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Keywords:

  • Angelman syndrome;
  • Rett syndrome;
  • EEG;
  • Genetics

Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES

Summary:  Purpose: To draw attention to the phenomenon that EEG characteristics of both Angelman syndrome (AS) and Rett syndrome (RS) can be found in the same patient, as evidenced by the description of one case. There are specific EEG patterns in AS patients, in which the most frequently occurring EEG characteristics are rhythmic triphasic 2- to 3-Hz, high-voltage (200–500 μV) activity, mixed with spikes or sharp waves, with a maximum over the frontal regions. EEG changes in RS patients are less specific and can show multifocal, mostly central or centrotemporal epileptiform discharges in combination with slow background activity.

Methods: A 6-year-old girl with RS and a proven MECP2 mutation was described.

Results: She had an EEG pattern at age 2 years comparable with the clinical diagnosis of RS, and an EEG at age 6 years comparable with an AS EEG.

Conclusions: We wish to draw attention to this phenomenon, although there is as yet no evident explanation for it. We advise MECP2 examination in AS patients of unknown genetic etiology whose EEG examinations are/were pathognomonic for AS to exclude RS.

Rett syndrome (RS), first described by Andreas Rett in 1966 (1), is a progressive encephalopathy that almost exclusively affects female subjects. It is characterized by normal development between the ages of 6 months and 2 years, followed by developmental regression. Severe mental retardation with autistic features, stereotyped purposeful hand movements, episodes of hyperventilation, epileptic seizures, and acquired microcephaly will develop (2). The prevalence is between one in 10,000 and one in 15,000 female births. The recurrence risk is low. Identification of a DNA methyl-binding protein gene, MECP2, as the cause of RS now allows mutation testing. Mutation sensitivity is currently ∼50%(3). EEG examinations in RS patients may show multifocal epileptiform discharges predominantly over the central and centrotemporal regions in both awake and sleeping conditions in combination with gradual slowing and flattening of the background activity (4,5). EEG abnormalities found in RS patients are age dependent and follow rather than precede the onset of the regression (6). The EEG abnormalities in RS are, however, quite aspecific and also may occur in a variety of other disorders (7).

Angelman syndrome (AS), first described by Harry Angelman in 1965 (8), is a genetic disorder characterized by severe mental retardation, absent speech, paroxysms of laughter, abnormal puppet-like gait, characteristic facial features, epileptic seizures, and EEG abnormalities. Prevalence is approximately one in 20,000 in the U.K. (9). The clinical diagnosis of AS can be confirmed by a variety of genetic mechanisms in ∼80% of cases. In the majority of patients, AS is due to a maternally inherited large deletion of chromosome 15q11-13 (60%). Paternal uniparental disomy of chromosome 15, an imprinting defect, or a mutation in the E3 ubiquitin protein ligase gene (UBE3A) account for 20%. Attempts to confirm the diagnosis fail in ∼20% of AS cases, and the recurrence risk varies from zero to 50% depending on the genetic cause. There are characteristic EEG patterns in AS patients, in which the most frequently occurring EEG characteristics are rhythmic 2- to 3-Hz triphasic, high-voltage (200–500 μV) activity, mixed with spikes or sharp waves with a maximum over the frontal regions (10). This specific pattern is seen in childhood and adulthood.

We describe a 6-year-old girl with RS and a proven MECP2 mutation; an earlier EEG examination apparently corresponded to the diagnosis RS, but within a few years, this pattern had changed to a typical AS EEG.

CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES

A six-year-old girl (Fig. 1) has been visiting our outpatient clinic since the age of 2 years. Her psychomotor development seemed to be normal until age 9 months, but then progress stagnated, and it became difficult to make contact with her. She developed stereotyped hand movements at age 18 months and experienced paroxysmal episodes of hyperventilation. She became severely retarded and was diagnosed as having RS at age 2 years. Pediatric rheuma was detected at age 3 years. Atonic seizures and atypical absence seizures also started at age 3 years, and it was decided to initiate treatment with valproic acid (VPA), which she tolerated well, resulting a seizure-free period for 1 year followed by a lower seizure frequency. At age 5 years, the diagnosis of RS was confirmed with a truncating mutation (nonsense mutation) in the MECP2 gene. At age 6 years, epileptic seizures deteriorated. She is now receiving treatment with a combination of VPA, clobazam (CLB), and lamotrigine (LTG), and her epileptic seizures are now under control. Magnetic resonance imaging (MRI) of the brain revealed no abnormalities. Metabolic examination of urine and plasma as well as chromosomal investigation produced normal results. Her first EEG, at age 2 years, showed slowing of background rhythms for her age and epileptiform activity in the central and temporal regions, more prominent during sleep. These EEG abnormalities are comparable with RS (Fig. 2). EEG examinations at age 6 years, in the awake state, revealed a diffuse disturbed EEG with almost continuous high-amplitude (375 μV) slow waves (2–3 Hz) mixed with triphasic waves and spikes with a maximum over the frontal regions, often found in AS patients (Fig. 3). There also was an independent focus of epileptiform activity over the right central area. A sleeping EEG showed bilateral discharges of high-amplitude (470 μV) slow waves mixed with spikes and triphasic waves preceded by short flattening periods (Fig. 3).

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Figure 1. A 6-year-old girl with Rett syndrome and a proven MECP2 mutation.

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Figure 2. EEG of Rett syndrome patient at age 2 years (awake and asleep).

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Figure 3. EEG of Rett syndrome patient at age 6 years with typical triphasic waves over the frontal regions (awake and asleep).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES

It may be difficult to reach a clinical diagnosis of RS and AS at a young age, as the classic features are not always apparent in infancy and may overlap, especially when there is no history of regression (10,11). EEG examinations can play an important role because specific EEG patterns have a high diagnostic value, especially in AS patients (12). It may be important to recognize these patterns because they can point the physician in the direction of these syndromes. Later, specific genetic examinations can be carried out [i.e., MECP2 examination in patients with suspected RS, and FISH (fluorescence in situ hybridization), chromosome analysis, methylation studies, or UBE3A mutation examination in AS patients]. Parents can be counseled that the recurrence risks in RS are low because most of these cases arise de novo, and the risk can vary from nearly zero to 50% in AS.

Our RS patient with a proven MECP2 mutation, however, demonstrates first an EEG comparable with RS and then, at age 6 years, an EEG that is often found in AS patients. Although, as far we are aware, this is the first RS patient to be described with this typical EEG pattern, we wish to draw attention to this phenomenon. Formerly we were reserved about performing an MECP2 mutation examination in AS patients with specific EEG characteristics, but now every AS patient with an unknown genetic etiology undergoes this test. Because there is a phenotypic overlap between AS and RS, the question arises: could the two conditions be etiologically related through a common pathogenesis (11)? One hypothesis is that UBE3A is one of the target genes downstream from MECP2 for which alteration of expression is particularly critical. Further investigation of this hypothesis may also explain an overlapping EEG pattern. It will be necessary to carry out further EEG examinations of AS and RS patients, especially at a young age, and to analyze clinical characteristics of both syndromes.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES
  • 1
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  • 2
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