ABSTRACT
Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years).
Subject(s)
Cadherins/genetics , Epilepsy/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Mutation/genetics , Female , Heterozygote , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Protocadherins , Seizures/complications , Sex FactorsABSTRACT
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.
Subject(s)
Epilepsy/epidemiology , Lipid Metabolism, Inborn Errors/epidemiology , Acyl-CoA Dehydrogenase/deficiency , Acyl-CoA Dehydrogenase/genetics , Adolescent , Butyryl-CoA Dehydrogenase/genetics , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Incidence , Infant , Infant, Newborn , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Male , Mutation/genetics , Netherlands/epidemiology , PediatricsSubject(s)
Anticonvulsants , Carbamazepine , Carbamazepine/analogs & derivatives , Anticonvulsants/adverse effects , Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Carbamazepine/adverse effects , Carbamazepine/blood , Carbamazepine/chemistry , Epilepsy/drug therapy , Humans , OxcarbazepineABSTRACT
Ring chromosome 20 mosaicism is associated with dysmorphic features, mental retardation, and intractable seizures, including recurrent episodes of nonconvulsive status epilepticus. The authors' findings in four children, all without dysmorphic features, indicate that mental deterioration and frequent subtle nocturnal frontal lobe seizures, associated with a characteristic EEG pattern, represent prominent additional clinical features not previously described in this syndrome. This emphasizes the importance of full-night video-EEG in children with frontal lobe seizures and cognitive deterioration.
Subject(s)
Chromosomes, Human, Pair 20 , Electroencephalography , Epilepsy, Frontal Lobe/genetics , Ring Chromosomes , Adolescent , Brain Damage, Chronic/diagnosis , Brain Damage, Chronic/genetics , Child , Epilepsy, Frontal Lobe/diagnosis , Female , Follow-Up Studies , Humans , Male , Neuropsychological Tests , Status Epilepticus/diagnosis , Status Epilepticus/geneticsABSTRACT
PURPOSE: Extensive experience with video-EEG seizure monitoring, notably in the setting of epilepsy surgery programs, has exposed the limited value of the current International Classification of Epileptic Seizures (ICES) for providing relevant localizing information. To overcome this limitation, a Semiologic Seizure Classification (SSC) has recently been proposed. This study aimed to assess and to compare the usefulness and reliability of both systems in the setting of a tertiary epilepsy center. METHODS: Three epileptologists independently reviewed video-taped seizures, randomly selected from the archive of the Epilepsy Monitoring Unit. They were blinded to the EEG findings and final diagnosis and classified all seizures according to both classifications. RESULTS: One hundred thirty-eight seizures from 60 patients (age range, 2-59 years) were reviewed (maximum, three seizures per patient). Fifty-five seizures from 20 patients were recorded in the setting of presurgical evaluations, and the remainder as part of regular diagnostic evaluations. The average interobserver agreement was higher for SSC (63.3%, kappa = 0. 56) than for ICES (38.6%, kappa = 0.41). Some categories of SSC, such as hypermotor or automotor, had the best interobserver agreement, and were strongly correlated with the anatomic localization of the seizures (frontal and temporal lobe, respectively). All reviewers agreed that SSC provided a better description of the seizures than did ICES, in 60% of the patients. CONCLUSIONS: SSC provides a more comprehensive picture of epileptic seizures than does ICES, notably in patients with localized epilepsy syndromes, and appears to be very useful and reliable, particularly in the setting of specialized epilepsy centers.
Subject(s)
Epilepsy/classification , Epilepsy/diagnosis , Adolescent , Adult , Child , Child, Preschool , Classification/methods , Electroencephalography/classification , Electroencephalography/statistics & numerical data , Humans , Middle Aged , Monitoring, Physiologic/classification , Monitoring, Physiologic/statistics & numerical data , Observer Variation , Reproducibility of Results , Terminology as Topic , Videotape Recording/statistics & numerical dataABSTRACT
Progressive myoclonus epilepsy of the Lafora type or Lafora disease (EPM2; McKusick no. 254780) is an autosomal recessive disorder characterized by epilepsy, myoclonus, progressive neurological deterioration and glycogen-like intracellular inclusion bodies (Lafora bodies). A gene for EPM2 previously has been mapped to chromosome 6q23-q25 using linkage analysis and homozygosity mapping. Here we report the positional cloning of the 6q EPM2 gene. A microdeletion within the EPM2 critical region, present inhomozygosis in an affected individual, was found to disrupt a novel gene encoding a putative protein tyrosine phosphatase (PTPase). The gene, denoted EPM2, presents alternative splicing in the 5' and 3' end regions. Mutational analysis revealed that EPM2 patients are homozygous for loss-of-function mutations in EPM2. These findings suggest that Lafora disease results from the mutational inactivation of a PTPase activity that may be important in the control of glycogen metabolism.
Subject(s)
Epilepsies, Myoclonic/genetics , Genes/genetics , Protein Tyrosine Phosphatases/genetics , Amino Acid Sequence , Base Sequence , Chromosomes, Human, Pair 6/genetics , DNA/analysis , DNA/genetics , DNA Mutational Analysis , DNA, Complementary/chemistry , DNA, Complementary/genetics , Epilepsies, Myoclonic/enzymology , Epilepsies, Myoclonic/pathology , Female , Humans , Male , Microsatellite Repeats , Molecular Sequence Data , Mutation , Pedigree , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Sequence Alignment , Sequence Homology, Amino AcidABSTRACT
Isolated mineralocorticoid deficiency is described in a 5-week-old boy. The deficiency progressed to general adrenal insufficiency during the boy's first year of life. The family history suggested X-linked inheritance. At 18 months of age the patient developed acute bilateral infantile striatal necrosis, which might suggest a possible relationship between both entities.
Subject(s)
Adrenal Insufficiency/genetics , Corpus Striatum/abnormalities , Adrenal Insufficiency/diagnosis , Basal Ganglia Diseases/diagnosis , Basal Ganglia Diseases/genetics , Cerebral Infarction/diagnosis , Cerebral Infarction/genetics , Child, Preschool , Corpus Striatum/pathology , Diagnosis, Differential , Dominance, Cerebral/physiology , Follow-Up Studies , Genetic Linkage/genetics , Humans , Infant , Magnetic Resonance Imaging , Male , Necrosis , Neurologic Examination , Sex Chromosome Aberrations/diagnosis , Sex Chromosome Aberrations/genetics , X ChromosomeABSTRACT
Two half-sisters aged 14 and 18 years are described with a rigid spine syndrome as the cardinal clinical feature of an autosomal dominant neuromuscular disorder. Ten years previously, a diagnosis of multicore disease had been made from the clinical signs and muscle biopsy findings. Long term follow-up revealed a non-specific muscular dystrophy with axial predominance and a rigid spine in the younger girl; the older sister presented at the age of 18 with a rigid spine as the only myopathic sign. Computed tomography of the muscles showed severe involvement of the paraspinal musculature, in contrast with either less or no involvement of the other muscles.