A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population.

Familial focal epilepsy with variable foci (FFEVF) is a heterogeneous epilepsy syndrome originally described in the French-Canadian (FC) population. Mutations in DEPDC5 have recently been identified in multiple cases of FFEVF as well as in a wide spectrum of other familial focal epilepsies. In this study, we aimed to determine the frequency of mutation of this gene in our large cohort of FC individuals with FFEVF, as well as familial and sporadic cases with focal epilepsy. We report a recurrent p.R843X protein-truncating mutation segregating in one large FFEVF and two small focal epilepsy FC families. Fine genotyping suggests an ancestral allele. A new p.T864M variant, predicted to be disease-causing, was also identified in a small FC family. Overall, we identified DEPDC5 mutations in 5% of our familial and sporadic focal epilepsy cases (4/79). Our results support the view that mutations in the DEPDC5 gene are an important cause of autosomal dominant focal epilepsies in the FC population, including a founder mutation that is specific to this population. These findings may facilitate molecular diagnosis in clinical practice.

Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease.

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.

Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1.

Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition. Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G-->C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C-->T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families. A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable approximately 600-900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences.

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.

Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.

OBJECTIVE: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. METHODS: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. RESULTS: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. INTERPRETATION: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

Genetics of the polymicrogyria syndromes.

Polymicrogyria is a relatively common malformation of cortical development, characterised by multiple small gyri with abnormal cortical lamination. The different forms of polymicrogyria encompass a wide range of clinical, aetiological, and histological findings. Advances in imaging have improved the diagnosis and classification of the condition. The molecular basis of polymicrogyria is beginning to be elucidated with the identification of a gene, GPR56, for bilateral frontoparietal polymicrogyria. Functional studies of the GPR56 gene product will yield insights not only into the causes of polymicrogyria but also into the mechanisms of normal cortical development and the regional patterning of the cerebral cortex. Based on imaging studies, several other region specific patterns of polymicrogyria have been identified, and there is increasing evidence that these may also have a significant genetic component to their aetiology. This paper reviews current knowledge of the different polymicrogyria syndromes, with discussion of clinical and imaging features, patterns of inheritance, currently mapped loci, candidate genes, chromosomal abnormalities, and implications for genetic counselling.

Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22.

BACKGROUND: Lafora disease is a progressive myoclonus epilepsy with polyglucosan accumulations and a peculiar neurodegeneration with generalised organellar disintegration. It causes severe seizures, leading to dementia and eventually death in early adulthood. METHODS: One Lafora disease gene, EPM2A, has been identified on chromosome 6q24. Locus heterogeneity led us to search for a second gene using a genome wide linkage scan in French-Canadian families. RESULTS: We mapped a second Lafora disease locus, EPM2B, to a 2.2 Mb region at 6p22, a region known to code for several proteins, including kinesins. Kinesins are microtubule dependent motor proteins that are involved in transporting cellular components. In neurones, they play a major role in axonal and dendritic transport. CONCLUSION: Analysis of the present locus in other non-EPM2A families will reveal whether there is further locus heterogeneity. Identification of the disease gene will be of major importance towards our understanding of the pathogenesis of Lafora disease.

Searching for human epilepsy genes: a progress report.

Application of new genetic techniques has brought remarkable discoveries in the study of genetic diseases. The potential benefits from applying such technology to idiopathic epilepsies include improved understanding of cellular mechanisms and potential new methods of prevention and treatment. The complex problems involved in studying the hereditary epilepsies include: defining of specific phenotypes; detecting genetic and non-genetic heterogeneity; and specifying the appropriate mode of inheritance and penetrance. The gene loci for three primary epilepsies have been localized to specific chromosomal regions, and serve to demonstrate the process used in generalized linkage studies of hereditary epilepsy syndromes. Benign familial neonatal convulsions (BFNC) and Unverricht-Lundborg progressive myoclonus epilepsy are rare single-gene disorders that are sufficiently localized to chromosomal regions that positional cloning studies are likely to succeed. Juvenile myoclonic epilepsy (JME), a common hereditary syndrome with an uncertain mode of inheritance, has been reported to be linked to chromosome 6p. JME presents a challenge for generalized linkage methodology that may be overcome by attending to potential problems reviewed here. The candidate-gene method, combined with studies using animal models, holds promise for understanding these as well as other hereditary epilepsies.

Evidence for abnormal regulation of insulin receptors in Friedreich's ataxia.

Friedreich's ataxia is associated with a high incidence of diabetes mellitus. We have previously demonstrated that insulin resistance is present in nondiabetic patients with Friedreich's ataxia. This was associated with a reduction in the affinity of insulin receptors on freshly isolated monocytes. In this study we investigated the ability of the monocyte insulin receptor to acutely alter its affinity in response to oral glucose. Glucose and insulin concentrations were higher in the patients with Friedreich's ataxia after an oral glucose load, consistent with the presence of insulin resistance. The normal increase in the affinity of insulin receptors on monocytes 5 h after oral glucose was absent in the five patients with Friedreich's ataxia. Receptor affinity actually decreased in three of the five patients. These findings support the concept that a membrane abnormality that alters the binding function of the insulin receptor is present in these patients.

Long-term efficacy and safety of piracetam in the treatment of progressive myoclonus epilepsy.

BACKGROUND: Piracetam has been proven to be effective and well tolerated in the treatment of myoclonus in short-term studies. OBJECTIVE: To assess its long-term clinical efficacy, 11 patients with disabling myoclonus due to progressive myoclonus epilepsy were treated with piracetam in an open-label study. METHODS: Neurologic outcome (at the 1st, 6th, 12th, and 18th month of treatment) was assessed by an adjusted sum score of the following 3 indices: motor impairment, functional disability, and global assessment of disability due to myoclonus. Severity of other neurologic symptoms (seizure frequency and severity, dysarthria, and gait ataxia) also was assessed. Treatment with piracetam was initiated at a dose of 3.2 g/d that was gradually increased until stable benefit was noted (maximal dose in the trial was 20 g/d). Concomitant antiepileptic drugs were maintained at their previous dose. RESULTS: Statistically significant improvement in the total rating score was observed after introduction of piracetam at the 1st, 6th, and 12th month of treatment. Severity of other neurologic symptom scores did not improve significantly. Two patients reported drowsiness during the first 2 weeks of treatment. CONCLUSIONS: Piracetam given as add-on therapy seems to be an effective, sustained, and well-tolerated treatment of myoclonus. In patients with progressive myoclonus epilepsy, the efficacy of the drug increased during the first 12 months of treatment and then stabilized.

Mechanisms of teratogenesis: folic acid and antiepileptic therapy.

Gestational folate deficiency has been associated with abnormal growth and development in both experimental animal and human studies and has been postulated as a putative mechanism for the teratogenic effects of antiepileptic drugs (AEDs). Animal studies have shown that the administration of AEDs results in folate depletion and teratogenic effects. Attempts to prevent the teratogenic effects of AEDs by coadministration of folate have shown variable results, perhaps because of a lack of understanding about the specific effects of AEDs on folate metabolism. Our prospective study of women with epilepsy showed that blood folate levels decreased with increasing plasma AED levels and with the number of AEDs. Low blood folate levels before and/or early in pregnancy were significantly associated with spontaneous abortion and the occurrence of developmental anomalies in the offspring. These findings suggest that folate supplementation might be one means of preventing the occurrence of abnormal pregnancy outcome in women with epilepsy, including neural-tube defects in the offspring.

Benign familial nocturnal alternating hemiplegia of childhood.

In infancy, two brothers developed recurrent attacks of alternating or bilateral hemiplegia arising exclusively out of sleep. The episodes were terminated by even brief sleep. Neither child had hypotonia, dystonic attacks, paroxysmal eye movement abnormalities, or other features characteristic of the now-classic form of alternating hemiplegia of childhood (AHC). The development of the brothers has so far remained normal. Both parents have a history of migraine. In the older boy, magnetic resonance spectroscopy (MRS) of muscle showed increased inorganic phosphate similar to what is found in children with AHC. In the younger brother and parents, MRS of muscle was normal. Other investigations were unrevealing. Flunarizine greatly reduced the duration of attacks. This genetically determined disorder represents a specific entity that is probably migraine-related and is easily misdiagnosed as AHC. Because of its benign course, particularly as far as mental development is concerned, it must be distinguished from classic AHC, which has a terrible prognosis.

Physiological studies of spinal inhibitory pathways in patients with hereditary hyperekplexia.

Because hereditary hyperekplexia results from a defect in the glycine receptor, we studied in five patients several spinal inhibitory pathways that are thought to use either glycine or gamma-aminobutyric acid as a neurotransmitter. Three patients had a mutation in the alpha1 subunit of the glycine receptor, whereas two sisters with the same clinical syndrome did not have this mutation. Compared with normal subjects, reciprocal inhibition between flexor and extensor muscles of the forearm was diminished during the first period of inhibition and preserved during the second period of inhibition in all three patients tested. Facilitation after the early period of inhibition was prominent. Recurrent inhibition of the soleus H reflex was normal in four patients, as was inhibition of the H reflex produced by Achilles' tendon vibration. There was no significant difference in nonreciprocal (Ib) inhibition between patients and normal individuals, The findings suggest that disynaptic reciprocal inhibition in humans is mediated through glycinergic interneurons, but that recurrent inhibition may have a contribution from nonglycinergic mechanisms.

Reflex seizures induced by calculation, card or board games, and spatial tasks: a review of 25 patients and delineation of the epileptic syndrome.

Nine patients had reflex activation of seizures by calculation, card and board games, or spatial tasks. The common denominator for these and the 16 others reported in the literature appears to be activity related to function of the parietal lobe. The clinical and EEG findings in all 25 patients support the diagnosis of primary generalized epilepsy. Seizures usually start during adolescence and consist of myoclonus, absences, and generalized convulsions. Specific inquiry about reflex activation should be carried out in patients with generalized epilepsy since this is rarely provided spontaneously. Attacks could be controlled satisfactorily in 89% of our patients. The genetic features are those of a primary generalized epileptic disorder without evidence for a specific inheritance of reflex sensitivity. Neuropsychological analysis of the stimuli points to parietal cortical dysfunction. These stimuli lead to activation of a generalized epileptic process analogous to the occipital cortical participation in the activation of generalized epileptic abnormality occurring in patients with photosensitive epilepsy.

Familial temporal lobe epilepsy: a clinically heterogeneous syndrome.

We describe the clinical characteristics of a group of patients with familial temporal lobe epilepsy (TLE) in 11 kindreds with 36 affected individuals identified and investigated at the Montreal Neurological Hospital. Seizure types were simple partial (n = 20), complex partial (n = 29), and rare generalized tonic-clonic. Simple and complex partial seizures were infrequent or well controlled by anticonvulsant medication in 17 of 29 patients (59%) and without optimal response to medical therapy in 12 of 29 patients (41%). Pedigree analysis suggested autosomal dominant inheritance with incomplete penetrance. The syndrome of familial TLE has heterogeneous clinical manifestations and is not always benign.

Lafora's disease: peroxisomal storage in skeletal muscle.

A 17-year-old patient had myoclonic epilepsy caused by Lafora's disease. Biopsy showed polysaccharide accumulations within membrane-bound spaces in skeletal muscle cells. Some of the accumulations were morphologically similar to Lafora bodies as they have been seen in the brain. The histochemical reactions of these membrane-bound spaces suggested that they were peroxisomes. Polysaccharide accumulations also were demonstrated in hepatic cells, where they probably were located in the endoplasmic reticulum. Lafora's disease can be diagnosed by histochemical and electron microscopic study of skeletal muscle.

Concepts of absence epilepsies: discrete syndromes or biological continuum?

There are two current approaches to the clinical conceptualization of the generalized epilepsies. The syndromic approach attempts to subdivide the patient population into relatively homogeneous groups, largely on the basis of clinical and EEG criteria. In contrast, the neurobiological approach aims to formulate a unique profile for each patient by incorporating particulars of the patient onto the background of knowledge regarding the etiologic factors important in generalized epilepsy. The value of these two approaches is discussed with regard to the dual aims of, first, improving the understanding of generalized epilepsy, and second, providing a precise diagnosis, an accurate prognosis, and optimal treatment for the patient.

Sweat gland vacuoles in Unverricht-Lundborg disease: a clue to diagnosis?

There has been no reported pathologic abnormality outside the central nervous system in patients with Unverricht-Lundborg disease (ULD). We report membrane-bound vacuoles with clear contents in eccrine clear cells and dark cells in five of seven patients with ULD, as well as in one clinically unaffected sibling. Vacuoles were not seen in the biopsies of two patients and of eight controls with Lafora's disease. These findings, though not entirely specific, suggest that skin biopsy may serve as a diagnostic aid to give supportive evidence for ULD.

Benign nocturnal alternating hemiplegia of childhood: six patients and long-term follow-up.

Benign familial nocturnal alternating hemiplegia of childhood refers to recurrent attacks of hemiplegia arising from sleep, described in young children without neurologic or mental impairment. It is probably migraine related. The authors report two unrelated patients with nocturnal attacks starting at 22 and 31 months, followed by daytime episodes in one. The authors confirm the benign course of this disorder. It is distinct from the classic malignant form of alternating hemiplegia of childhood.

Nocturnal temporal lobe epilepsy.

OBJECTIVE: To analyze clinical, electrophysiologic, and neuroradiologic characteristics and prognostic factors in a group of patients with temporal lobe epilepsy (TLE) and complex partial seizures (CPS) occurring exclusively or predominantly after they fall asleep or before they awaken. BACKGROUND: CPS arising during sleep are classically identified with frontal lobe epilepsy. TLE associated with seizures occurring only or predominantly during sleep (nocturnal TLE) is less common. METHODS: From a series of patients with refractory TLE studied between 1980 and 1996, the authors identified 26 patients (15 men) with nonlesional nocturnal TLE (mean age, 40 years). Clinical and laboratory characteristics of these individuals were studied and compared with a group of 72 age-matched, randomly selected patients with nonlesional TLE and predominantly diurnal seizures (diurnal TLE). RESULTS: Mean age at seizure onset was similar for both groups (16.3 versus 18.7 years). In the nocturnal TLE group, 2 of 26 patients had a positive family history of epilepsy, 18 reported an aura, 4 presented with CPS in clusters, 11 had unilateral and 15 bilateral temporal EEG abnormalities, and 14 of 21 studied had unilateral mesial temporal atrophy. None of these factors differed significantly in the two groups except for higher frequency of the following in the diurnal TLE group compared with the nocturnal TLE group: positive family history for epilepsy (33% versus 8%, p=0.01), estimated frequency of seizures (median, 14 versus 2 per month; p < 0.01), and presence of antecedent febrile convulsions (33% versus 11%, p=0.04). In the nocturnal TLE group, eight patients underwent surgical therapy and became seizure free (follow-up, > 12 months). Only two were seizure free on medication. CONCLUSIONS: Infrequent and nonclustered seizures, rare family history of epilepsy, and low prevalence of childhood febrile convulsions characterize nocturnal TLE. Within the TLEs, the nocturnal TLE form seems to have a better surgical prognosis.