Brain Advance Access published online on September 13, 2004
Brain, doi:10.1093/brain/awh263
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1 Neurogenetics Unit, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: eva.andermann{at}mcgill.ca.
Summary 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.
Revised June 7, 2004
Accepted June 10, 2004
Article
Action myoclonus--renal failure syndrome: characterization of a unique cerebro-renal disorder
2 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne Victoria, Australia
3 Department of Pathology, Alfred Hospital, Melbourne Victoria, Australia
4 Department of Anatomical Pathology, Royal Melbourne Hospital, Melbourne Victoria, Australia
5 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; MRS Unit, McGill University, Montreal, Quebec, Canada
6 Department of Neurology, Royal Melbourne Hospital, Melbourne Victoria, Australia
7 British Columbia Neuropsychiatry Program, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
8 Parkinson's Disease and Other Movement Disorders Center, Mayo Clinic, Scottsdale, Arizona, USA
9 Universität Göttingen, Paracelsus-Elena-Klinik, Kassel, Germany
10 Max Planck Institut für Psychiatrie and Institute of Human Genetics, National Research Center, Munich, Germany
11 Service de Neurologie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
12 Département de Génetique Médicale, Hôpital Sainte-Justine, Montreal, Quebec, Canada
13 Instituto de Neurologia Pilar, Hospital N. S. Pilar, Curitiba, Brazil
14 Serviço de Anatomia Patológica, Hospital de São João, Porto, Portugal
15 Epilepsy Service, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada
16 Neurogenetics Unit, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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