Brain Advance Access originally published online on September 13, 2004
Brain 2004 127(10):2173-2182; doi:10.1093/brain/awh263
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Brain Vol. 127 No. 10 © Guarantors of Brain 2004; all rights reserved
Action myoclonus–renal failure syndrome: characterization of a unique cerebro-renal disorder
1 Neurogenetics Unit and 2 Epilepsy Service, Montreal Neurological Hospital and Institute, 3 Department of Human Genetics, 4 Department of Neurology and Neurosurgery, 5 Department of Pediatrics and 6 MRS Unit, McConnell Brain Imaging Center, McGill University, 7 Département de Génetique Médicale, Hôpital Sainte-Justine, Montreal, 8 Service de Neurologie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, 9 British Columbia Neuropsychiatry Program, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada, 10 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, 11 Department of Pathology, Alfred Hospital, 12 Department of Anatomical Pathology, Royal Melbourne Hospital, 13 Department of Neurology, Royal Melbourne Hospital, Melbourne Victoria, Australia and 14 Parkinson's Disease and Other Movement Disorders Center, Mayo Clinic, Scottsdale, Arizona, USA, 15 Universität Göttingen, Paracelsus-Elena-Klinik, Kassel, 16 Max Planck Institut für Psychiatrie and Institute of Human Genetics, National Research Center, Munich, Germany, 17 Instituto de Neurologia Pilar, Hospital N. S. Pilar, Curitiba, Brazil and 18 Serviço de Anatomia Patológica, Hospital de São João, Porto, Portugal
Correspondence to: Eva Andermann, MD, PhD, FCCMG, Neurogenetics Unit, Room 127, Montreal Neurological Hospital and Institute, 3801 University Street, Montreal, Quebec H3A 2B4, Canada E-mail: eva.andermann{at}mcgill.ca
Action myoclonus–renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17–26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14–29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20–28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0–8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.
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