A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping.

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.

Effect of erythropoietin therapy on polyneuropathy in predialytic patients.

BACKGROUND: Peripheral neuropathy commonly develops in patients with advanced chronic renal failure. The uremic neuropathy is often subclinical and detectable only by electrophysiological studies. Receptors to erythropoietin (EPO) have been described on non-hematopoietic cells including neuronal cells. METHODS: In order to evaluate the effect of five months' EPO therapy on polyneuropathy in predialytic patients, nerve conduction studies (NCS) were done in 46 anemic predialytic patients without neurological complaints. In 22 (twelve non-diabetic and ten diabetic) neuropathy was detected and these patients were included in the study. After five months of subcutaneous EPO therapy NCSs were repeated. RESULTS: Hemoglobin increased significantly (p=0.0001) with no significant increase in plasma creatinine. Motor nerve conduction velocity (MNCV) and compound muscle action potentials (CMAP) of the ulnar nerve were normal before EPO therapy and at the end of the study. MNCV of the median, peroneal and tibial nerves improved significantly (p<0.05). CMAP of the median nerve rose significantly, to the normal range (p=0.01). Sensory nerve conduction velocity (SNCV ) and sensory nerve action potentials (SNAP) were reduced in all sensory nerves and did not improve. The improvement in non-diabetic patients was better than in diabetic patients. No significant correlation was found between the increase in hemoglobin and the improvement in MNCV. CONCLUSIONS: Subcutaneous EPO therapy improved motor polyneuropathy in uremic patients, especially non-diabetic individuals. The improvement in MNCV may reflect remyelination. This non-hematopoietic effect may be related to some direct action through EPO receptors on peripheral neuronal cells.