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Brain Advance Access published online on January 17, 2008
Brain, doi:10.1093/brain/awm337
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Recessive hereditary methaemoglobinaemia, type II: delineation of the clinical spectrum

C. Ewenczyk1, A. Leroux2, A. Roubergue3, V. Laugel4, A. Afenjar3, J. M. Saudubray5, P. Beauvais3, T. Billette de Villemeur3, M. Vidailhet1 and E. Roze1,6

1Pôle des maladies du système nerveux, Fédération de neurologie, groupe hospitalier Pitié-Salpêtrière, AP-HP, 2Département Génétique et Développement, Institut Cochin, INSERM U567, Université Paris-V René-Descartes, 3Service de Neuropédiatrie, hôpital Trousseau, AP-HP, 4Service de Pédiatrie, Hôpital de Hautepierre, Strasbourg, France, 5Service de maladie Neurométaboliques, Hôpital Necker-enfants malades, AP-HP, and 6Unité de Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Université Paris VI Pierre et Marie Curie, Paris, France

Correspondence to: Dr E. Roze, MD, PhD, Pôle des Maladies du Système Nerveux, Fédération de Neurologie, Groupe hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75651 Paris Cedex 13, France E-mail: emmanuel.roze{at}psl.aphp.fr

Type II recessive hereditary methaemoglobinaemia (RHM) is a rare disease due to generalized NADH-cytochrome b5 reductase (cytb5r) deficiency. It results in mild cyanosis and severe neurological impairment. The clinical features and long-term outcome are poorly documented, and there are no systematic reviews. We examined six cases of type II RHM, four of which were new, together with 45 previously published cases, in order to establish the range of phenotypic expression. The clinical picture was very similar in most cases, with severe encephalopathy, microcephaly, generalized dystonia, movement disorders and mild cyanosis. The neurological prognosis was poor; in particular, none of the patients walked or spoke. In addition, the possibility of an atypical and milder phenotype was considered. We concluded that children with unexplained severe encephalopathy associated with generalized dystonia should be examined for cyanosis and have a methaemoglobinaemia assay performed. The diagnosis can be confirmed by very low cytb5r activity in both red and white blood cells. Here we report three novel mutations in the NADH-cytochrome b5 reductase gene. Prenatal diagnosis of this extremely severe disease should be proposed to affected families.

Key Words: cyanosis; dystonia; cerebral palsy; methaemoglobinaemia; cytochrome b5 reductase

Abbreviations: cytb5r, cytochrome b5 reductase; RHM, recessive hereditary methaemoglobinaemia.

Received October 11, 2007. Revised November 26, 2007. Accepted December 19, 2007.


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