The ring 14 r(14) syndrome, first described by Gilgenkrantz et al. in 1971, is a rare cytogenetic disorder. It is generally associated with a variable loss of genetic material of the terminal long arm of the chromosome (14q32.31-qter) (Gilgenkrantz et al., 1971; Zelante et al., 1991; Wintle et al., 1995; Zollino et al., 2009). Individuals with r(14) syndrome generally have developmental delay, distinctive facial features, varying degrees of cognitive disability, behavioral disorders, and seizures. Other common features include hypotonia, microcephaly, growth retardation, ocular abnormalities, and mild skeletal abnormalities. Epilepsy is the most common and severe feature encountered in the syndrome, with very few exceptions (Bowser-Riley et al., 1981; Gilgenkrantz et al., 1984; Zelante et al., 1991). Accurate clinical and genetic characterization of this condition has been recently attempted, and putative genes involved in epileptogenesis do not seem to map to the terminal 14q region, usually deleted in formation of the ring (Zollino et al., 2009). In fact, a linear terminal 14q deletion syndrome does not include epilepsy among its component manifestations. Instead, seizures are likely caused by the ring itself, rather than loss of chromosomal material (Van Karnebeek et al., 2002; Zollino et al., 2009). Furthermore, the evidence of other ring chromosomes without epilepsy emphasizes the importance of selected rings in mapping epilepsy susceptibility genes.
Epilepsy occurs in virtually all cases of r(14) syndrome, but its electroclinical phenotype is poorly characterized and a detailed description of clinical and electroencephalography (EEG) findings and their natural history is lacking.
The purpose of the present study is to better define the seizure types, natural history, and drug responsiveness of r(14) syndrome, a highly epileptogenic chromosomal condition.
Subjects and Methods
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- Subjects and Methods
- Supporting Information
With the support of the Ring 14 International Association, a total of 22 patients with ring chromosome 14, coming from several countries (eight from Italy, six from France, three from United Kingdom, three from the United States, one from Sweden, and one from Brazil) were enrolled in the present study up to December 2009. Sixteen of the patients have been described previously in a detailed genetic study (Zollino et al., 2009). Subjects included were 13 male and 9 female patients, aged 26 months to 22 years.
All data have been obtained from the following: (1) medical records and questionnaires translated in different languages and filled in by general practitioners and neurologists, and (2) systematic assessments of patients seen at participating medical centers or at dedicated clinics during meetings of the Ring 14 family support group. All data were entered and extrapolated from the password-protected Electronic International Database of Ring 14 by two medical doctors (SG and AS). This registry collects selected and linked-anonymized clinical and genetic information of patients with chromosome 14 aberrations (www.ring14.com). Consent forms were signed by parents or legal guardians regarding medical record examination, physical examination, and performance of genetic and instrumental tests.
The following characteristics of epilepsy were examined: age at onset, seizure semiology and frequency at onset and at follow-up, drug responsiveness/resistance, and interictal/ictal EEG data.
Seizures were classified in accordance with the International League Against Epilepsy (ILAE) classification of epilepsy and epileptic syndrome (Engel, 2001). EEG studies were recorded according to the international 10-20 system during wakefulness, spontaneous sleep, and arousal. Long-term video-EEG was performed in a few select cases.
Clinical history was collected in terms of family history of epilepsy, intrauterine development, delivery (Apgar scores), and developmental milestones (motor, language, and social behavior). Clinical evaluation was also completed including physical, neurologic, and neuropsychological data. Assessment of patient characteristics and resources included an evaluation of the child's cognitive function through direct norm-referenced tests when possible, and adaptive functioning including behavioral concerns and evaluation of the ecologic context. All patients underwent neuroimaging studies, most commonly by magnetic resonance imaging (MRI).
In an attempt to construct a deletion map and to establish genotype–phenotype correlation, we previously performed a detailed genetic study, as reported separately, to establish the mosaic status of the ring and the size of a cryptic terminal deletion in the ring (Zollino et al., 2009). Subsequently, genetic findings were compared with clinical features to establish a potential correlation between the severity of cognitive, epileptic, and neuroradiologic phenotypes and loss of chromosomal material.
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- Subjects and Methods
- Supporting Information
Epilepsy represents a major complication of r(14) syndrome; it occurs in almost all cases described and does not seem to be related to a structural brain anomaly or to the genetic material loss in the ring (Zollino et al., 2009). To our knowledge, apart from a few recent reports (Ville et al., 2009; Specchio et al., 2012), the electroclinical phenotype of r(14) syndrome is still poorly known and, in the literature, epilepsy is mainly described as nonspecific, generalized, and drug resistant. Moreover, information about epilepsy in chromosomal disorders is predominantly found in genetics journals where descriptions are often very sparse and, as a result, there are only a small number of chromosome abnormalities in which epilepsy represents a consistent feature and its phenotype is well described, such as ring 20 syndrome (Inoue et al., 1997), Angelman syndrome (Laan et al., 1997), deletion 1p36 (Bahi-Buisson et al., 2008), and Wolf-Hirschhorn (Battaglia et al., 2009). In this review, we attempted to better describe the semiology of epileptic seizures, epilepsy evolution, and ictal/interictal EEG patterns in a series of 22 patients with r(14) syndrome.
Epilepsy in r(14) syndrome seems to be a chronic condition with a stormy onset, and repetitive and prolonged seizures that can affect for a long time the evolution of the child's emotional, cognitive, and linguistic development in a critical phase. Based on analysis of our results, it seems possible to recognize a rather typical evolution of epilepsy with few exceptions. As already suggested (Zollino et al., 2012), this study confirms that epilepsy could be empirically divided into three successive age-dependent stages. In the onset phase (stage 1), epilepsy presents a very high activity, sometimes before the development of other recognizable clinical features. According to Morimoto and Ville (Morimoto et al., 2003; Ville et al., 2009), epilepsy is frequently the presenting symptom without any other significant clinical findings (negative familial and personal history, unremarkable pregnancy and delivery, no/subtle dysmorphic features), posing many diagnostic and therapeutic challenges. In fact, if seizure recurrence is in clusters, in young female patients a differential diagnosis with PCDH19 gene mutations encephalopathy has to be considered (Dibbens et al., 2008). Whether seizures are concomitant with fever, a differential diagnosis with Dravet syndrome is mandatory. Seizures from familial and literature descriptions appear generalized, but, in our series, EEG recordings frequently showed a focal origin, tonic or clonic seizure with a rapid secondary generalization. These seizures are mainly afebrile and occur during nocturnal sleep or upon awakening and often recur in clusters. Noteworthy, half of the cases presented with a generalized and focal convulsive status epilepticus (CSE). The strong susceptibility to clusters of prolonged tonic–clonic seizures and CSE may have important therapeutic implications. In these patients, initial treatment with benzodiazepines often failed to obtain seizure control; high dosage administration of barbiturate and phenytoin were often required. In stage 2 (up to 20 years), follow-up phase, different types of seizures are present in the same subject consisting of both generalized and focal seizures, more often from frontal or posterior temporal regions. Seizures can be nocturnal and diurnal with a tendency to group in clusters but, compared to the onset, intercluster time seems longer with fewer episodes of SE. A kind of NCSE and “minor motor seizures,” which appear after cessation of prolonged single or few repetitive seizures, may also occur in the context of partial epilepsy. Nevertheless, seizures are drug-resistant, and if seizure activity persists, really severe and intellectual decline and speech problems become evident. Then, neuronal excitability gradually decreases, perhaps in relation to the cerebral maturation process, achieving a steady state. In fact, entering the stage 3 (above the age of 20) there is a tendency for seizures to decrease, up to cessation in some patients; in a few cases tonic short events can persist during sleep and atypical absences occur during daytime. Further clinical progression does not seem to occur, whereas moderate to severe cognitive disability, severe language impairment, and behavioral concerns persist.
It's interesting to underscore that cognitive disability is prominent in the context of this chromosomal disorder. On the other hand, at the onset of epilepsy, children are usually reported to be normally developed from a psychomotor point of view. Of interest, case 9, a patient who since the age of 6 years experienced drug-sensitive absences as the only type of seizures at the last psychometric evaluation, showed mild cognitive impairment and adequate linguistic skills at age 12. Moreover, cases 2 and 15, respectively, 3 and 2 years old, had sporadic and not severe seizures, and they showed mild cognitive impairment at the last follow-up. Which will be their cognitive performance at the age of 12 if their seizures will persist to be sporadic?
We believe that it could be possible to speculate that the severity of epilepsy occurring in the first 10 years of life, a critical phase of child psychomotor development, may negatively influence it, according to the recent concept of “encephalopathic effects of the epilepsy,” as defined in the “Report of the ILAE Commission on Classification and Terminology,” (Berg et al., 2010).
Serial EEG investigations revealed a slow and poorly organized background activity during wakefulness and sleep, frequent bursts of asynchronous rhythmic high amplitude slow waves over the frontal and medioposterior regions, and spike wave complexes over the posterior regions, sometime diffuse and activated by eye closure. These EEG features seem in some way similar to activities seen in Angelman, Wolf Hirschorn, and ring 20 syndromes (Kobayashi et al., 1998; Valente et al., 2003; Uemura et al., 2005), but significant clinical differences are evident among these syndromes, such as the lack of myoclonic epileptic status in r(14) syndrome, the rhythmic cortical myoclonus seen in Angelman syndrome (Guerrini et al., 1996), and the absence of a clear occurrence of non-NCSE typical of ring 20 syndrome.
In our series, MRI findings do not show clear cortical abnormalities that could be strictly correlated to the epileptic phenotype. Nevertheless, functional neuroimaging studies could be useful in the future to better understand pathogenetic mechanisms underlying epilepsy, as demonstrated in ring 20 syndrome in which the data from 18 F-fluoro-L-dopa PET showed reduction in striatal dopamine uptake, leading to the suggestion that the striatal dopaminergic transmission in the basal ganglia plays a key role in seizure interruption (Biraben et al., 2004). Eventually, we tried to establish a correlation between the deletion size in the ring and the severity of epileptic and clinical phenotypes. Unfortunately, as demonstrated in previous studies (Schlade-Bartusiak et al., 2005; Maurin et al., 2006; Zollino et al., 2009, 2012), epilepsy and cognitive disability do not seem to correlate with the deletion size in the ring context and it seems unlikely that a specific deleted locus predisposes to seizures and learning disability. Two hypotheses can be proposed to explain the presence of seizures in r(14) syndrome: (1) instability of the ring, resulting in monosomy 14 in a proportion of cells; and (2) haploinsufficiency of critical genes by position effects, leading to decreased expression of genes contained on the adjacent 14q arm (Kleinjan & van Heyningen, 1998; Baur et al., 2001; Van Karnebeek et al., 2002; Grewal & Moazed, 2003; Lloyd et al., 2003; Schlade-Bartusiak et al., 2005; Zollino et al., 2009, 2012). The latter intriguing hypothesis concerning possible candidate genes involved in neurologic and epileptic phenotype emerged from gene content analysis. In fact, by comparing clinical signs of patients with ring chromosome with those of patients carrying a proximal or a distal deletion, we found that seizures and microcephaly seem to be related to genes residing proximally on 14q11q13 (Zollino et al., 2009, 2012). Contained in the region is the FOXG1B gene, expressed in the developing fetal brain. This gene belongs to the forkhead family of transcription factors having a role in the development of the brain and telencephalon (Hanashima et al., 2004). Heterozygous knockout (KO) mice show significant brain anomalies that might be the cause of epilepsy.
In summary, epilepsy occurs in all reported cases. We have not identified characteristic seizure types or a specific ictal/interictal EEG patterns in this syndrome, but in contrast to the prevalence of generalized seizures reported in the previous literature, we would underscore that seizures may be predominately focal, frontal, and temporal in origin. Epilepsy evolves in three successive stages in which seizures over time may become less frequent and severe. During the active phase, epilepsy may be really severe and variably affecting child psychomotor development (encephalopathic effects of the epilepsy). Epilepsy does not seem related to consistent underlying cortical malformations, rather being a functional consequence of the chromosomal abnormalities.