Clinical Utility of Electrophysiological Evaluation in Crigler-Najjar Syndrome

Abstract

We evaluated the neurological and neurophysiological features in ten patients with genetically characterized Crigler-Najjar (CN) syndrome: four with typical type I CN had undergone orthotopic liver transplantation (OLT); six had type II CN, and three of them developed severe hyperbilirubinemia with a limited response to phenobarbital leading to an intermediate phenotype I/II. Clinical neurological and multimodal electrophysiological evaluations [electroencephalogram (EEG), visual (VEPs), motor (MEPs) and brainstem auditory (BAEPs) evoked potentials] were performed. Neurological examinations showed mild hand tremor in four patients (one pre-OLT and one post-OLT type I, two type I/II). EEG revealed high voltage paroxysmal discharges in four patients (three type I/II, and one type I with a marked improvement after OLT). VEPs showed P100 wave increased latency in five patients (three type I, and two type I/II considered for OLT evaluation). MEPs showed prolonged central motor conduction time in five patients (two type I; one type I/II; two type II). Only EEG and VEPs findings showed a correlation with high bilirubin levels. BAEPs were normal. In conclusion, VEPs and EEG contribute to identify and monitor bilirubin neurotoxic effects, and may play a decisional role in some cases of severe hyperbilirubinemia without overt neurologic damage.

Key words

Crigler-Najjar syndrome - electrophysiological features - UGT1A1 gene

References

• 1 Ambrosino G, Varotto S, Strom SC, Guariso G, Franchin E, Miotto D. et al . Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1.  Cell Transplant. 2005;  14 151-157
• 2 Arias IM, Gartner LM, Cohen M, Ben-Ezzer J, Levi AJ. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyltransferase deficiency: clinical, biochemical, pharmacologic and genetic evidence for heterogeneity.  Am J Med Genetics. 1969;  47 395-409
• 3 Blaschke TF, Berk PD, Scharschmidt BF, Guyther JR, Vergalla JM, Waggoner JG. Crigler-Najjar syndrome: an unusual course with development of neurological damage at age eighteen.  Pediatr Res. 1974;  8 573-590
• 4 Chalasani N, Chowdhury NR, Chowdhury JR, Boyer TD. Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect.  Gastroenterology. 1997;  112 2099-2103
• 5 Crigler JF, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus.  Pediatrics. 1952;  10 169-180
• 6 Duhamel G, Blanckaert N, Metreau JM, Preaux AM, Bouvry M, Fevery J. et al . An unusual case of Crigler-Najjar disease in the adult. Classification into types I and II revisited.  J Hepatol. 1985;  1 47-53
• 7 Gollan JL, Huang SN, Billing B, Sherlock S. Prolonged survival in three brothers with severe type 2 Crigler-Najjar syndrome. Ultrastructural and metabolic studies.  Gastroenterology. 1975;  68 1543-1555
• 8 Gordon ER, Shaffer EA, Sass-Kortsak A. Bilirubin secretion and conjugation in Crigler-Najjar syndrome type II.  Gastroenterology. 1976;  70 761-765
• 9 Gridelli B, Lucianetti A, Gatti S, Colledan M, Benti R, Bruno A. et al . Orthotopic liver transplantation for Crigler-Najjar type I syndrome.  Transplant Proc. 1997;  29 440-441
• 10 Grompe M. Principles of therapeutic liver repopulation.  J Inherit Metab Dis. 2006;  29 421-425
• 11 Kniffin CL.. , #606785 Crigler-Najjar syndrome, type II. OMIM. Available at:URL: http://www.ncbi.nlm.nih.gov/
• 12 Labrune PH, Myara A, Francoual J, Trivin F, Odievre M. Cerebellar symptoms as the presenting manifestations of bilirubin encephalopathy in children with Crigler-Najjar type I disease.  Pediatrics. 1992;  89 768-770
• 13 Persico M, Romano M, Muraca M, Gentile S. Responsiveness to phenobarbital in an adult with Crigler-Najjar disease associated with neurological involvement and skin hyperextensibility.  Hepatology. 1991;  13 213-215
• 14 Recommendations for the practice of clinical neurophysiology: Guidelines of the International Federation of Clinical Neurophysiology.  , Deuschl G, Eisen A, Editors. Electroencephalogr Clin Neurophysiol Suppl. 1999;  52 1-304
• 15 Rubboli G, Ronchi F, Cecchi P, Rizzi R, Gardella E, Meletti S. et al . A neurophysiological study in children and adolescents with Crigler-Najjar syndrome type 1.  Neuropediatrics. 1997;  5 281-286
• 16 Seppen J, Bakker C, de Jong B, Kunne C, van den Oever K, Vandenberghe K. et al . Adeno-associated virus vector serotypes mediate sustained correction of bilirubin UDP glucuronosyltransferase deficiency in rats.  Mol Ther. 2006;  13 1085-1092
• 17 Servedio V, D’Apolito M, Maiorano N, Minuti B, Torricelli F, Ronchi F. et al . Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation.  Hum Mut. 2005;  25 317-325
• 18 Shevell M, Majnemer A, Schiff D. Neurological perspectives of Crigler-Najjar syndrome type I.  J Child Neurol. 1998;  13 265-269
• 19 Solomon G, Labar D, Galbraith RA, Schaefer J, Kappas A. Neurophysiological abnormalities in adolescents with type 1 Crigler-Najjar syndrome.  Electroencephalogr Clin Neurophysiol. 1990;  76 473-475
• 20 Strauss KA, Robinson DL, Vreman HJ, Puffenberger EG, Hart G, Morton DH. Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease.  Eur J Pediatr. 2006;  165 306-319
• 21 Suresh G, Lucey JF. Lack of deafness in Crigler-Najjar syndrome type 1: a patient survey.  Pediatrics. 1997;  100 E9
• 22 Tabarki B, Khalifa M, Yacoub M, Tlili K, Essoussi AH. Cerebellar symptoms heralding bilirubin encephalopathy in Crigler-Najjar syndrome.  Ped Neurol. 2002;  27 234-236
• 23 Vajro P, De Vincenzo A, Lucariello S, Migliaro F, Sokal E, Bernard O. et al . Unusual early presentation of Gilbert syndrome in pediatric recipients of liver transplantation.  J Pediatr Gastroenterol Nutr. 2000;  31 238-243
• 24 Van der Veere CN, Sinaasappel M, MacDonagh AF, Rosenthal P, Labrune P, Odievre M. et al . Current therapy for Crigler-Najjar Syndrome type 1: report of a world registry.  Hepatology. 1996;  24 312-315

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