Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2-4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Novel mutations in the FUCA1 gene that cause fucosidosis.

Fucosidosis is a rare lysosomal storage disorder inherited in an autosomal recessive manner. Its estimated frequency is below 1 in 200,000 live births. Its clinical phenotypes include progressive neurological and mental deterioration, coarse facial features, growth retardation, visceromegaly, angiokeratomas, and seizures. The disease is caused by mutations in the FUCA1 gene that lead to deficiency of a-L-fucosidase. Here, we describe the clinical and molecular features of a Thai boy with fucosidosis. Whole exome sequencing and array-based comparative genomic hybridization analysis revealed that the patient was compound heterozygous for a single base-pair deletion (c.670delC; p.P224LfsX2) inherited from his father, and a 3281-base-pair deletion covering exon 3 inherited from his mother. Neither mutation has been reported before so the FUCA1 mutational spectrum is herein expanded.

Prenatal diagnosis of a novel mutation, c.529C>T (p.Q177X), in the BCKDHA gene in a family with maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder caused by defective activity of the branched-chain alpha-keto-acid dehydrogenase (BCKD) complex. The disease-causing mutations can affect the BCKDHA, BCKDHB or DBT genes encoding for the E1a, E1b, and E2 subunits, respectively, of the BCKD complex. Here we report a girl who first presented to our clinic at 4 years of age with profound mental retardation. A diagnosis of MSUD was subsequently made based on the results of plasma amino acid analysis. Mutation analysis confirmed that she was homozygous for a novel mutation, c.529C>T (p.Q177X) in BCKDHA, while both parents, who were first cousins, were heterozygous. This enabled us to give an option of prenatal diagnosis to the parents. The prenatal testing for MSUD was performed during the mother's subsequent pregnancy and revealed that the fetus was heterozygous for the mutation. The healthy male neonate was born and his genotype was tested by restriction enzyme analysis, which confirmed the result of the prenatal testing. In summary, a late diagnosis of MSUD in patients without an unusual odour could occur especially in countries without neonatal screening programs as seen in the index patient. Mutation detection was, however, still beneficial to the family since prenatal testing could be performed in subsequent pregnancies. In addition, a novel mutation was found, expanding the mutation spectrum of this disease.

A new method using neuromagnetic stimulation to measure conduction time within the cauda equina.

Using principles derived from electric field measurements and studies of phrenic nerve in vitro, neuromagnetic stimuli in humans were predicted to excite selective low threshold sites in proximal and distal cauda equina. Physical models, in which induced electric fields were recorded in a segment of human lumbosacral spine immersed in a saline filled tank, supported this prediction. Conclusions from the model were tested and confirmed in normal human subjects. Ipsilateral motor evoked potentials were elicited in lower limb muscles and striated sphincters by magnetic coil (MC) stimulation of both proximal and distal cauda equina. Over proximal cauda equina a vertically oriented MC junction and cranially directed induced current elicited a newly identified compound muscle action potential (CMAP). The F response latency and lack of attenuation when the target muscle was vibrated suggest that the proximal response is a directly elicited M response arising near or at the rootlet exit zone of the conus medullaris. Over distal cauda equina, lumbar roots were optimally excited by a horizontally oriented MC junction, and sacral roots by an approximately vertically oriented MC junction, eliciting CMAPs with similar appearance but shorter latency consistent with the known intrathecal lengths of the lower lumbar and sacral nerve roots. The induced current was usually most effective when directed towards the spinal fluid filled thecal sac. Normal subjects showed stable CMAP onset latencies elicited at proximal and distal cauda equina despite wide variation in amplitude. Thus, cauda equina conduction time can be directly calculated. This new method may improve the detection and classification of peripheral neuropathies affecting lower limbs and striated sphincters.