More severe epilepsy and cognitive impairment in the offspring of a mother with mosaicism for the ring 20 chromosome

doi:10.1016/j.eplepsyres.2006.09.006

Epilepsy Research

Volume 73, Issue 1, January 2007, Pages 122-128

https://doi.org/10.1016/j.eplepsyres.2006.09.006 Get rights and content

Summary

Purpose

Ring chromosome 20 [r(20)] syndrome is a rare chromosomal disorder. Cases tend to be sporadic. We elucidate the characteristics of an inherited r(20) mosaicism by describing the clinical features of three family members: a mother and her two children.

Results

The mosaicism rate of the mother was 10% and that of the children 40%. The mother experienced her first epileptic seizures at 24 years of age. Epilepsy was diagnosed two years later. After an unstable period lasting 3 years, she has been seizure-free for 13 years on a combination of valproate and lamotrigine. She has normal intelligence with full working capacity. The daughter exhibited her first epileptic seizures at the age of 7 years and she continues to have seizures weekly. The first epileptic seizures in the son were observed at 5 years of age. The son's epilepsy has been drug resistant from the onset, and a vagal nerve stimulator (VNS) has been ineffective. Psychomotor development was normal in both children up to the onset of epilepsy. Learning difficulties increased throughout school age and both children needed special educational programs. Neuropsychological evaluations have shown deterioration of cognitive levels. Both children had behavioural problems during school age but no longer in adolescence. All three subjects are nondysmophic, normocephalic and of normal growth.

Conclusion

In this family the phenotype of r(20) mosaicism seems to be more severe in the successive generation along with a greater level of mosaicism. The aggravated clinical picture in inherited r(20) mosaicism concerned the onset of epilepsy, drug responsiveness, the cognitive level and behavioural features.

Introduction

Ring chromosome 20 [r(20)] syndrome is a rare chromosomal disorder characterized by refractory epilepsy, cognitive impairment, behavioural problems and sometimes dysmorphic features (Atkins et al., 1972, Schinzel, 2001). About 60 cases have been reported. Patients generally show mosaicism, the ratio of r(20) varying from 1–100% in lymphocytes. Typical features of epilepsy in r(20) syndrome are drug-resistant epileptic seizures and periods of nonconvulsive status epilepticus (NCSE) (Inoue et al., 1997, Augustijn et al., 2001, Biraben et al., 2004). Cognitive problems are common and vary from mild learning disabilities to moderate mental retardation (Back et al., 1989, Augustijn et al., 2001, Biraben et al., 2004, Nishiwaki et al., 2005, Macleod et al., 2005). Earlier it was concluded that the mosaicism ratio was unrelated to the clinical phenotype. However, a reassessment of 57 published cases showed that the ratio significantly correlated with the age of onset of the seizures, the intelligence quotient and malformations, but not with the response to antiepileptic drug (AED) treatment (Nishiwaki et al., 2005).

Reported cases with r(20) syndrome tend to be sporadic. Only two families, one with two affected members and the other with two members and one carrier, have previously been described (Back et al., 1989, Canevini et al., 1998). In this report we enlighten the clinical features in a family in which three members are affected in successive generations.

Section snippets

Methods

We report the clinical characteristics of three patients with r(20) syndrome in the same family, the mother and her two children. All three patients have been followed up by Kuopio Epilepsy Center since the time they were first referred because of their seizures and epilepsy was diagnosed. Multiple EEG, ambulatory EEG and video EEG are available for all three patients. Three or more successive neuropsychological assessments with age-specific tests during the follow-up period have been performed

Clinical data

The clinical characteristics of the patients are presented in Table 1. The mother was first examined due to epilepsy after the first generalized convulsive seizure in 1989 at the age of 26 years. However, her medical history revealed that she had had staring spells without aura, abrupt stopping of activities and difficulties in understanding speech for two years, especially when tired. During the first 3 years after the diagnosis, seizure control was unsatisfactory with diurnal seizures and

Discussion

The main feature of r(20) syndrome is epilepsy, which was diagnosed in the mother at the age of 26, in the daughter at the age of 7 and in the son at the age of 5. The onset of epilepsy was rather late for the mother compared to the mean age of 6 years in a reassessment of the published cases in the literature (Nishiwaki et al., 2005). However, the earliest age for the onset of epilepsy in r(20) syndrome has been neonatal (Burnell et al., 1985, Thomsen et al., 1989, Lancman et al., 1993, Chawla

Conclusion

All familial cases reported show higher levels of mosaicism in succeeding generations associated with a more severe phenotype. This discovery concerns the severity of epilepsy and of cognitive dysfunction. The mechanism of progression between generations remains unknown.

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Cited by (24)

A further case of familial ring chromosome 20 mosaicism - molecular characterization of the ring and review of the literature
2019, European Journal of Medical Genetics
Ring chromosome 20 syndrome is a rare chromosomal disorder characterized by childhood-onset drug-resistant epilepsy, behavioral problems and variable cognitive impairment. While most cases occur sporadically, parent-to-child transmission of ring 20 mosaicism has only been reported in a few exceptional families. We identified a further family with mother-to-child transmission of ring 20 mosaicism. Detailed characterization of the ring chromosome showed a complete ring with preserved telomere repetitive sequences. SNP genotyping excluded mosaic uniparental disomy and indicated that the chromosome was transmitted without recombination from mother to child. These results corroborate the findings of a previous study and support the hypothesis that inherited mosaicism is due to transmission of an unstable chromosome either prone to ring opening or to ring re-formation.
Specificity of electroclinical features in the diagnosis of ring chromosome 20
2018, Epilepsy and Behavior
Citation Excerpt :
Additionally, five more patients were also excluded because they were younger than 3 years, age at which the electroclinical expression of the syndrome is rarely fully developed [7,11–14]. Complete information was gathered in 111 patients and, according to the descriptions of those cases, 91 (81.98%) of them had the full triad [1–11,15–39], eleven (9.91%) had two features (one lacked the typical EEG, four did not have drug-resistant frontal seizures, and six did not have NCSE) [2,3,5,7,8,10,31], and, finally, nine patients (8.11%) had none or only one feature [2,10,11,15,32,39] (Supplementary Material 1). In the literature, we found 170 cases of R20 syndrome.
Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20.
In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases.
We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%.
Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad.
In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted.
Epilepsy in ring chromosome 20 syndrome
2016, Epilepsy Research
Citation Excerpt :
Based on our previous experience (Canevini et al., 1998; Vignoli et al., 2009), the association of valproic acid and lamotrigine was the best choice, although seizures remained drug resistant in most patients. Despite reports of a favorable outcome related to vagus nerve implantation (Parr et al., 2006; Herrgård et al., 2007), this option was ineffective in our as well as in other series (Alpam et al., 2005; Zou et al., 2006). Most patients exhibited normal to borderline cognitive abilities at seizure onset, but cognitive decline became progressively apparent in 72% of them.
Ring chromosome 20 syndrome is characterized by severe, drug resistant childhood onset epilepsy, often accompanied by cognitive impairment. We characterized the electro-clinical phenotype and the long-term course of epilepsy in a large series.
We reviewed the electro-clinical phenotype of 25 patients (aged 8–59 years), and assessed the relationship between epilepsy severity and clinical and/or genetic variables. We also searched for reports of patients diagnosed with r(20) syndrome in the literature, included those whose clinical information was sufficiently accurate, and compared their clinical features with the ones of our patients.
Epilepsy exhibited an age dependent course. When seizure onset occurred in childhood (21 patients), terrifying hallucinations associated with focal motor seizures, often sleep-related (8 patients), or dyscognitive seizures (13 patients), were prominent features, often evolving into epileptic encephalopathy associated with non-convulsive status epilepticus (11 patients). In the long-term, progressive stabilization of drug resistant epilepsy associated with non-convulsive status epilepticus, focal seizures with motor and autonomic features, and eyelid myoclonia were noticed. Epilepsy onset in adolescence (3 patients) was accompanied by a milder developmental course, dyscognitive seizures and non-convulsive status epilepticus, and no cognitive decline. Only three older patients became seizure free (>5 years) We found statistically significant correlations between age at epilepsy onset and cognitive level. Although in the study cohort the relationship between r(20) ratio, age at epilepsy onset and cognitive level was non-statistically significant, it reached significance evaluating the larger cohort of patients previously published.
In ring(20) syndrome, epilepsy has an age dependent course and a worse outcome when age at seizure onset is earlier. The r(20) ratio and severity of cognitive impairment appear to be directly related to each other and inversely correlated with the age at epilepsy onset.
Ring chromosome 20
2012, European Journal of Medical Genetics
Citation Excerpt :
From the review of published literature, no single drug is most effective, and medical intractability frequently leads to multiple antiepileptic drug exposure. Some authors report more favorable outcome with a combination of valproate and lamotrigine [8,9,32]. Epilepsy in r(20) syndrome is not amenable to resective surgery [13,43].
Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20's in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis.
Ring chromosome 20 syndrome: Electroclinical description of six patients and review of the literature
2012, Epilepsy and Behavior
Ring chromosome 20 syndrome is a rare chromosomal disorder.
In six patients, we focused on the presenting epileptic phenotype, the behavioral and mental problems and the relationship between the ratio of mosaicism and the age at onset of the epilepsy.
All patients presented with pharmacoresistant frontal lobe complex partial seizures. The earliest onset of epilepsy was seen in patients without mosaicism. There were three patients out of six with behavioral disturbances before the onset of seizures. All patients had mild to moderate cognitive impairment. Electroencephalogram recordings showed rhythmic theta waves with frontal predominance and non-convulsive status epilepticus (NCSE).
The ring chromosome 20 syndrome is characterized by childhood-onset refractory epilepsy continuing throughout adult life, mental disability, and behavioral disturbances which can originate before seizure onset. Ictal EEG reveals a unique pattern. Our findings indicate a possible link between the percentage of affected cells and the age of epilepsy onset.
The evolving electroclinical syndrome of "epilepsy with ring chromosome 20"
2012, Seizure
Citation Excerpt :
It was characterized as a specific genetic syndrome in 1976 by Borgaonkar and colleagues at Johns Hopkins University, following which over 60 cases of r(20) have been reported in the literature.5 Most cases are sporadic, only a few are familial.6–8 Recently, much attention has been drawn to this under reported genetic syndrome as one of the potential etiologies of cryptogenic epilepsy syndromes, although it has not hitherto been classified as a “genetic syndrome” causing epilepsy in the Indian League Against Epilepsy (ILAE) classification.
Ring chromosome 20 {r(20)} – manifests as a refractory epilepsy syndrome with complex partial seizures (CPS), nocturnal frontal lobe seizures and non-convulsive status epilepticus (NCSE) in the majority of cases. r(20) lacks a specific phenotypic expression or dysmorphic features. Psychomotor development may be normal, making the diagnosis difficult unless there is a high index of suspicion. This description of further cases is intended to improve recognition of this syndrome.
Karyotyping for r(20) was done in patients presenting with cryptogenic refractory epilepsy suggestive of r(20) from August 2008 to September 2010. We identified three patients with r(20) associated with refractory epilepsy. All were investigated with long-term video EEG. Their unique electro clinical features; epilepsy syndrome and outcome are discussed and compared to the available literature.
Karyotyping revealed ring 20 in 6–40% of lymphocytes. All manifested with seizures beginning at 2–10 years of age. All had CPS; two had NCSE and one a seizure disorder resembling Lennox–Gastaut syndrome. The interictal EEG showed epileptiform abnormalities predominantly over the frontotemporal regions. Two patients had NCSE with generalized, frontally dominant theta and spike and wave discharges. None had facial dysmorphism or imaging abnormalities. They remained resistant to antiepileptic drugs.
The use of routine karyotyping can easily pick up r(20); this information is especially useful in resource-poor countries. We have evolved an algorithm stating the indications to attempt r(20) karyotyping in a given patient in the light of the results of the present study and the existing literature.

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View full text

More severe epilepsy and cognitive impairment in the offspring of a mother with mosaicism for the ring 20 chromosome

Summary

Purpose

Results

Conclusion

Introduction

Section snippets

Methods

Clinical data

Discussion

Conclusion

Ann. Genet.

Electroencephalogr. Clin. Neurophysiol.

Brain Dev.

A ring-20 chromosome

J. Med. Genet.

Ring chromosome 20 epilepsy syndrome in children: electroclinical features

Neurology

Familial ring (20) chromosomal mosaicism

Hum. Genet.

PET evidence for a role of the basal ganglia in patients with ring chromosome 20 epilepsy

Neurology

A case of ring 20 chromosome with cardiac and renal anomalies

Aust. Paediatr. J.