Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder

Abstract

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.

Mutation of SCARB2 in a Patient With Progressive Myoclonus Epilepsy and Demyelinating Peripheral Neuropathy

“…9 Clinical peripheral neuropathy is not a feature of human patients with AMRF; however, electrophysiological evidence of neuropathy has occasionally been noted, but not extensively studied. 3,11 The data previously published on this case demonstrates the longitudinal stability of electrophysiological abnormalities, consistent with a demyelinating neuropathy. 6 Thus electrophysiological evidence of a demyelinating neuropathy can be a clinical clue to the presence of a SCARB2 mutation, whose identification is very important in terms of prognosis and genetic counseling.…”

“…3,8 Unfortunately, the neurological disorder is relentlessly progressive, with most patients dying of the complications of uncontrolled myoclonus in their third or fourth decadeoflife.Wehavefollowedupsomepatientsfor15years, from the onset of PME to death, and renal impairment had not developed. 7 This case appears to be a further example of either absent or severely delayed development of renal features, suggesting that there are differential pathophysiologicalmechanismsforthekidneyandbrainmanifestations.Both heterozygous mutations in this case have been seen previously as homozygous mutations in cases of classic AMRF 4 (unpublished data), so the specific SCARB2 mutations do not seem to determine the pattern of organ involvement.…”

Collapsing Glomerulopathy

“…This expanding literature likely represents a greater overall trend in the diagnosis of CG. When broadly categorized, these reported disorders fall into six areas: Infections (herein includes poorly defined febrile illnesses) (12,13,37-46), autoimmune diseases (13,47-51), malignancies (13,52-54), genetic disorders (55)(56)(57)(58), drug exposures (59 -63), and during the posttransplantation period (64 -70). Not surprising, wide-ranging hypotheses for the pathogenesis of CG have been posited over the years on the basis of this growing list, and no one definable pathogenic trigger for CG has emerged clearly from examining these disparate disorders as a group.…”

Movement Disorders in Systemic Diseases

“…With disease progression, multifocal myoclonic jerks dominate the clinical picture. 80 The disease is caused by a loss-of-function mutation of the SCARB2 gene encoding the lysosomal integral membrane protein type 2 (LIMP-2) gene. 81 …”