We describe a pedigree in which eight individuals presented with a non-progressive disorder with onset between the ages of 12 and 50 years. It was characterized by predominantly distal, semi-continuous rhythmic myoclonus (all patients), generalized tonic-clonic seizures (all patients) and complex partial seizures (three patients). Most individuals had rarely suffered seizures and had a normal cognitive level, but three individuals with intractable seizures had mild mental retardation. The pattern of inheritance was autosomal dominant with high penetrance. We defined this disorder as autosomal dominant cortical myoclonus and epilepsy (ADCME). All patients had frontotemporal as well as generalized interictal EEG abnormalities. A neurophysiological study of the myoclonus suggested a cortical origin. Back-averaging of the data generated a series of waves with a frequency that mirrored the frequency of EMG bursts. Frequency analysis identified significant peaks with coherence between EMG and EEG, which were recorded over the contralateral rolandic area in five patients. The frequency of coherence was 8-25 Hz and phase spectra confirmed that EEG activity preceded EMG activity by 8-15 ms. In two individuals there was also significant coherence between the ipsilateral EEG and EMG, consistent with the transcallosal spread of myoclonic activity. The C-reflex at rest was enhanced and somatosensory and visual evoked potentials were of high amplitude. The resting motor threshold intensity to transcranial magnetic stimulation was significantly reduced (38%; SD +/- 7; P = 0.01) and the post-motor evoked potential silent period (101 ms; SEM +/- 10) was significantly shortened compared with the controls (137 ms; SEM +/- 18). These clinical and neuro- physiological characteristics suggest diffuse cortical hyperexcitability and high propensity for intra-hemispheric and inter-hemispheric cortical spread, as well as rhythmic myoclonic activity. Genome-wide linkage analysis identified a critical region spanning 12.4 cM between markers D2S2161 and D2S1897 in 2p11.1-q12.2, with a maximum two-point LOD score of 3.46 at Theta 0.0 for marker D2S2175. Multipoint LOD score values, reaching 3.74 around D2S2175, localize the ADCME gene to the centromeric region of chromosome 2. The exclusion of the locus for familial adult myoclonic epilepsy on chromosome 8q23.3-q24 from linkage to our family and the new localization of the responsible gene to chromosome 2cen, together with the different phenotype, define a new epilepsy syndrome. We hypothesize that the responsible gene causes cortical hyperexcitability that is widespread but particularly involves the frontotemporal circuits.

PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented.

We describe a pedigree in which 3 members in the same generation are affected by Rolandic epilepsy (RE), paroxysmal exercise‐induced dystonia (PED), and writer's cramp (WC). Both the seizures and paroxysmal dystonia had a strong age‐related expression that peaked during childhood, whereas the WC, also appearing in childhood, has been stable since diagnosis. Genome‐wide linkage analysis performed under the assumption of recessive inheritance identified a common homozygous haplotype in a critical region spanning 6 cM between markers D16S3133 and D16S3131 on chromosome 16, cosegregating with the affected phenotype and producing a multipoint LOD score value of 3.68. Although its features are unique, this syndrome presents striking analogies with the autosomal dominant infantile convulsions and paroxysmal coreoathetosis (ICCA) syndrome, linked to a 10 cM region between D16S401 and D16S517, which entirely includes the 6 cM of the RE–PED–WC critical region. The same gene may be responsible for both RE–PED–WC and ICCA, with specific mutations explaining each of these Mendelian disorders. This report shows that idiopathic focal disorders such as epilepsy and dystonia, can be caused by the same genetic abnormality, may have a transient expression, and may be inherited as an autosomal recessive trait. Ann Neurol 1999;45:344–352

SUMMARYPurpose: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients. Methods: We studied 35 patients with PCDH19 generelated epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them. Key Findings: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity. Significance: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.

Frequency analysis may have some advantages over back-averaging in the neurophysiological assessment of patients with suspected cortical myoclonus in whom myoclonic EMG bursts repeat rhythmically at high frequency. However, the clinical utility of EEG-EMG coherence and related EMG-EMG coherence is not established. Equally, there is an incomplete understanding of the physiology of the systems contributing to the coherence evident between signals in cortical myoclonus. Here we address these issues in an investigation of EEG-EMG and EMG-EMG coupling in proximal and distal muscles of the upper extremities in nine patients with multifocal high frequency rhythmic myoclonus due to non-progressive conditions. We found exaggerated coherence between EEG and contralateral EMG and between pairs of ipsilateral EMG signals. The results of frequency analysis of EMG-EMG mirrored those for EEG-EMG, but the former technique was superior in distinguishing a pathologically exaggerated common drive in distal upper limb muscles. Both techniques were more sensitive than back-averaging. Frequency analysis also revealed important disparities between proximal and distal upper limb muscles. In the latter case, the functional coupling between cortex and muscle was dominated by efferent processes. In contrast, there was considerable inter-individual variation in the extent to which EEG-EMG and EMG-EMG coupling in proximal muscles reflected afferent and efferent loops. Thus, the processes sustaining myoclonic discharges may differ for proximal and distal muscles and between patients.

Objective:To describe electroclinical features and outcome of 6 patients harboring KCNB1 mutations.Methods:Clinical, EEG, neuropsychological, and brain MRI data analysis. Targeted next-generation sequencing of a 95 epilepsy gene panel.Results:The mean age at seizure onset was 11 months. The mean follow-up of 11.3 years documented that 4 patients following an infantile phase of frequent seizures became seizure free; the mean age at seizure offset was 4.25 years. Epilepsy phenotypes comprised West syndrome in 2 patients, infantile-onset unspecified generalized epilepsy, myoclonic and photosensitive eyelid myoclonia epilepsy resembling Jeavons syndrome, Lennox-Gastaut syndrome, and focal epilepsy with prolonged occipital or clonic seizures in each and every one. Five patients had developmental delay prior to seizure onset evolving into severe intellectual disability with absent speech and autistic traits in one and stereotypic hand movements with impulse control disorder in another. The patient with Jeavons syndrome evolved into moderate intellectual disability. Mutations were de novo, 4 missense and 2 nonsense, 5 were novel, and 1 resulted from somatic mosaicism.Conclusions:KCNB1-related manifestations include a spectrum of infantile-onset generalized or focal seizures whose combination leads to early infantile epileptic encephalopathy including West, Lennox-Gastaut, and Jeavons syndromes. Long-term follow-up highlights that following a stormy phase, seizures subside or cease and treatment may be eased or withdrawn. Cognitive and motor functions are almost always delayed prior to seizure onset and evolve into severe, persistent impairment. Thus, KCNB1 mutations are associated with diffuse brain dysfunction combining seizures, motor, and cognitive impairment.

Summary:Purpose: To report on the association of childhood absence epilepsy and paroxysmal dyskinesia (PD).Methods: We describe six patients aged 6 to 27 years (mean, 14 years) who were identified in five centers participating in a European study group. Patients had been followed up clinically from the first symptoms and had been studied with video-EEG recordings of absence seizures, videotaping of dyskinetic attacks, and brain magnetic resonance imaging (MRI).Results: Four patients were sporadic, and two were siblings. Age at onset of absence seizures was unusually early (range, 3 months to 3 years 6 months; mean, 16 months), with four children having their first episodes within the first year of life, and the remaining two by age 3 years 6 months. Resistance to multiple appropriate drugs was seen in five children, in four of whom absences improved remarkably when ethosuximide was added. Absences remitted between age 8 and 13 years in the three patients in whom follow-up was long enough. Different types of PD were seen including paroxysmal kinesigenic dyskinesia (one patient), paroxysmal exercise-induced dystonia (three patients), and paroxysmal tonic upgaze (two siblings). In most patients, PD appeared at a later age than, co-occurred with, and outlasted absence seizures. Only in the two siblings with tonic upgaze, dyskinetic attacks had an earlier onset. PD improved with increasing age and did not usually produce severe disability.Conclusions: There is a widening spectrum of epilepsy and PD syndromes, within which epilepsy has the characteristics of the common idiopathic syndromes, with some atypical features.

Summary Objective PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors. Methods We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. Results At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). Significance We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.