Desprechins B, Loeb HL (1989) Bathing-induced seizures. Pediatr Neurol 5:124–125CrossRefPubMedGoogle Scholar
  19. Leviton A, Cowan LD (1982) Epidemiology of seizure disorders in children. Neuroepidemiology 1:62–83CrossRefGoogle Scholar
  20. Mani KS, Gopalakrishnan PN, Vyas JN, Pillai MS (1968) Hot-water epilepsy—a peculiar type of reflex epilepsy. A preliminary report. Neurol India 16:107–110PubMedGoogle Scholar
  21. Mani KS, Mani AJ, Ramesh CK (1974) Hot-water epilepsy—a peculiar type of reflex epilepsy: clinical and EEG features in 108 cases. Trans Am Neurol Assoc 99:224–226PubMedGoogle Scholar
  22. Mani KS, Rangan G, Srinivas HV, Kalyansundaram S, Narendran S, Reddy AK (1998) The Yelandur study of community based approach to epilepsy in rural south India: epidemiological aspects. Seizure 7:281–288CrossRefPubMedGoogle Scholar
  23. Mofenson HC, Weymuller CA, Greensher J (1965) Epilepsy due to water immersion: an unusual case of reflex sensory epilepsy. JAMA 191:600–601PubMedGoogle Scholar
  24. Moran J (1976) So-called water immersion epilepsy. Ir J Med Sci 145:140Google Scholar
  25. Morimoto T, Hayakawa T, Sugie H, Awaya Y, Fukuyama Y (1985) Epileptic seizures precipitated by constant light, movement in daily life, and hot water immersion. Epilepsia 26:237–242CrossRefPubMedGoogle Scholar
  26. Pinto D, Westland B, de Haan GJ, Rudolf G, da Silva BM, Hirsch E, Lindhout D, Trenite DG, Koeleman BP (2005) Genome-wide linkage scan of epilepsy-related photoparoxysmal electroencephalographic response: evidence for linkage on chromosomes 7q32 and 16p13. Hum Mol Genet 14:171–178CrossRefPubMedGoogle Scholar
  27. Ratnapriya R, Satishchandra P, Kumar SD, Gadre G, Reddy R, Anand A (2009) A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3. Hum Genet 125:541–549CrossRefPubMedGoogle Scholar
  28. Satishchandra P (2003) Hot-water epilepsy. Epilepsia 44(Suppl 1):29–32CrossRefPubMedGoogle Scholar
  29. Satishchandra P, Shivaramakrishna A, Kaliaperumal VG, Schoenberg BS (1988) Hot water epilepsy: a variant of reflex epilepsy in Southern India. Epilepsia 29:52–56CrossRefPubMedGoogle Scholar
  30. Satishchandra P, Ullal GR, Sinha A, Shankar SK (1999) Pathophysiology and genetics of hot-water epilepsy. In: Bercovic S, Genton P, Marescaux C, Picard F (eds) Genetics of focal epilepsies: clinical aspects and molecular biology. John Libbey, London, pp 169–176Google Scholar
  31. Satishchandra P, Ullal GR, Shankar SK (2004) Trigger mechanisms in hot water epilepsy. In: Wolf P, Inoue Y, Zifkin B (eds) Reflex epilepsies. John Libbey, UK, pp 105–114Google Scholar
  32. Scheffer I, Berkovic S (1997) Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 120:479–490CrossRefPubMedGoogle Scholar
  33. Shaw NJ, Livingston JH, Minns RA, Clarke M (1988) Epilepsy precipitated by bathing. Dev Med Child Neurol 30:108–111PubMedCrossRefGoogle Scholar
  34. Skradski SL, White HS, Ptácek LJ (1998) Genetic mapping of a locus (mass1) causing audiogenic seizures in mice. Genomics 49:188–192CrossRefPubMedGoogle Scholar
  35. Skradski SL, Clark AM, Jiang H, White HS, Fu YH, Ptácek LJ (2001) A novel gene causing a mendelian audiogenic mouse epilepsy. Neuron 31:537–544CrossRefPubMedGoogle Scholar
  36. Stensman K, Ursing B (1971) Epilepsy precipitated by hot water immersion. Neurology 21:559–562PubMedGoogle Scholar
  37. Szymonowicz W, Meloff KL (1978) Hot-water epilepsy. Can J Neurol Sci 5:247–251PubMedGoogle Scholar
  38. Tauer U, Lorenz S, Lenzen KP, Heils A, Muhle H, Gresh M, Neubauer BA, Waltz S, Rudolf G, Mattheisen M, Strauch K, Nurnberg P, Schmitz B, Stephani U, Sander T (2005) Genetic dissection of photosensitivity and its relation to idiopathic generalized epilepsy. Ann Neurol 57:866–873CrossRefPubMedGoogle Scholar
  39. Velmurugendran CU (1985) Reflex epilepsy. J Neurol 232(Suppl):212Google Scholar
  40. Wang P, Saraswati S, Guan Z, Watkins CJ, Wurtman RJ, Littleton JT (2004) A Drosophila temperature-sensitive seizure mutant in phosphoglycerate kinase disrupts ATP generation and alters synaptic function. J Neurosci 24:4518–4529CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Rinki Ratnapriya
    • 1
  • Parthasarthy Satishchandra
    • 2
  • S. Dilip
    • 2
  • Girish Gadre
    • 2
  • Anuranjan Anand
    • 1
  1. 1.Molecular Biology and Genetics UnitJawaharlal Nehru Centre for Advanced Scientific ResearchBangaloreIndia
  2. 2.Department of NeurologyNational Institute of Mental Health and NeurosciencesBangaloreIndia

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