Electroencephalographic findings in KBG syndrome ...

Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene Debopam Samanta & Erin Willis

Acta Neurologica Belgica ISSN 0300-9009 Acta Neurol Belg DOI 10.1007/s13760-014-0413-9

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Author's personal copy Acta Neurol Belg DOI 10.1007/s13760-014-0413-9

LETTER TO THE EDITOR

Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene Debopam Samanta • Erin Willis

Received: 28 November 2014 / Accepted: 13 December 2014 Ó Belgian Neurological Society 2014

Keywords KBG syndrome ANKRD11 mutation Epilepsy Characteristic EEG

Introduction KBG syndrome is characterized by intellectual impairment and various craniofacial, skeletal and other minor physical anomalies (Table 1) [1]. Recently, mutations in the ANKRD11 gene encoding ankyrin repeat domain 11, was found to be the genetic mutation associated with this syndrome. Neurologic involvement with developmental delay, seizures, EEG abnormalities and prominent neuropsychiatric features has been described. EEG abnormalities have been previously described as mostly nonspecific in the literature. We report a case of KBG syndrome with evolution of EEG findings over 6 years in a pediatric patient.

Patient description A 7-year-old boy was seen with developmental delay, epilepsy and behavioral concerns in the child neurology clinic. He had focal epilepsy with secondary generalization since 1 year of age. Seizures semiology consisted of episodes of unresponsiveness along with picking of his clothes for 1–2 min. He had frequent focal seizures but had enjoyed seizure-free state intermittently up to 9 months. He also had rare secondarily generalized tonic–

D. Samanta (&) E. Willis Division of Child Neurology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA e-mail: [email protected]

clonic seizures, less than one episode in a year. A brain MRI done at the age of 1 year was normal. EEG at the age of 3 years was normal but repeat EEG at age of 5 years revealed epileptiform discharges in the right centroparietal area (Fig. 1). Intermittent bisynchronous temporooccipital 3 cps rhythmic delta activity was also noted. He was initially placed on levetiracetam and dose was increased up to 40 mg/kg/day, but it was weaned off secondary to auditory hallucinations and suicidal ideations. Oxcarbazapine (36 mg/kg/day) and topiramate (6 mg/kg/day) were later added. He had seizure- remission with combination of these antiepileptic drugs but continued to have intermittent staring spells. Repeat EEG was performed at 7 years of age and revealed persistence of intermittent bisynchronous temporooccipital rhythmic delta activity though the right centroparietal discharges were not seen (Fig. 2). Episodes of staring spells were captured with no EEG changes suggesting inattentive spells. A genetics consultation was ordered due to his facial dysmorphism (round face, wide and arched eyebrows, thick eye lashes, macrodontia, synophrys, epicanthal fold, prominent upturned nose, relatively long philtrum and thin upper lip) and developmental delay. It was also noted that his biological father had similar facial features. Karyotype and genomic microarray were performed, but no abnormalities were found. Whole exome sequencing was done next and one pathogenic mutation (c. 4765C[T, p.Q1589X) was identified in the ankyrin repeat domain containing protein 11 gene (ANKRD11) which was confirmed by Sanger sequencing. This mutation results in a stop codon leading to truncation of ANKRD11 and potential loss of expression and/or function of the encoded protein, causing KGB syndrome. This particular mutation has never previously been reported to the best of our knowledge.

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Author's personal copy Acta Neurol Belg Table 1 Characteristic features of KBG syndrome Central nervous system

Mental retardation, seizures, abnormal EEG without seizures, hyperactivity, aggressive– compulsive behaviors, impaired social interaction, anxiety, ADHD

Growth

Short stature

Craniofacial anomalies

Brachycephaly, round face, broad eyebrows, hypertelorism, prominent ears, upturned nose, long hypoplastic philtrum, macrodontia,

Digital anomalies

5th finger clinodactyly

Skeletal anomalies

Accessory cervical ribs, abnormal vertebral shape, short tubular extremity bones, wormian bones, short femoral neck, unilateral hip dysplasia

Discussion Less than 50 cases of KBG syndrome have been reported. The name of the syndrome is based on the initials of the Fig. 1 Right centroparietal spike discharge

Fig. 2 Intermittent bisynchronous temporooccipital 3 cps rhythmic delta activity

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surname of the first 3 families (total 7 patients) reported in the literature. In the past, only clinical features have been used to make the diagnosis and it is likely that this disease has been an under-diagnosed cause of intellectual impairment and short stature. More recently, frequent use of whole exome sequencing has helped make a prompt diagnosis of this syndrome. Prominent EEG changes, seizures and developmental delay in KBG syndrome can be explained by the important role of ANKRD11 as a transcriptional regulator analogous to the MeCP2 gene involved in Rett syndrome by interacting with histonemodifying enzymes. It localizes to the nuclei of neurons and accumulates in discrete inclusions when neurons are depolarized (but has homogeneous diffuse distribution in the resting state) and plays a role in neural plasticity [2]. More than half of the reported patients have EEG abnormalities, but systematic and thorough descriptions of EEG abnormalities have not been reported. EEG abnormalities were mainly described as nonspecific or of

Author's personal copy Acta Neurol Belg

uncertain significance [3]. Other EEG findings such as high-voltage rhythmic slowing and unusually sharp wave discharges were also mentioned in some reports [4]. One report of video EEG recording in a patient during a complex partial seizure showed asymmetric rhythmic build-up of alpha activity over the midline [4]. Different type of seizures including ‘grand mal’, complex partial epilepsy and absence seizures had been described in the literature [4]. One patient with ‘transient pubertal seizures’ was also reported [4]. Transient childhood epilepsy is common in reported patients, but description of semiology and natural history of progression is scarce. Most adults with this syndrome are seizure free. In addition, in a few patients EEG abnormalities were seen without clinical epilepsy (Table 2). A systemic review of initial patients with this condition reported that 72 % of patients had EEG changes, yet only one-quarter of the patients were diagnosed with epilepsy. Unfortunately, description of exact EEG abnormalities or evolution of electrographic changes over the years was extremely limited in the literature. Our patient had significant changes in the EEG findings over 6 years when his EEG changed from normal activity to right-sided central spike wave activity and bisynchronous temporooccipital intermittent rhythmic delta activities followed by disappearance of spike activity yet persistence of intermittent rhythmic delta activities. Our patient also had clinical seizures in addition to his interictal abnormalities, though currently he is seizure free. Long-term follow-up will help us know if he remains seizure free. Our patient did not have any structural abnormalities of the central nervous system on MRI brain Table 2 Epilepsy and EEG changes described in the literature [3, 8, 9]

Twin A

Twin B

Total 7 patients

Seizures

EEG findings

Seizure from age 8 years, partial complex and absence seizure. Remission from partial complex seizure at age 9.5 years but continued to experience 1–2 absence seizures/month Similar onset from age 8 years with complex and absence seizures

At age 9, sharp waves of uncertain significance. At age 10, asymmetric rhythmic build-up of alpha activity over the midline with greater amplitude on left

Abnormal EEGs without clinical seizure activity

High-voltage rhythmic slow waves


Widespread convulsive activity with high-voltage paroxysmal slowing


Unusually sharp wave discharges

Transient pubertal seizure

EEG, not reported

and this is consistent with other reports of imaging in patients with this disorder. Previously diagnosis of KBG syndrome was based on clinical diagnosis and was considered to be an extremely rare disease. This syndrome is usually not associated with severe complications and diagnosis is likely delayed if made by the clinical observation of macrodontia which usually is not achieved before the age of 7–8 years when eruption of permanent central incisors occur [1]. However, neuropsychological assessment, growth velocity monitoring along with comprehensive audiologic and orthodontic evaluation is necessary to prevent long-term complications. As the majority of the patients with this syndrome have EEG abnormalities, further characterization of typical EEG abnormalities may help to diagnose patients sooner. Further reports of the EEG abnormalities seen with this syndrome can help to identify if characteristic EEG pattern exists in KGB syndrome. Known EEG patterns exist for other childhood genetic disorders such as Fragile X syndrome, Angelman syndrome and Rett syndrome, and can guide the physician in diagnosis. Transient interictal centrotemporal spikes seen our in our patient are quite similar to the interictal epileptiform activity of Fragile X syndrome where this abnormality is most often seen between the ages of 4 and 8 years [5]. Very prominent bisynchronous temporooccipital intermittent rhythmic delta activities were also seen in our patient. Intermittent rhythmic delta activities are usually present secondary to diffuse encephalopathy and occipital intermittent rhythmic delta activities (OIRDA) are relatively more frequent in children likely secondary to the caudal to rostral pattern of myelination in the maturing brain. However, OIRDA may represent an epileptiform finding, analogous to TIRDA in patients with temporal lobe epilepsies, in absence epilepsy and possibly other generalized epilepsies. It is unclear if the rhythmic delta activities in our patient represented epileptiform activities or a mere indication of diffuse central nervous system dysfunction. Characteristic rhythmic slow activities have been described in different genetic syndromes such as Rett syndrome where 4–6 cps rhythmic central vertex region theta activity is noted as well as Angelman syndrome with findings of diffuse, bilateral frontal dominant, high-amplitude notched or triphasic slow waves [6, 7]. This case report describes a rare disease along with detailed description and evolution of EEG findings. It also highlights the importance of detailed reporting of EEG findings to determine if a characteristic EEG abnormality present in this genetic syndrome like many other childhood genetic syndromes. The possible existence of characteristic EEG changes may help with earlier diagnosis as well as expedited completion of appropriate studies in this rare syndrome.

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Author's personal copy Acta Neurol Belg Acknowledgments The study was done at Arkansas Children’s Hospital, Little Rock, Arkansas. Conflict of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References 1. Brancati F, Sarkozy A, Dallapiccola B (2006) KBG syndrome. Orphanet J Rare Dis. 12(1):50 2. Maegawa GH, Leite JC, Felix TM, Da Silveira HL, Da Silveira HE (2004) Clinical variability in KBG syndrome: report of three unrelated families. Am J Med Genet Part A 131A:150–154 3. Skjei KL, Martin MM, Slavotinek AM (2007) KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria. Am J Med Genet A 143(3):292–300 4. Brancati F, D’Avanzo MG, Digilio MC et al (2004) KBG syndrome in a cohort of Italian patients. Am J Med Genet Part A 131A:144–149

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5. Musumeci SA, Hagerman RJ, Ferri R et al (1999) Epilepsy and EEG findings in males with fragile X syndrome. Epilepsia 40(8):1092–1099 6. Minassian BA, DeLorey TM, Olsen RW et al (1998) Angelman syndrome: correlations between epilepsy phenotypes and genotypes. Ann Neurol 43(4):485–493 7. Niedermeyer E, Naidu SB, Plate C (1997) Unusual EEG theta rhythms over central region in Rett syndrome: considerations of the underlying dysfunction. Clin Electroencephalogr 28(1):36–43 8. Sirmaci A, Spiliopoulos M, Brancati F et al (2011) Mutations in ANKRD11causeKBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet 89(2):289–294 9. Herrmann J, Pallister PD, Tiddy W, Opitz JM (1975) The KBGsyndrome: a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. BirthDefects Orig Artic Ser 11:7–18