Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder.

OBJECTIVE: Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K(+) /H(+) exchange and in Ca(2+) homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. METHODS: Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1. RESULTS: Three unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1. SIGNIFICANCE: We consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Epilepsy in shunted posthemorrhagic infantile hydrocephalus owing to pre- or perinatal intra- or periventricular hemorrhage.

Epilepsy is relatively common in infants with hydrocephalus. Its mechanism is controversial; in fact, studies on etiologically heterogeneous series are not able to clarify the mechanism generating epilepsy or to suggest effective prevention and treatment strategies. Our study is aimed at assessing the onset and evolution of epilepsy, as well as concurrent cognitive development of a homogeneous series of shunted posthemorrhagic hydrocephalus owing to pre- or perinatal intra- or periventricular hemorrhage. Forty patients were enrolled in the study. Twenty-six were patients with grade II-III intraventricular hemorrhage, 16 of whom had associated ischemic lesions. In the remaining 14 patients, a grade IV intra-ventricular hemorrhage was found. Epilepsy was observed in 27 patients. Aside from 10 cases with nonsyndromic forms of epilepsy, it was possible to define at least three different age-dependent epileptic syndromes: symptomatic neonatal location-related epilepsy with transient West's syndrome in infancy in 5 patients; West's syndrome in 8 patients; and continuous spike-waves during sleep in 4 patients. Epilepsy was significantly correlated with ischemic lesions only. Early thalamic injuries frequently evolved toward continuous spike-waves during sleep, indicating that patients with thalamic injury must be monitored to detect continuous spike-waves during sleep early. Cerebellar atrophy, in addition to epilepsy and other brain injuries, accounted for disorders of cognitive development.

Epileptic negative myoclonus in a newborn with hemimegalencephaly.

PURPOSE: We report the case of a male newborn with Ohtahara syndrome and right hemimegalencephaly who presented epileptic negative myoclonus in the first days of life. METHODS: Prolonged polygraphic studies were performed, as well as MRI and a full clinical examination. RESULTS: EEG showed a constant and nonreactive pattern of burst suppression. There were several kinds of electro-clinical seizures (generalized myoclonia, short atonias, typical spasm and tonic spasms) at the beginning of the EEG's burst. The periods of EMG silence, lasting less than 300 ms, were associated with stereotyped EEG transients. CONCLUSIONS: Epileptic negative myoclonus can be observed also in neonatal age. The short transient impairment of motor function observed in the newborn seems linked to the slow component of spike-wave discharge, but its mechanism is still not clear.

Electroclinical patterns and evolution of epilepsy in the 4p- syndrome.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a well-known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p- syndrome). Seizures occur in almost all the cases, but studies on the electroclinical disorder and its evolution are still scarce. We present a longitudinal study of the electroclinical features in 10 children with WHS. METHODS: Ten patients (five boys and five girls) underwent a detailed clinical assessment and a prolonged EEG study. Six of the 10 also had video-polygraphy. RESULTS: Nine of the 10 patients had seizures; they were generalized or unilateral clonic and tonic-clonic, and atypical absences associated with myoclonic jerks. Age at onset of seizures varied from 1 day to 2.5 years. In all the patients, including the only one without seizures, two stereotyped EEG patterns were observed, consisting of (a) bursts of rhythmic (3-5 Hz), high-voltage slow waves located in the posterior regions and increased by sleep, or bursts of rapid spike-wave complexes in the centroparietal and parietooccipital regions; and (b) repetitive rapid posterior spikes. Sleep organization was constantly absent or very poor. The evolution of epilepsy was frequently good, with four seizure-free cases at the end of follow-up, two of them weaned from antiepileptic drugs (AEDs). CONCLUSIONS: Seizure onset in WHS also can occur at neonatal age. At least two electrical stereotyped patterns of the epileptic disorder are associated with a relevant disorganization of the sleep states. Prognosis of epilepsy is generally good both for the seizure control and for its evolution.