A study of EEG and epilepsy profile in Wolf–Hirschhorn syndrome and considerations regarding its correlation with other chromosomal disorders

doi:10.1016/s0387-7604(02)00223-1

Brain and Development

Volume 25, Issue 4, June 2003, Pages 283-287

https://doi.org/10.1016/s0387-7604(02)00223-1 Get rights and content

Abstract

Wolf–Hirschhorn syndrome (WHS) is a genetic disorder caused by a deletion of the short arm of chromosome 4. Sgrò et al. described an electroclinical profile for WHS, but data regarding this issue are scarce. We report an 8-year-old girl presenting the classic phenotype for WHS, confirmed by FISH test. Epilepsy started during infancy with myoclonic seizures. Later, she presented atypical absences, which gradually increased in frequency, and at the age of 2.5 years, she presented a non-convulsive status epilepticus. Epilepsy was controlled with valproate at the age of 6 years. Serial EEGs were performed and showed unusual bursts of generalized, high amplitude delta waves with superimposed low–moderate amplitude sharp waves. A literature review was performed and our case was compared to others, where EEG and/or epilepsy were addressed. Our case and previously published data show that WHS presents a stereotyped epilepsy profile and EEG patterns. A discussion concerning similarities between these findings and those observed in Angelman syndrome has been performed, since in both syndromes, GABA genes are involved and may play a role in the pathogenesis. Although fascinating, this theory is simplistic, since patients with Angelman syndrome without GABA deletion may present epilepsy and EEG abnormalities. Another issue is the striking overlap regarding these features, between WHS and Pitt–Rogers–Danks syndrome, which may be a key in showing that these disorders could be a spectral variation of the same entity.

Introduction

Wolf–Hirschhorn syndrome (WHS) is an uncommon disorder caused by a partial deletion of the short arm of chromosome 4. It is characterized by severe growth and mental retardation, microcephaly, ‘Greek helmet’ facies, and closure defects [1]. Although the prevalence of epilepsy in this syndrome seems to be high (80–90%) [1], most of the reports are clinical studies. In 1995, Sgrò et al. [2] described a particular EEG pattern and epilepsy profile in four patients with WHS, but few authors have emphasized these aspects. Although approximately 140 cases have been reported, epilepsy and EEG were properly addressed only in seven and five papers, respectively.

In a recent review, Singh et al. [3] emphasized the importance of studying epilepsy in chromosomal disorders. These authors conclude that, if clinical epileptologists can associate specific epileptic syndromes with particular chromosomal regions, candidate epilepsy genes could be pursued. At the same time, in their comprehensive research the authors assert that most articles had only limited descriptions of the epileptology and stated that future case reports of patients with epilepsy and a chromosome abnormality should include diligent classification of epilepsy and epileptic syndromes, according to the International League Against Epilepsy (ILAE) guidelines [4].

We report evolutionary aspects of the electroclinical profile in one patient with WHS and review published cases, where these features are described.

Section snippets

Case report

An 8-year-old girl, the third child of healthy, non-consanguineous parents, was born at term, from normal delivery. Since birth, her mother noticed peculiar facial traits and feeding difficulties (poor suction). At 24 months of age, she presented developmental delay, weight and height were below the 2.5 percentile, and she had dysmorphic features suggesting WHS. Genetic investigation (FISH test) confirmed the clinical hypothesis. Neurological acquisitions were very slow and, at the time of the

Discussion

Chromosomal disorders have a high prevalence of epilepsy, but usually do not present suggestive electroclinical characteristics. An exception is Angelman syndrome (AS), which presents a suggestive EEG and epilepsy profile, allowing diagnosis of AS at early ages [11], [12] or in patients without genetic confirmation [13].

Since its original description, WHS has been a well-studied entity on clinical bases but only recently have EEG and epilepsy findings raised interest. Despite the high

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Partial deletion of the short arm of chromosome no. 4 (4p−): clinical studies in five unrelated patients
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Cited by (21)

Atypical absence seizures and gene variants: A gene-based review of etiology, electro-clinical features, and associated epilepsy syndrome
2024, Epilepsy and Behavior
Atypical absence seizures are generalized non-convulsive seizures that often occur in children with cognitive impairment. They are common in refractory epilepsy and have been recognized as one of the hallmarks of developmental epileptic encephalopathies. Notably, pathogenic variants associated with AAS, such as GABRG2, GABRG3, SLC6A1, CACNB4, SCN8A, and SYNGAP1, are also linked to developmental epileptic encephalopathies. Atypical absences differ from typical absences in that they are frequently drug-resistant and the prognosis is dependent on the etiology or related epileptic syndromes. To improve clinicians' understanding of atypical absences and provide novel perspectives for clinical treatment, we have reviewed the electro-clinical characteristics, etiologies, treatment, and prognosis of atypical absences, with a focus on the etiology of advancements in gene variants, shedding light on potential avenues for improved clinical management.
Successful treatment of migrating partial seizures in Wolf-Hirschhorn syndrome with bromide
2016, Brain and Development
Citation Excerpt :
Moreover, multiple genes in the 0.7–1.3 Mb terminal [2] are considered to represent another seizure locus in WHS. One possible explanation for the seizure phenotype in our patient is that the migrating partial seizures are present in other WHS patients, described as “erratic myoclonus” [8] or “alternative hemiconvulsions” [4]. CTBP1 at 1.2 Mb and CPLX1 at 0.7 Mb may intensify the seizure susceptibility by LETM1 deletion.
A girl with mild psychomotor developmental delay developed right or left hemiclonic convulsion at 10 months of age. One month later, clusters of hemiclonic or bilateral tonic seizures with eyelid twitching emerged, resulting in status epilepticus. Treatment with phenobarbital and potassium bromide completely terminated the seizures within 10 days. Ictal electroencephalography revealed a migrating focus of rhythmic 3–4 Hz waves from the right temporal to right frontal regions and then to the left frontal regions. Genetic analysis was conducted based on the characteristic facial appearance of the patient, which identified a 2.1-Mb terminal deletion on chromosome 4p. This is the first case of Wolf–Hirschhorn syndrome complicated by epilepsy with migrating partial seizures.
Epilepsy and electroencephalographic anomalies in chromosome 2 aberrations. A review
2008, Epilepsy Research
Citation Excerpt :
Information on the electroclinical features and their natural history is crucial for pediatricians and child neurologists who provide health care to patients with epilepsy associated with chromosome aberration (Battaglia and Guerrini, 2005). Recent reports led to the identification of peculiar electroclinical patterns in patients with specific chromosome anomalies (Laan et al., 1999; Heilstedt et al., 2003; Valente et al., 2003; Grosso et al., 2004a; Zuberi and Biraben, 2004; Bahi-Buisson et al., 2005; Battaglia and Guerrini, 2005). However, it remains difficult to delineate the clinical and electroencephalographic (EEG) features of patients with chromosome anomalies because of the sporadic nature of reports (Grosso et al., 2005).
Epilepsy and electroencephalographic (EEG) anomalies are common in subjects carrying chromosomal aberrations.
We report clinical and EEG investigations on 13 patients carrying chromosome 2 anomalies, including two patients with inversions, six with translocations, two with partial duplications and three with interstitial deletion syndromes.
Epilepsy and/or EEG anomalies were found in one patient with a chromosome 2 translocation, in both of those carrying partial duplications and in all three with interstitial deletion syndromes. No epilepsy or EEG anomalies were detected in the remaining patients.
Epilepsy may be associated with chromosome 2 aberrations. Gross rearrangements involving the long arm of chromosome 2 might be more often associated with epilepsy than those involving the short arm. The association of epilepsy with chromosome 2 duplications is less clear. In particular, our observations and a review of the literature appear to suggest that a strict relationship between epilepsy and interstitial deletions involving the 2q24–q31 region. In the latter disorder tonic and focal seizures occur early in life. Generalized and focal myoclonic jerks tend to appear in infancy and are subsequently followed by seizures mixed in type. Seizures usually persist up to late childhood and are drug resistant. Further studies are necessary to better define the electroclinical patterns of patients carrying deletions in 2q24–q31. These may help to direct systematic study of this—probably underestimated—cause of severe epilepsy.
Epilepsy in chromosome aberrations
2005, Archives de Pediatrie
L'épilepsie est l'un des symptômes les plus fréquemment rencontrés dans de nombreuses aberrations chromosomiques. Bien que la plupart d'entre elles soient associées à une grande variété de crises, il existe quelques aberrations chromosomiques qui comportent un profil électroencéphalographique ainsi qu'un phénotype épileptique spécifique. Parmi les 400 aberrations chromosomiques qui comportent une épilepsie, huit possèdent une association forte avec un phénotype spécifique : la monosomie 1p36, le syndrome de Wolf-Hirschhorn (syndrome 4p-), le syndrome d'Angelman, le syndrome de Miller-Dieker, l'inversion duplication du 15, la trisomie 21, les syndromes du chromosome 20 en anneau et du 14 en anneau. Ces régions chromosomiques constituent des cibles extrêmement importantes pour les généticiens à la recherche de gènes responsables d'épilepsie. Par ailleurs, une meilleure caractérisation de ces syndromes épileptiques pourrait conduire à un traitement antiépileptique adapté.
Epilepsy is among the most frequent finding in many chromosome aberrations. While most chromosome aberrations can be associated with different seizure types, there are few aberrations which feature specific seizures and EEG patterns. Among the 400 different chromosomal imbalances described with seizures and EEG abnormalities, eight have a high association with epilepsy. These comprise: the monosomy 1p36, Wolf-Hirschhorn syndrome (4p-), Angelman syndrome, Miller-Dieker del 17p13.3, the inversion duplication 15 syndrome, ring 20 and ring 14 syndromes, Down’s syndrome. These chromosomal regions where aberrations have an evident association with epilepsy may be useful targets for gene hunters. On the other hand, a better characterisation of epileptic syndrome in these disorders may lead to a better and specific treatment.
Sleep polygraphy in Angelman syndrome
2004, Clinical Neurophysiology
Objective: Sleep disturbances are frequent in Angelman syndrome (AS); however, beside the few studies which have investigated sleep disorders in AS by means of questionnaires, to our knowledge, no systematic polysomnographic recordings have been carried out in AS patients. The present study represents the first attempt to study sleep patterns of AS by polysomnography, to evaluate the influences of sleep on the paroxysmal electroencephalogram (EEG) patterns of AS and to assess the eventual age-related changes of sleep architecture and of sleep EEG abnormalities in children and adolescents with AS.
Methods: Fifteen children with AS (7 males and 8 females, mean age 7.2 years, range 3–16 years), attending the Sleep Center of the Department of Child Neurology and Psychiatry of the University of Rome ‘La Sapienza’ and the Sleep Research Centre of the Oasi Institute (IRCCS) of Troina were included and subdivided into two subgroups by age: subgroup 1, aged 3–5 years, and subgroup 2, aged 9–17 years. Two control groups of age-matched normal subjects were also included: one aged less than 8 years and another aged more than 8 years; additionally, two other groups of age-matched children with epilepsy and mental retardation of different origin, one aged less and one aged more than 9 years were taken into consideration. The statistical comparison between the sleep parameters obtained from the patients and those from the other groups was carried out by means of the non-parametric Kruskal–Wallis ANOVA and the Mann–Whitney U test.
Results: The most frequent EEG abnormality found in AS patients appeared to be the 2–3 c/s poorly defined spike/waves complexes. This pattern was influenced by sleep stages; the duration of the runs showed an increasing length with sleep deepening from sleep stage 1 to slow-wave sleep (SWS). Moreover, the 2–3 c/s bursts activity present in sleep stage 2 showed a slowing to 1–2 c/s during SWS. Regarding sleep architecture, in subjects with AS aged <8 year there was a significant reduction in sleep efficiency as compared to normal controls, while the percentage and duration of REM sleep was significantly lower and the percentage of SWS was significantly higher. REM sleep time was reduced in AS subjects aged >8 years than in normal controls. The comparison between AS groups and mental retardation with epilepsy groups did not show significant differences.
Conclusions: Similarly to other types of genetically determined mental retardation syndromes, also subjects with AS seems to show important abnormalities of their sleep polysomnographic patterns.
Significance: This is the first study which reports, in detail, these abnormalities and opens a new path for further insight into the knowledge of additional sleep-related disturbances which are reported in sleep questionnaires by the caregivers of AS subjects.
Status Epilepticus in Chromosomal Disorders Associated with Epilepsy: A Systematic Review
2023, Genes

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Case reportA study of EEG and epilepsy profile in Wolf–Hirschhorn syndrome and considerations regarding its correlation with other chromosomal disorders

Abstract

Introduction

Section snippets

Case report

Discussion

Adv Pediatr

J Pediatr

4p(−) syndrome: a chromosomal disorder associated with a particular EEG pattern

Epilepsia

Chromosomal abnormalities and epilepsy: a review for clinicians and gene hunters

Epilepsia

Proposal for revised classification of epilepsies and epileptic syndromes

Epilepsia

The 4p− syndrome. A clinically recognizable chromosomal deletion syndrome

Am J Dis Child

Translocation 4p− syndrome: a general review

Am J Dis Child

Familial Wolf's syndrome with a hidden 4p deletion by translocation of an 8p segment. Unbalanced inheritance from a maternal translocation (4;8)(p15.3;p22). Case report, review and risk estimates

Clin Genet

Case report
A study of EEG and epilepsy profile in Wolf–Hirschhorn syndrome and considerations regarding its correlation with other chromosomal disorders