Biomedical subjects

Giuliano Avanzini

Publications and source records attributed to Giuliano Avanzini.

9 recordsLinked to original sources

PubMed2003

Mutations in NHLRC1 cause progressive myoclonus epilepsy.

Lafora progressive myoclonus epilepsy is characterized by pathognomonic endoplasmic reticulum (ER)-associated polyglucosan accumulations. We previously discovered that mutations in EPM2A cause Lafora disease. Here, we identify a second gene associated with this disease, NHLRC1 (also called EPM2B), which encodes malin, a putative E3 ubiquitin ligase with a RING finger domain and six NHL motifs. Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy.

Base Sequence↗

PubMed2003

Epileptic and imaging findings in perinatal hypoxic-ischemic encephalopathy with ulegyria.

Hypoxic-ischemic encephalopathy due to fetal or neonatal asphyxia is a major cause of acute mortality and chronic disability involving cerebral palsy, seizures, and mental retardation. The gestational age of the infant is one of the main variables determining the neuropathological picture of hypoxic-ischemic brain injury, and ulegyria (one of its neuropathological correlates) typically affects full-term infants. The damage usually involves the deeper sulcal portion of the convolutions while sparing the crowns, and includes subcortical white matter atrophy and gliosis. The aim of this study was to characterize the electroclinical features of hypoxic-ischemic encephalopathy when ulegyria is one of its main neuropathological features. To this end, nine patients with MRI-proven ulegyria and epilepsy underwent a complete neurological work-up. The ulegyric lesions were mainly distributed in the parasagittal watershed areas and frequently associated with other hypoxic-ischemic lesions. The neurological picture was characterized in most patients by mental retardation, motor deficits, and drug-refractory partial epilepsy. The ulegyria in our patients was associated with a complex clinical picture: epilepsy was a prominent component, and its severity directly correlated with the extent of the ulegyria and the associated hypoxic-ischemic lesions. Drug refractoriness was an almost constant correlate of this form of symptomatic epilepsy.

Adolescent↗

PubMed2003

Cellular biology of epileptogenesis.

The ionic currents that underlie the mechanisms of epileptogenesis have been systematically characterised in different experimental preparations. The recent elucidation of the molecular structures of most membrane channels and receptors has enabled structure-function analyses in both physiological and pathophysiological conditions. The neurophysiological and biomolecular features of epileptogenic mechanisms that putatively account for human epilepsies are summarised in this review. Particular emphasis is given to epilepsies that are associated with genetically determined alterations of ligand-gated and voltage-gated ion channels. Changes in ionic currents that flow through sodium, potassium, and calcium channels can lead to different types of epilepsies. Inherited or acquired changes that alter the function of receptors for acetylcholine, glutamate, and gamma-aminobutryic acid are also involved. better understanding of the role of these epileptogenic mechanisms will promote new advances in the development of selective and targeted antiepileptic drugs.

Cell Membrane↗

PubMed2003

Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families.

PURPOSE: [corrected] To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE). METHODS: A personal and family history was obtained from each affected and unaffected member, along with a physical and neurologic examination. Routine and sleep EEGs, computed tomography (CT), or magnetic resonance imaging (MRI) were performed in almost all the patients. DNAs from family members were typed with several microsatellite markers localized on either side of LGI1 at 10q24 and screened for LGI1 mutations. RESULTS: The seven families included a total of 34 affected individuals (10 deceased). The age at onset ranged between 8 and 50 years (average, 22 years). Twenty-six patients had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Less frequent ictal symptoms were visual, psychic, or aphasic seizures, the latter occurring in isolation in one family. The attacks were rare and well controlled by antiepileptic drug treatment but recurred after drug discontinuation. Interictal EEGs were usually unrevealing. MRI or CT scans were negative. Analysis of LGI1/Epitempin exons failed to show mutations in three pedigrees. Linkage analysis strongly suggested exclusion of linkage in one of these families. We found two novel missense mutations, a T-->C substitution in exon 6 at position 598, and a T-->A transition in exon 8 at position 1295, the latter being detected in a family with aphasic seizures. CONCLUSIONS: Our data confirm the inclusion of aphasic seizures within the ADLTE clinical spectrum, suggest the existence of locus heterogeneity in ADLTE, and provide new familial cases with LGI1 missense mutations associated with the disease.

Adolescent↗

PubMed2003

Na+-activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons.

The ionic mechanisms underlying the termination of action-potential (AP) bursts and postburst afterhyperpolarization (AHP) in intrinsically bursting (IB) neocortical neurons were investigated by performing intracellular recordings in thin slices of rat sensorimotor cortex. The blockade of Ca(2+)-activated K(+) currents enhanced postburst depolarizing afterpotentials, but had inconsistent and minor effects on the amplitude and duration of AHPs. On the contrary, experimental conditions resulting in reduction of voltage-dependent Na(+) entry into the cells caused a significant decrease of AHP amplitude. Slice perfusion with a modified artificial cerebrospinal fluid in which LiCl (40 mM) partially replaced NaCl had negligible effects on the properties of individual APs, whereas it consistently increased burst length and led to an approximately 30% reduction in the amplitude of AHPs following individual bursts or short trains of stimulus-induced APs. Experiments performed by partially replacing Na(+) ions with choline revealed a comparable reduction in AHP amplitude associated with an inhibition of bursting activity. Moreover, in voltage-clamp experiments carried out in both in situ and acutely isolated neurons, partial substitution of extracellular NaCl with LiCl significantly and reversibly reduced the amplitude of K(+) currents evoked by depolarizing stimuli above-threshold for Na(+)-current activation. The above effect of Na(+)-to-Li(+) substitution was not seen when voltage-gated Na(+) currents were blocked with TTX, indicating the presence of a specific K(+)-current component activated by voltage-dependent Na(+) (but not Li(+)) influx. The above findings suggest that a Na(+)-activated K(+) current recruited by the Na(+) entry secondary to burst discharge significantly contributes to AHP generation and the maintenance of rhythmic burst recurrence during sustained depolarizations in neocortical IB neurons.

Action Potentials↗

PubMed2003

Prospects for novel antiepileptic drugs.

The currently available antiepileptic drugs (AEDs) provide a satisfactory level of seizure control in up to 70% of patients with epilepsy. The rational use of these drugs implies a precise syndromic diagnosis and a good familiarity with the clinical pharmacology and tolerability of the AEDs. Significant advances in drug tolerability have occurred in the last 15 years with the development of newer antiepileptic agents that are targeted to cellular epileptogenic mechanisms and have fewer side effects. As a result of integrated molecular and neurophysiological research strategies, further advances in the pharmacological treatment of epilepsy may lead to the design of more selectively tailored AEDs, which will reduce the proportion of drug refractory patients and counteract the development of the epileptogenic process.

Animals↗

PubMed2002

Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy.

Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two families affected by this disorder. Both mutations introduce premature stop codons and thus prevent the production of the full-length protein from the affected allele. By immunohistochemical studies, we demonstrate that the LGI1 protein, which contains several leucine-rich repeats, is expressed ubiquitously in the neuronal cell compartment of the brain. Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene.

Alternative Splicing↗

PubMed2002

Is refractory epilepsy preventable?

About a third of the patients diagnosed with epilepsy will not be fully controlled with antiepileptic drugs (AEDs), and many of them will have frequent and disabling seizures. These patients will undergo multiple drug trials, most often without complete seizure remission. Moreover, refractory epilepsy is associated with increased morbidity (from seizures and medications), social isolation, unemployment, and overall reduced quality of life. There is evidence that refractory epilepsy can be a progressive disorder, which, if controlled early, might never develop into a full syndrome with all of its associated sequelae. The difficulty lies in identifying at an early stage patients who are likely to progress to intractability. No currently known markers enable clinicians to make this identification with confidence. Advances in pharmacogenomics and our understanding of pharmacologic responsiveness in epilepsy may change this situation. Even now, we are able to identify many patients with a poor prognosis earlier than before, particularly in the pediatric population, in which syndromic classification may provide an approach to predict intractability. The early initiation of aggressive therapy may improve outcome and overall quality of life.

Disease Progression↗

PubMed2002

AlphaCaMKII and NMDA-receptor subunit expression in epileptogenic cortex from human periventricular nodular heterotopia.

PURPOSE: Periventricular nodular heterotopia (PNH) is the most common human brain dysgenesis, very frequently characterized by focal drug-resistant epilepsy. To understand the cellular mechanisms underlying its intrinsic hyperexcitability, we investigated the expression of glutamate-receptor subunits and related proteins in four human patients affected by PNH. METHODS: PNH was diagnosed by means of magnetic resonance imaging. The epileptogenic area was revealed by depth electrode recordings and removed during epilepsy surgery. Sections from the removed cerebral tissue were analyzed by means of immunocytochemistry (ICC), with antibodies directed against N-methyl-d-aspartate (NMDA)-receptor subunits, the alpha subunit of the Ca2+/calmodulin-dependent kinase II (alphaCaMKII), and its active phosphorylated form. RESULTS: The ICC data demonstrated that the subcortical heterotopic nodules were consistently characterized by lower expression of alphaCaMKII and its activated form. In more pronounced cases (i.e., when the extension of the nodules to the neocortex determined clear layering abnormalities), the heterotopic tissue also was characterized by a decreased expression of NMDA-receptor subunits, which was particularly evident in the dendritic compartment. CONCLUSIONS: These data suggest the existence of an alteration of alphaCaMKII and the NMDA-receptor complex in the epileptogenic brain tissue of human PNH, which may play a role in the basic mechanisms of hyperexcitability associated with this brain dysgenesis.

Adult↗