Neuronal Intranuclear Inclusion Disease: Longitudinal Case Report of Motor and Nonmotor Symptoms.

Neuronal intranuclear inclusion disease is a rare, neurodegenerative disorder with onset in childhood. We report a single case natural history over 10 years and present a review of juvenile parkinsonism and neuronal intranuclear inclusion disease. Our patient was initially seen at the University of Rochester at age 12 years after 4 years of progressive dysarthria, dysphagia, and clumsiness. His neurologic examination was notable for parkinsonism. He had excellent initial response to levodopa, but subsequently developed dopa-induced motor fluctuations, dyskinesias, psychosis, and dystonia. Later in the course, he developed multiple nonmotor symptoms and ultimately died from respiratory failure. Neuropathology demonstrated large eosinophilic nuclear inclusions and small ubiquitin-related modifier 1 (SUMO-1) immunoreactivity, confirming the diagnosis of neuronal intranuclear inclusion disease. This diagnosis should be considered in a patient presenting with juvenile parkinsonism. Clues to the diagnosis include early-onset dopa-induced dyskinesias, gastrointestinal dysfunction, and oculogyric crises.

Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel.

Postsynaptic AMPA/glutamate receptors, essential for neuronal excitability, are important targets for anticonvulsant therapy. This single channel study of the selective noncompetitive AMPA receptor antagonist, perampanel, was performed on homotetrameric GluA3 receptor-channels that open in a stepwise manner to four distinct conductance levels through independent subunit activation. Previous structural studies show that perampanel binds to four sites located within the extracellular/transmembrane boundary of closed AMPA receptor-channel subunits. We found that channels exposed to 1 or 2 µM perampanel opened mainly to the two lower conductance levels in a dose-dependent manner. Comparison of the single channel results in the structures of the full length AMPA receptor in the closed state bound to perampanel, and the open state provide insights into the mechanism of allosteric reduction of AMPA-receptor-mediated excitation in epilepsy.

Noncompetitive antagonists induce cooperative AMPA receptor channel gating.

Glutamate is released from presynaptic nerve terminals in the central nervous system (CNS) and spreads excitation by binding to and activating postsynaptic iGluRs. Of the potential glutamate targets, tetrameric AMPA receptors mediate fast, transient CNS signaling. Each of the four AMPA subunits in the receptor channel complex is capable of binding glutamate at its ligand-binding domains and transmitting the energy of activation to the pore domain. Homotetrameric AMPA receptor channels open in a stepwise manner, consistent with independent activation of individual subunits, and they exhibit complex kinetic behavior that manifests as temporal shifts between four different conductance levels. Here, we investigate how two AMPA receptor-selective noncompetitive antagonists, GYKI-52466 and GYKI-53655, disrupt the intrinsic step-like gating patterns of maximally activated homotetrameric GluA3 receptors using single-channel recordings from cell-attached patches. Interactions of these 2,3-benzodiazepines with residues in the boundary between the extracellular linkers and transmembrane helical domains reorganize the gating behavior of channels. Low concentrations of modulators stabilize open and closed states to different degrees and coordinate the activation of subunits so that channels open directly from closed to higher conductance levels. Using kinetic and structural models, we provide insight into how the altered gating patterns might arise from molecular contacts within the extracellular linker-channel boundary. Our results suggest that this region may be a tunable locus for AMPA receptor channel gating.

Juvenile Parkinsonism.

We present the case of a 14-year-old boy presented with a recent history of progressive neurologic decline and extrapyramidal features. The history and findings with illustrative figures are detailed, and a diagnostic approach to the presentation is considered. The therapeutic options and broader management issues are briefly reviewed.

The loss of an electrostatic contact unique to AMPA receptor ligand binding domain 2 slows channel activation.

Ligand-gated ion channels undergo conformational changes that transfer the energy of agonist binding to channel opening. Within ionotropic glutamate receptor (iGluR) subunits, this process is initiated in their bilobate ligand binding domain (LBD) where agonist binding to lobe 1 favors closure of lobe 2 around the agonist and allows formation of interlobe hydrogen bonds. AMPA receptors (GluAs) differ from other iGluRs because glutamate binding causes an aspartate-serine peptide bond in a flexible part of lobe 2 to rotate 180° (flipped conformation), allowing these residues to form cross-cleft H-bonds with tyrosine and glycine in lobe 1. This aspartate also contacts the side chain of a lysine residue in the hydrophobic core of lobe 2 by a salt bridge. We investigated how the peptide flip and electrostatic contact (D655-K660) in GluA3 contribute to receptor function by examining pharmacological and structural properties with an antagonist (CNQX), a partial agonist (kainate), and two full agonists (glutamate and quisqualate) in the wildtype and two mutant receptors. Alanine substitution decreased the agonist potency of GluA3(i)-D655A and GluA3(i)-K660A receptor channels expressed in HEK293 cells and differentially affected agonist binding affinity for isolated LBDs without changing CNQX affinity. Correlations observed in the crystal structures of the mutant LBDs included the loss of the D655-K660 electrostatic contact, agonist-dependent differences in lobe 1 and lobe 2 closure, and unflipped D(A)655-S656 bonds. Glutamate-stimulated activation was slower for both mutants, suggesting that efficient energy transfer of agonist binding within the LBD of AMPA receptors requires an intact tether between the flexible peptide flip domain and the rigid hydrophobic core of lobe 2.

Delayed recognition of initial stroke in children: need for increased awareness.

OBJECTIVE: The goal was to identify the delays involved in diagnosing pediatric arterial ischemic stroke (AIS), a major cause of morbidity and death in children. METHODS: Neonates (

Juvenile onset globoid cell leukodystrophy masquerading as XL-adrenoleukodystrophy.

Krabbe's disease, or globoid cell leukodystrophy (GLD), is an autosomal recessive condition where the commonest presentation is the rapid neurological deterioration typical of the early onset subtype. Later onset subtypes, with more protean presentations and outcomes, also exist. These must be distinguished from other types of leukodystrophies, such as Adrenoleukodystrophy, as the prognosis is extremely variable. We describe a patient with late onset GLD (LOGLD) with imaging findings consistent with a diagnosis of Adrenoleukodystrophy. The importance of interpreting imaging findings in conjunction with the clinical and biochemical information is highlighted.

Central nervous system signs in X-linked Charcot-Marie-Tooth disease after hyperventilation.

The X-linked Charcot-Marie-Tooth disease is the second most common form of inherited neuropathy and, unlike most other forms of this disease, may present with atypical manifestations because of central nervous system involvement. Episodic central nervous system symptoms in X-linked Charcot-Marie-Tooth disease may be triggered by illness, dehydration, physical exercise, or exposure to altitude. We describe a child with transient episodes of hemiplegia after simple hyperventilation, a presentation not previously described in pediatric Charcot-Marie-Tooth disease type X.

Febrile seizures.

BACKGROUND: Febrile convulsions, or febrile seizures, are frequently encountered in paediatrics, and despite often being self limiting, these seizures strike fear in the hearts of patients' carers. OBJECTIVE: This article reviews the assessment and management of febrile seizures in children. DISCUSSION: The initial assessment of a child who convulses with fever should be directed at finding a cause for the fever, rather than the seizure itself, once the seizure has abated. A lumbar puncture should be performed if there is clinical suspicion of meningitis. Electroencephalograms and neuroimaging studies are not routinely indicated. Overall, febrile seizures carry a good prognosis, although one-third of children have recurrent attacks. Febrile seizures are genetic in origin. The risk of later epilepsy is small but increased if the child has a complex febrile seizure, neurological deficit, or a family history of epilepsy. Carers should be counselled in the management of seizures. The effectiveness of prophylactic treatment with medication remains controversial.

Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case for.

A lower threshold for treatment of paracetamol (acetaminophen) poisoning has been advocated in chronic heavy users of alcohol, based originally on animal studies indicating that chronic alcohol ingestion increased hepatotoxicity. This was attributed to increased production of the toxic metabolite, N-acetyl-p-benzoquinoneimine, by cytochrome P450 (CYP)2E1 induction. The clinical evidence for increased risk is limited to four retrospective studies with potential for referral and reporting bias and conflicting results. No study has specifically addressed the issue of the treatment threshold for acute paracetamol overdose in chronic alcohol users. However, animal studies in multiple species have consistently shown a lower dose of paracetamol is required to produce hepatotoxicity after chronic alcohol use. The knowledge of potential mechanisms has expanded to include effects of other alcohols, such as isopentanol, induction of CYP enzymes other than CYP2E1 and glutathione depletion. There are no convincing reasons or data to suggest these findings do not apply to humans. However, further human toxicokinetic and clinical research is required to quantify the extent of the interaction. Arguments about treating overdoses should not be confused with those about whether there is an alcohol-paracetamol interaction at therapeutic doses. Halving the threshold dose/concentration for treatment is a conservative educated guess that has been widely adopted. In overdose, the potential benefits of treatment at this lower threshold clearly outweigh the minimal risks of acetylcysteine.