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OBJECTIVE To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1). METHODS Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus. RESULTS The monitoring-based myoclonus index correlated significantly (p

The purpose of this paper was to present our experience following the longterm treatment of 11 patients with Unverricht-Lundborg disease (ULD) confirmed by molecular testing. Methods We analyzed the clinical course, cognitive state, neuroimaging and neurophysiology results. Results The data were collected from 9 unrelated families (F/M: 4/7) aged 25-49. The most frequent early manifestations of ULD include generalized tonic-clonic seizures (GTCS) accompanied by myoclonus 2 years later. Myoclonus was observed in all of the patients; its severity made it impossible for 91% to move independently. In two patients- mild atrophy of brain were observed in the MRI. More than half of the patients who underwent evoked potential presented no abnormalities. The dominant EEG-change was slow background activity in all of the patients. Seven patients had generalized seizure activity. The patients received antiepileptic therapy modifications depending on the severity of symptoms and stage of the disease. Five patients received N-acetyl-cysteine. Conclusions ULD patients require anti-epileptic polytherapy, mostly benefitting from managing GTCS and myoclonus with valproic acid and clonazepam treatment. Patients may benefit from add-on therapy with levetiracetam or topiramate. An increase in myoclonus, resulting from the progressive nature of the disease leads to significant disability in the majority of patients.

Background and purpose Unverricht-Lundborg disease (ULD) is a common type of progressive myoclonic epilepsy (PME). It is caused mostly by biallelic dodecamer repeat expansions in the promoter region of CSTB gene. Despite highly prevalent in the Mediterranean countries, no studies have been reported from Egypt. This article study the presence of CSTB gene mutations among Egyptian patients clinically suspected with ULD, and describes the clinical and genetic characteristics of those with confirmed gene mutation. Methods Medical records of patients following up in two specialized epilepsy clinics in Cairo, Egypt were retrospectively reviewed. Twenty patients who belonged to 13 unrelated families were provisionally diagnosed with ULD based on the clinical presentation. Genetic testing was done. Clinical characteristics, demographic data and EEG findings were documented. Results Genetic studies confirmed the presence of the CSTB dodecamer repeat expansion in 14 patients from 8 families (frequency 70 %). The mean duration of the follow-up was 5 years. Male to female distribution was 1:1 with a mean age of onset 9.7 years. Consanguinity was noted in 4 families. Eight patients had their first seizure between the age of 10 and 20 years. Myoclonic jerks ranged in severity from mild in three unrelated patients to severe in one. Only 3 had cognitive impairment. Conclusion Our study confirms the presence of CSTB mutation among Egyptian patients suspected with ULD. There was no clear phenotype-genotype correlation among the studied group of patients. In addition, we noticed variable inter and intra familial severity among patients from the same family.

Summary Objectives To describe the EEG characteristics of patients with Unverricht-Lundborg disease (ULD) and their changes during the long-term evolution of the disease. Methods A retrospective study including all patients with ULD confirmed by molecular biology and more than 15 years’ duration of disease progression at the time of inclusion. EEGs were recorded at inclusion, 2 years and 5 years of follow-up. Patients who discontinued treatment during follow-up had an EEG monitoring 1 year after reintroduction of therapy. Results Forty-seven EEGs were performed in 17 patients. The mean age at onset was 12.0 ± 5.5 years. The mean duration of follow-up was 26.5 ± 6.9 years. The average background rhythm was 8.2 c/s, and was normal in 30 EEGs (64%), slow in 17 (36%) and disorganized in 11 (23%). Epileptic abnormalities were found in 22 EEGs (47%). Myoclonic jerks were found in 13 EEGs (28%). After re-adaptation of antiepileptic medication in patients who had previously stopped treatment, control EEG showed a normal background rhythm with no epileptic abnormalities throughout the monitoring period. Conclusion This study shows that the progressive disappearance of EEG abnormalities is rather due to antiepileptic treatment than a gradual spontaneous tendency to decrease over time.

Objective To assess functional organization of the motor cortex in patients with Unverricht-Lundborg disease (EPM1A) using a combined neurophysiologic and imaging approach. Methods EPM1A patients underwent transcranial magnetic stimulation (TMS)-based cortical mapping of the motor hand area. Moreover, they performed neuroimaging studies to assess functional magnetic resonance imaging (fMRI) activation maps related to motor hand task and cortical thickness (CTH) on T1-weighted 3D images. Results The hand cortical representation was different in EPM1A patients from that of the control subjects both in TMS and in fMRI brain mapping, characterized by a posterior dislocation and a mild reduction in the activation of motor areas. CTH analysis revealed a thinning of both precentral and paracentral areas in the patients. Conclusions We hypothesize that the altered cortical motor map reflects a functional reorganization of the residual cortical neuronal pool of the sensorimotor hand areas driven by plastic reorganization and/or pathophysiological mechanisms. Significance Both pathophysiological process and plastic changes may represent two sides of the same phenomenon in the EPM1A patients; structural and functional brain mapping may help to identify functional reorganization of the cortical motor system.

Background Unverricht-Lundborg disease (ULD) is an autosomal recessive form of progressive myoclonus epilepsy with a wide range of neurologic and psychiatric symptoms including tonic-clonic seizures, myoclonus, ataxia, tremor, dysarthria, depression, and mild intellectual decline. The aim of the study was to describe the EEG features of patients with ULD and their changes during the long-term follow-up. Material and methods We retrospectively evaluated the EEG features of 11 patients with genetically confirmed ULD. Results We included 4 females and 7 males with the mean age 38.3 ± 7.6 years and the mean age at onset 9.4 years. The average background rhythm was 8.4 Hz and was normal in 2 patients and slightly slowed in 9. Spike and wave discharges (SWD) were found in 9 patients and photosensitivity in 2 patients. In all patients myoclonic jerks were recorded in videoEEG, most of the myoclonic movements were not time-locked to epileptiform discharges. In 3 patients SWD and myoclonic jerks were aggravated by ill -advised antiepileptic drugs (phenytoin and carbamazepine) and their frequency diminished after treatment change. Despite the increased frequency and severity of myoclonic jerks the frequency of SWD decreased gradually with time. Conclusion The most common EEG abnormalities in patients with ULD include background slowing and spike and wave discharges; epileptiform discharges can be aggravated by ill-advised antiepileptic drugs.

Objective To evaluate the relationship between sensory hyperexcitability as revealed by giant SEPs and the SEP recovery function (SEP-R) in a series of patient with progressive myoclonic epilepsy of Unverricht–Lundborg type, identified as epilepsy, progressive myoclonic 1A (EPM1A), MIM #254800. Methods We evaluated SEPs by applying median nerve stimuli and SEP-R using paired stimuli at inter-stimulus intervals (ISIs) of between 20 and 600 ms in 25 patients and 20 controls. The SEPs were considered “giant” if the N20P25 and P25N33 amplitudes exceeded normal mean values by +3SD. Results During the paired-stimulus protocol, the SEPs elicited by the second stimulus (S2) were detectable at all ISIs but consistently suppressed in the 13 patients with giant SEPs reflecting a significantly delayed SEP-R. Maximal suppression roughly corresponded to the plateau of a broad middle latency (>100 ms) wave pertaining to the S1 response. Conclusions The cortical processing dysfunction generating giant SEPs in EPM1A patients consistently combines with a long-lasting suppression of hyperexcitability that leads to a delayed giant SEP-R without obstructing the response to incoming stimuli. Significance The delayed SEP-R is not due to true inhibition but the suppression of aberrant hyper-synchronisation sustaining giant SEPs. A broad middle latency SEP component adds a significantly suppressive effect. This suggests that cortico-subcortical circuitries contribute to both the gigantism and the delayed SEP-R.

Objective To delineate long-term change of cortical excitability by measuring somatosensory evoked potentials (SEPs) in patients with Unverricht–Lundborg disease (ULD). Methods SEPs to median nerve stimulation were repeatedly examined in two genetically proven ULD patients manifesting stable condition over 16 years, namely disabling but non-progressive myoclonus and cessation of generalised tonic–clonic seizures. Results In both patients, five sets of early cortical components were identified 16 years ago: two tangential components of N20–P20 and P30–N30 and three radial components of P25, N35 and N40. Cortical SEPs were regarded as abnormally enhanced ‘giant’ based on the N35 amplitude (>mean + 3 SD of normal controls). The bimodal negative peaks of N35 and N40 showed different spatial distribution: N35 maximum in the central area and N40 in the centro-parietal area. At present, N35 remained giant while N40 disappeared in both patients. Conclusions It is possible that currently preserved giant SEPs at least at N35 reflect disabling cortical myoclonus and that disappearance of N40 might reflect a lesser degree of increased cortico-cortical connectivity and/or decreased cortical hyperexcitability in the association cortices. It might possibly have resulted in the disappearance of GTCSs. Significance We delineated long-term change of giant SEP in ULD.

Purpose Unverricht–Lundborg disease (EPM1) is the most common form of progressive myoclonus epilepsies. The genetic background is a homozygous dodecamer repeat extension mutation in the cystatin B (CSTB) gene. However, mutations occurring in a compound heterozygous form with the expansion mutation have also been reported. In Finland, we have found five EPM1 patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene (chEPM1). There are no previous clinical or neurophysiological studies on these patients. Thus, we aimed to characterize possible functional alterations in primary motor cortical areas. Methods Five chEPM1 patients were compared with homozygous patients and healthy controls. All patients underwent a clinical evaluation to characterize the severity of the symptoms. Navigated transcranial magnetic stimulation (TMS) was used to study cortical excitability by determining the motor thresholds (MT), silent periods (SP) and motor evoked potential (MEP) characteristics. Continuous electroencephalography (EEG) was recorded during the measurements. Voxel-based MRI morphometry (VBM) was used to study differences in gray matter volume. Results The chEPM1 patients exhibited an inhibitory cortical tonus reflected as elevated MTs and prolonged SPs. EEG showed spontaneous focal epileptiform activity in centro-temporal and parietal areas in addition to more widespread and generalized discharges. VBM revealed loss of gray matter volume in primary motor cortical areas and thalami. Discussion The chEPM1 patients exhibited functional and structural changes in primary motor cortical areas. The functional changes are more profound as compared to homozygous patients, suggesting a neurophysiological background for the more severe clinical symptoms.

We conducted a search for white matter changes (WMCs) in 13 Unverricht-Lundborg disease patients and compared the prevalence of WMCs in these patients to age-matched long-term epileptics and healthy controls. ULD patients had significantly more T2-weighted high-intensity signals on MRI than control subjects, due to the increased prevalence of these signals in the basal ganglia. Interestingly, ULD patients with the basal ganglia changes were overweight. Basal ganglia T2-weighted high-intensity signals are novel findings in ULD.

Progressive myoclonus epilepsies (PMEs) comprise a heterogeneous group of conditions characterized by an imbalance between excitatory and inhibitory neuronal mechanisms. The aim of this study was to assess the function of the motor cortex in Unverricht-Lundborg disease (ULD), progressive myoclonus epilepsy type 1 (EPM1).Genetically verified EPM1 patients (n=24) were studied and compared with healthy subjects (n=24). MRI-navigated transcranial magnetic stimulation (TMS) was used to study the function of the motor cortex. Motor threshold (MT) and cortical silent period (SP) were used as parameters to evaluate cortical excitability. Peripheral muscle responses were recorded at the thenar and hypothenar using on-line electromyography (EMG).The normal shortening of SP duration with age was not evident in EPM1. Thus, older patients exhibited significantly prolonged SPs in comparison to healthy control subjects (p0.05). The MTs, measured as both stimulator output percentage and induced electric field strength (EF), were significantly higher in EPM1 patients than in control subjects (p0.001). The stimulation of the thenar caused a co-activation in the hypothenar with significantly higher amplitudes as compared to controls (p0.05).The prolongation of the SPs with age in EPM1 patients suggests a prevailing inhibitory tonus of the primary motor cortex (M1) as possible reactive mechanism to the disease. Antiepileptic drugs may contribute to the increased MT but do not affect the SP. The results and methodology of this study can lead to a better understanding of the pathophysiology and progression of EPM1.

This study determined the neuropsychological pattern of Unverricht-Lundborg disease (ULD) and its relationship to disease-related variables. Twenty-one ULD patients were evaluated using neuropsychological tests for abstract reasoning, attention, planning, set-shifting, theory of mind, visual perception, visuomotor coordination, ideomotor, orofacial and constructive praxis, language, learning, and memory. The control groups consisted of 21 healthy subjects and 21 patients with cryptogenic temporal lobe epilepsy (TLE). Multivariate analysis of variance showed that, in comparison with both control groups, the ULD patients showed significantly impaired abstract reasoning, attention, planning, word fluency, constructive praxis, and visuospatial memory and learning. Factor analysis of the test scores obtained by the ULD and TLE groups identified four factors (processing and execution, praxis, memory, theory of mind), and separate ANOVAs using epilepsy-related and demographic variables as covariates showed that the ULD patients had significantly impaired processing and execution. Correlation and regression analyses showed that processing and execution was significantly associated with diagnosis, disease duration and education, and logistic regression analyses indicated that it significantly predicted a diagnosis of ULD. To conclude, ULD is characterised by impaired processing and execution functions. This impairment is a strong independent predictor of ULD and may contribute to the characterisation of the diagnosis.

Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and ataxia, without major cognitive decline. There is no systematic study on the long-term evolution of EEG in this condition.Twenty-five patients with ULD who came to our observation before 1995 and periodically followed in our Epilepsy Centres were included. All waking EEG traces were visually reviewed for the characterization background activity, with particular regard to the frequency of the posterior dominant rhythm (PR), and for the occurrence of spontaneous generalized spike or polyspike and wave discharges (GSWD) and photoparoxysmal response (PPR). Sleep recordings were analyzed with particular regard to the preservation of the physiological sleep patterns and the occurrence of GSWD and other epileptic abnormalities.PR was normal in 68% of patients at the beginning of the disease and kept stable over the years. GSWD were present in 92% of patients at the onset of the disease and gradually disappeared during the follow-up with a significant difference (p0.001) after the 15th year of disease. PPR was present in 88% of patients at the disease onset and gradually disappeared with a significant difference (p0.001) after the 10th year of disease. A gradual reduction of GSWD and a progressive disappearance of physiological sleep patterns were observed in sleep EEGs.In patients with ULD followed for an extended period of time, EEG shows no relevant deterioration of BA while a gradual reduction of GSWD and PPR is observed over time, well correlating with the good seizure outcome in this condition.

Progressive myoclonic epilepsy (PME) is a syndrome complex encompassing different diagnostic entities and often cause problems in diagnosis. We describe the clinical, electrophysiological and pathological features of 97 patients with the diagnosis of PME evaluated over 25 years. Case records of confirmed patients of Neuronal ceroid lipofuscinosis (NCL = 40), Lafora body disease (LBD = 38), Myoclonic epilepsy with ragged red fibers (MERRF = 10), and probable Unverricht-Lundberg disease (ULD = 9) were reviewed. The mean age at onset in patients with NCL (n = 40) was 5.9+/-9.1 years (M:F:: 28:12). Subtypes of NCL were: late infantile (n = 19), infantile (n = 8), juvenile (n = 11) and adult (n = 2) NCL. EEG (n = 37) showed varying degree of diffuse slowing of background activity in 94.6% and epileptiform discharges in 81.1% of patients. Slow frequency photic stimulation evoked photo-convulsive response in 5 patients only. Giant SSEP was demonstrated in 7 and VEP study revealed a prolonged P100 (2) and absent waveform (7). Electrophysiological features of neuropathy were present in 3 patients. Presence of PAS and Luxol Fast Blue (LFB) positive, auto fluorescent (AF) ceroid material in brain tissue (n = 12) and electron microscopy of brain (n = 5), skin (n = 28) and muscle (n = 1) samples showing curvilinear and lamellar bodies established the diagnosis. Patients of LBD (mean age of onset at 14.4+/-3.9 years, M:F:: 24:14) with triad of PME symptoms were evaluated. EEG (n = 37) showed variable slowing of background activity in 94.6% and epileptiform discharges in 97.4%. Photosensitivity with fast frequency was observed only in 5 patients. CT (n = 32) and MRI (n = 4) revealed diffuse cortical atrophy. Giant SSEP was demonstrated in 24 patients of LBD while VEP study revealed a prolonged P100 (4) and absent waveform (8). Electrophysiological features of neuropathy were present in one patient. Diagnosis was established by the presence of PAS positive diastase resistant, Lugol's Iodine labeled inclusions in sweat glands of axillary skin (n = 35), brain (n = 2) and liver (n = 1). Ten patients with MERRF (mean age at onset: 14.6+/-5.8 years; M: F:: 3:2) had triad of PME symptoms. Muscle biopsy revealed oxidative reaction product and classical ragged red fibers. In nine patients of PME without cognitive decline, probable diagnosis of ULD (mean age at onset: 13.8+/-9.5 years) was considered after biopsy of skin and/or muscle excluded other forms of PMEs. Neuronal ceroid lipofuscinosis and Lafora body diseases were the common causes of PME in the series from south India. This is one of the largest series from the Indian subcontinent to the best of our knowledge. Photosensitivity is notably less common in LBD/NCL in this series distinctly different from those reported in the literature. Further exploration is required to determine whether different genotype is responsible. Morphological changes were helpful in diagnosis and could be confirmed by biopsy of peripheral tissues like skin and muscle in majority (60%). Electron microscopy was helpful in the diagnosis NCL and MERRF.

In this work we analysed the characteristics of the cell-permeable peptide TAT-PTD fused to cystatin B (CSTB) to evaluate its potential for protein therapy of Unverricht-Lundborg (UL) epilepsy. TAT-PTD-CSTB does not penetrate the cells despite initial evidence of time and concentration-dependent transduction. Therefore, it cannot be used as a form of replacement of the intracytoplasmic protein missing in UL. Importantly, we discuss precautions to avoid false-positive results when working with TAT-PTD for protein therapy of neurological diseases.

We studied changes in event-related desynchronization/synchronization (ERD/ERS) patterns in patients with Unverricht-Lundborg disease (ULD), presenting with prominent action myoclonus. We analyzed the movement-related ERD/ERS in alpha and beta frequency bands in 15 patients using self-paced finger extension as a motor paradigm and we compared the results with those obtained in 12 healthy volunteers. In all ULD patients, alpha- and beta-ERD regularly occurred with onset and location similar to that found in healthy controls, but the desynchronization of alpha activity was significantly greater than in controls (C3: -64.4+/-9.8% vs. -49.7+/-14.8%; p=0.004). Moreover, in the patients, both alpha- and beta-ERD spread toward frontal electrodes. In controls, the post-movement beta-ERS regularly occurred; it was absent in eight patients with severe action myoclonus, while, in seven patients with mild or moderate myoclonus, the beta-peak was significantly smaller with respect to that measured in controls (55.6+/-15.1% vs. 153.9+/-99.8%, p=0.006). The failure of beta-ERS well-correlated with motor impairment resulting from action myoclonus, whereas SSEPs and long-loop reflexes performed to detect signs of cortical hyperexcitability showed inconsistent changes. In ULD patients, ERD/ERS changes indicate an increased activation of motor cortex during movement planning and a great reduction of post-excitatory inhibition of motor cortex. The changes involving beta-ERS had a significant relationship with the functional disability in individual patients and might play a pathogenic role in the motor dysfunction.

Loss of function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as an Unverricht-Lundborg disease (EPM1). EPM1 had been linked to chromosome 21q22.3 in Finnish families and it is an autosomal recessive inherited disorder with a homozygous minisatellite expansion in the cystatin B gene (stefin B gene). This disease is difficult to treat because it is refractory to most antiepileptic drugs and using multiple medications had been unsuccessful so far. To come a step closer to understanding of the nature of this disease, especially about the events on the molecular level, in vitro properties of missense EPM1 mutant G4R were determined. It was observed that the mutant has a prolonged lag phase of fibrillation at the same protein stability, which could indicate it were more toxic to the cells. Similar experiments with the N-terminal fragment of 67 aminoacid residues are ongoing, showing higher propensity to aggregate. Therefore, a hypothesis is launched that at least in a subset of Unverricht-Lundborg disease patients, cystatin B protein may aggregate in the cell. Protein aggregation can be secondary to external insults or aging, however, inherited forms of neurodegenerative diseases, such as familial Parkinson's, Huntington's or familial Alzheimer's disease, are directly linked to the mutant proteins aggregation. Protein aggregates in the form of amyloid plaques, neurofibrilary tangles, intra-cytoplasmic or intra-nuclear inclusions lead to increased production of the reactive oxygen species and dysfunction of the ubiquitine/proteasome system. Finally, mitochondrial dysfunction and cell death are observed. Certainly, it remains to be checked by experiments whether overexpression in cell culture of the missense mutants G4R and N-terminal fragment to residue 68 lead to cellular inclusions and the accompanying changes characteristic for the conformational disorders.

There is little information in the literature regarding the usefulness of ultrastructural examination of axillary skin biopsies in the evaluation of metabolic diseases. This is a retrospective clinicopathologic review of 143 patients who underwent axillary skin biopsies as part of evaluations for metabolic disease. Twenty-three (16%) had abnormalities, classified as follows: mitochondrial (n = 12), lysosomal (n = 6), increased glycogen (n = 3), nonspecific cytoplasmic inclusions (n = 2), ceroid lipofuscinosis (n = 1), and intradermal giant cells containing vacuoles and tubular inclusions (n = 1). Muscle biopsies were performed in 13 of the 23 patients; 11 showed abnormalities, including those related to mitochondria (n = 4) and other nonspecific changes (n = 7). Two patients underwent postmortem examination. Follow-up was available in 21 patients. A clinical or biochemical diagnosis was reached in 11 patients: metachromatic leukodystrophy (n = 2), electron transport chain abnormalities (n = 2), glutaric aciduria type II (n = 1), Unverricht disease (n = 1), Lennox-Gastaut syndrome (n = 1), ketotic hypoglycemia of childhood (n = 1), probable Leigh disease (n = 1), 5-methyl tetrahydrofolate homocystine methyltransferase deficiency (n = 1), and pyruvate dehydrogenase deficiency (n = 1). Of the 120 patients with negative skin biopsy results, 29 had abnormal findings on muscle (n = 27), nerve (n = 7), or brain (n = 3) biopsies. One patient had an abnormal heart biopsy result, and 3 patients underwent postmortem examinations. Follow-up was obtained in 27 of 29 patients. Diagnoses were achieved in 15 patients: electron transport chain abnormalities (n = 5), cortical dysplasia (n = 3), myoclonic epilepsy (n = 1), leukodystrophy (n = 2), Pallister-Killian mosaic syndrome (n = 1), Rett syndrome (n = 1), Landau-Kleffner syndrome (n = 1), and mitochondrial cardiomyopathy (n = 1). In conclusion, axillary skin biopsy is helpful in the evaluation of some causes of metabolic disease, but often the findings are nonspecific. A negative biopsy result does not rule out the possibility of metabolic disease, but a positive result may provide direction for further evaluation.

Duplications and triplications of the alpha-synuclein (SNCA) gene have been reported in Parkinson's disease patients belonging to the Southern Swedish "Lister family". Further genealogical research has now shown that these individuals are descended from a large kindred characterized by Herman Lundborg in 1901-1913. In the expanded pedigree, a total of 25 individuals had Parkinson's disease with an autosomal dominant pattern of inheritance. Hereditary dementia, and, historically, dementia praecox have been described in other family members. Furthermore, an autosomal recessively inherited pediatric disease with nocturnal tonic-clonic fits, subsequent progressive myoclonus, startle reactions, tremor and muscle rigidity was described by Lundborg in the same pedigree. The entity was later designated Unverricht-Lundborg disease (ULD) or progressive myoclonus epilepsy type 1 (EPM1). However, Lundborg's clinical description of this disease, based on 17 patients within this kindred, differs from the modern definition of EPM1, which relies on patients with a mutation in the cystatin B (CSTB) gene. We hypothesize that the former pediatric disease, as well as the parkinsonism and dementia phenotypes, are associated with duplications, triplications and possibly higher-order multiplications of the alpha-synuclein (SNCA) gene. This hypothesis is supported by the distribution of afflicted family members within the pedigree and by recently obtained genealogical information.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a rare, autosomal recessive disorder characterized by onset at age 6-16 years, generalized seizures, incapacitating myoclonus, and variable progression to cerebellar ataxia. The gene that causes EPM1, cystatin B, encodes a cysteine proteinase inhibitor. Only a minority of EPM1 patients carry a point mutation within the transcription unit. The majority of EPM1 alleles contain large expansions of a dodecamer repeat, CCC CGC CCC GCG, located upstream of the 5' transcription start site of the cystatin B gene; normal alleles contain two or three copies of this repeat. All EPM1 alleles with an expansion were resistant to standard PCR amplification. To precisely determine the size of the repeat in affected individuals, we developed a detection protocol involving PCR amplification and subsequent hybridization with an oligonucleotide containing the repeat. The largest detected expansion was approximately 75 copies; the smallest was approximately 30 copies. We identified affected siblings with repeat expansions, of different sizes, on the same haplotype, which confirms the repeat's instability during transmissions. Expansions were observed directly; contractions were deduced by comparison of allele sizes within a family. In a sample of 28 patients, we found no correlation between age at onset of EPM1 and the size of the expanded dodecamer. This suggests that once the dodecamer repeat expands beyond a critical threshold, cystatin B expression is reduced in certain cells, with pathological consequences.

Unverricht-Lundborg disease (ULD) is the most common seizure disorder in the rare subgroup of progressive myoclonic epilepsies. Patients typically present between the ages of 6 and 16 with onset of stimulus and/or photosensitive myoclonus as well as generalised tonic-clonic seizures. Progressive cerebellar degeneration leads to the development of ataxia, incoordination, dysarthria and intention tremor. ULD is typified by specific mutations in the CSTB gene located at chromosome 21q22.3. While the clinical features and genetic abnormalities of this disease are well known, detailed neuropathological examination is rarely described in the published literature. We present the neuropathological findings of a genetically verified case of Unverricht-Lundborg disease in a 74 year old female. The deceased had a history of recurrent seizures and presented to hospital after an episode of status epilepticus. She subsequently passed away after presumed aspiration. At autopsy, macroscopic examination of the brain revealed mild frontotemporoparietal atrophy. The cerebellum showed marked atrophy, particularly inferiorly and dorsally. Microscopic examination of the hippocampus was unremarkable, and in particular there was no evidence of hippocampal sclerosis. Marked cerebellar atrophy was confirmed microscopically affecting the cerebellar cortex and subjacent white matter. Incidental cerebellar heterotopias were also noted.

Rationale Unverricht–Lundborg disease (ULD) (EPM1) is an autosomal recessive neurodegenerative disease with progressive myoclonus epilepsy (PME). The onset is usually between 6 and 15years of age with myoclonus and generalized tonic-clonic seizures, variable severity and course, and variable degrees of cognitive deterioration. With good antiepileptic management, the patients can now survive into their 50's and 60's. The gene for this disorder was identified in 1996 as cystatin B ( CSTB ), a cysteine protease inhibitor. The most common mutation is a dodecamer repeat, although rare point mutations have also been described. Objective To present an extended phenotype of ULD (EPM1). Methods The proband who carried a diagnosis of juvenile myoclonus epilepsy (JME) presented with her partner for preconceptional genetic counseling. Since she had a distant family history of Unverricht–Lundborg disease on the maternal side, carrier screening for the CSTB gene was carried out for both, employing detection of the dodecamer repeat expansion and sequencing of the CSTB gene to rule out point mutations. Results This 30-year-old female had a single generalized tonic-clonic seizure during sleep at the age of 11years, and onset of myoclonic jerks on awakening at around the same time, which were well-controlled by valproic acid. She carries a clinical diagnosis of JME. She was born prematurely after 25weeks' gestation weighing 750 grams. Developmental milestones were normal, and she was on the honor roll at school in grade X. She works as a high school teacher for behaviourally challenged children. Both paternal grandparents were of Irish origin; both maternal grandparents were French–Canadian, from the Gaspe peninsula of Quebec. Four siblings of the maternal grandmother were diagnosed clinically with ULD and were known to us; the three affected sisters died in their 20's and 30's, and the affected brother died at age 65. A third degree cousin of the mother had epilepsy and died at 18years of age. A paternal uncle had a single generalized tonic-clonic seizure at the age of 7years. A distant cousin of the paternal great grandmother was also said to have PME. CSTB testing revealed that our patient was a compound heterozygote for two mutations: an expansion of the dodecamer repeat and a splice site c.67–1G>C mutation in intron 1, predicting a deletion of the downstream exon 2 with in-frame deletion of 34 aminoacids (p.delV23_K56). This is the second most common mutation underlying EPM1, and the most common point mutation. The husband has no potential EPM1-causing sequence alterations. Conclusion Although ULD is often confused with JME in the early stages of the disease, it is rare to find patients with ULD at age 30 who are as well controlled and high-functioning as this patient. Furthermore, other compound heterozygotes with the same combination of mutations have had more severe phenotypes with progressive deterioration. The reason for the milder phenotype in this individual remains unexplained, and may be due to modifying genes and/or gene–environment interactions.