Abstracts

RATIONALE: Action myoclonus-renal failure syndrome (AMRF, OMIM 254900) is a distinctive form of progressive myoclonus epilepsy associated with renal failure. 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 description of AMRF was in 4 French-Canadian patients (Adv Neurol 43:87-103, 1986).
We now describe 15 patients from 5 countries, allowing a more complete characterization of AMRF.
METHODS: The 15 patients (9 families) consisted of 11 additional individuals (from Australia, Canada, Cuba, Germany, and United States), and the original 4 described in 1986. Clinical phenotype and disease history of each patient was characterized. Genealogical history was obtained on each family. Pedigrees were constructed with Cyrillic 2.1. Statistical data were analyzed with SPSS software. Brain and renal pathology were reviewed.
RESULTS: The findings show that AMRF can present with either renal or neurological features. Tremor onset ranged from 17-26 years (mean:19.8). Onset of action myoclonus was from 19-29 years (mean 21.7). Convulsive seizures occurred in 11/15 patients (73%); onset ranged from 20-28 years (mean:22.7). Ataxia and dysarthria were observed in all as the disease progressed. There was no intellectual deterioration. Proteinuria detected at ages 10-30 years in all cases progressed to renal failure in 12/15 patients within 0-8 years (mean:3.8) after proteinuria detection.
Brain autopsy (2 patients) revealed extra-neuronal storage. Renal biopsy specimens showed focal sclerosing glomerulonephritis with features of collapsing glomerulopathy.
Autosomal recessive inheritance was determined in all 9 families based on: absence of affected cases in previous generations; 2 or more affected siblings (4 families); verified parental consanguinity (3 families); and parental origins from the same rural area (6 families).
CONCLUSIONS: This study extends the original AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a rare and probably under-diagnosed syndrome.
Our results show that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes already identified for focal segmental glomerulosclerosis involved with the glomerular basement membrane and related proteins are thus candidates for AMRF.
Moreover, the independent progression of the neurological and renal disorders in AMRF suggests pleiotropic effects of a unitary molecular lesion. Storage in the brain and lack of kidney storage leads to the hypothesis that the mutant protein is also expressed in brain but cannot be effectively cleared leading to the extraneuronal brain storage.
Treatment with anti-myoclonic drugs (valproic acid, clonazepam, piracetam or levetiracetam) and effective dialysis or transplantation can improve quality of life, since AMRF patients can survive for a number of years with retained intellect.
[Supported by: Canadian Institutes of Health Research]