CHROMOSOMAL ABNORMALITIES

Although many chromosomal abnormalities may be associated with epilepsy, some are important to recognize either because they have distinct seizure and EEG features or they are frequently seen in epilepsy populations. These are presented in this section of EpilepsyDiagnosis.org.

Karyotype assessment is important to consider in all epilepsies where the etiology is uncertain as dysmorphic features may be subtle or not apparent. Karyotype examination should be extended to 50-100 mitoses to exclude mosaicism. Karyotype examination may need to be supplemented by a FISH analysis with sub-telomeric region-specific probes or by a CGH microarray for the diagnosis of some chromosomal abnormalities. For some disorders, examination of cells other than blood lymphocytes may be required.

• 15q13.3 MICRODELETION SYNDROME
• 18q- SYNDROME
• INV-DUP (15) OR IDIC (15)
• DEL 1p36
• ANGELMAN SYNDROME
• DOWN SYNDROME (TRISOMY 21)
• KLINEFELTER SYNDROME (XXY)
• MILLER DIEKER SYNDROME (DEL 17p)
• PALLISTER KILLIAN SYNDROME (TETRASOMY 12p)
• RING 14 (r14) SYNDROME
• RING 20 (r20) SYNDROME
• TRISOMY 12p
• WOLF-HIRSCHHORN SYNDROME (DEL 4p)

15q13.3 MICRODELETION SYNDROME

This chromosomal abnormality is associated with intellectual impairment, developmental delay and epilepsy. Seizures of various types may occur, however these are typically generalized (myoclonic, absence and generalized tonic-clonic). Dysmorphic features may include everted lips, deep-set eyes, upslanting palpebral fissures, hypertelorism, synophris, prominent philtrum and hypotonic facies. A CGH microarray is usually the most useful diagnostic test.

18q- SYNDROME

This chromosomal abnormality is associated with intellectual impairment (moderate-severe), behavioral disorder, epilepsy and dysmorphic features including microcephaly, turricephaly, deep-set-eyes, broad nasal bridge, high arched or cleft palate, carp shaped mouth and small hands and feet. Cardiac defects may occur. Neuroimaging shows abnormal myelination, and may show cerebellar hypoplasia. Seizures are of early onset and seizures with focal autonomic seizures features are common (which may result in cardiac arrhythmia and apnoea). It is notable that this chromosome deletion may include the TCF4 gene, which is mutated in Pitt Hopkins Syndrome.

INV-DUP (15) OR IDIC (15)

This syndrome occurs when there is an inverted duplication of the proximal region of chromosome 15, typically including the unstable region 15q11-q13. A large duplication results in tetrasomy of 15p and partial tetrasomy of 15q. Maternal age at conception is a known risk factor. Patients usually have varying degrees of epilepsy, developmental delays, intellectual impairment, autistic spectrum disorders and minor dysmorphic features. Seizures can include epileptic spasms, and a range of other seizure types (both focal and generalized). This chromosomal abnormality is diagnosed on routine karyotype. FISH is used to confirm that the extra chromosomal material is from chromosome 15q or to establish the diagnosis in the event of an interstitial 15q duplication.

DEL 1p36

This chromosomal abnormality results in intellectual impairment (moderate to severe), epilepsy and multiple congenital abnormalities. Dysmorphic features include microcephaly, brachycephaly, large and late-closing anterior fontanelle, prominent forehead, straight (horizontal) eyebrows, deep-set eyes, short palpebral fissure, broad nasal bridge, midface hypoplasia, hypotonic facies, low-set abnormal ears, pointed chin and shortened hands and feet. Sensorineural hearing loss, skeletal, urogenital and cardiac defects may occur. Neuroimaging may show a range of structural brain abnormalities. Seizures occur in >50% of cases, typically starting in infancy or childhood with many types of seizures seen, including epileptic spasms, generalized and focal seizures. Seizures may cluster during febrile illness. Some patients may have early-infantile developmental and epileptic encephalopathy syndrome. Seizure control is usually not difficult to achieve. Routine karyotype assessment may not allow diagnosis of this syndrome, FISH analysis with sub-telomeric region-specific probes or CGH microarray are usually necessary.

ANGELMAN SYNDROME

Angelman syndrome results from deletion or inactivation of genes on the maternally-inherited chromosome 15q11-q13 region, while the paternal copy, which may be of normal sequence, is imprinted and therefore silenced. The patient has severe intellectual impairment, developmental delay, epilepsy, sleep disorder, jerky movements (especially hand-flapping), ataxia, frequent laughter or smiling, and usually a happy demeanor. Dysmorphic features are well recognized: microcephaly, prominent mandible, pointed chin, protruding tongue, and fair hair and complexion with blue eyes. Seizures are seen in up to 90% and usually start under the age of 2 years, commonly with generalized seizure types (generalized tonic-clonic, atypical absences, myoclonic seizures). Seizures may be aggravated by fever and by certain anti-seizure medications such as carbamazepine and lamotrigine. The EEG is usually very abnormal, and more abnormal than clinically expected. High amplitude 2-3Hz frontal predominant activity may be seen; symmetrical 4-6 Hz high voltage activity or 3-6 Hz occipital activity overlaid with spikes and sharp waves and associated with eye closure are other patterns that occur. A CGH microarray is usually the most useful diagnostic test.

DOWN SYNDROME (TRISOMY 21)

Down syndrome is a common chromosomal disorder with well-recognized dysmorphic features, epilepsy occurs in approximately 10% of individuals and age of seizure onset is bimodal with 40% having seizures before 1 year of age (commonly epileptic spasms) and 40% having seizures from the third decade of life. All major seizure types have been described in children with Down syndrome including focal seizures, epileptic spasms, myoclonic and generalized tonic-clonic seizures. Phenotypes seen may also include startle-induced seizures. Co-existing acquired structural brain abnormalities may occur, as a consequence of congenital cardiac disease.

KLINEFELTER SYNDROME (XXY)

Klinefelter's syndrome is a common sex chromosomal abnormality and the most common cause of male hypogonadism. This syndrome is characterized by cognitive and behavioral dysfunction and hypogonadism. Seizures usually start between 3 months and 3 years of age and are typically well controlled with anti-seizure medication. Variable electroclinical characteristics may be seen from patient to patient, however generalized seizures (absence, tonic-clonic) are common seizure types. This disorder is diagnosed on routine karyotype examination.

MILLER DIEKER SYNDROME (DEL 17p)

This clinical syndrome may arise from a microdeletion in chromosome 17p (17p13.3 microdeletion) or from other chromosomal abnormalities (e.g. translocations, ring chromosome, contiguous deletions) affecting 17p. The LIS1 gene is located on 17p and this syndrome includes the presence of classical (type 1) lissencephaly. The children have distinctive facial features with a short upturned nose, thickened upper lip with a thin vermillion upper border, frontal bossing, small jaw, low-set posteriorly rotated ears, sunken appearance in the middle of the face, widely spaced eyes, and hypertelorism. The forehead is prominent with bitemporal hollowing. Most (80%) of cases are sporadic, with 20% of cases inherited from an unaffected parent with a balanced translocation. Renal malformations and omphalocele have also been reported.

PALLISTER KILLIAN SYNDROME (TETRASOMY 12p)

This chromosomal abnormality results in dysmorphic features that include a coarsened flat facies, high forehead, reduced scalp hair over the frontal and temporal regions, hypertelorism, a broad nasal bridge, a small anteverted nose, a high arched palate, microretrognathia, a cupid-bow shaped upper lip and low-set ears. There may be cardiac, diaphragmatic and ocular abnormalities. There is developmental delay, severe intellectual impairment and epilepsy. Seizures of varied types have been reported, including epileptic spasms. The disorder is sporadic. Most patients are mosaic for tetrasomy 12p and it may be undetectable in blood lymphocytes. To diagnose this disorder, examination of fibroblasts may be required.

RING 14 (r14) SYNDROME

This is a rare chromosomal disorder, consistently associated with epilepsy. The epilepsy is usually of early onset and seizures are intractable but there are no recognized distinctive seizure or electrographic features. Focal seizures facilitated during febrile illness and early-infantile developmental and epileptic encephalopathy syndrome have been reported associated with this chromosomal abnormality. Intellectual impairment (moderate-severe), microcephaly, facial dysmorphism (narrow long face, retrognathia, short neck), cardiac (pulmonary stenosis) and ocular abnormalities (cataract, retinal pigmentation, macular abnormality) occur. Most cases are sporadic, but familial cases have been reported. Most patients are mosaic for ring 14 abnormality. To diagnose this disorder a karyotype should be performed examining 50-100 mitoses, this has to be specifically requested, as it may not be part of routine karyotype assessment. CGH microarray may not detect this disorder if no deletion occurs in the ring formation.

RING 20 (r20) SYNDROME

This is a rare chromosomal disorder with epilepsy as the striking feature. Although some patients may have microcephaly, intellectual impairment (two thirds of patients) and behavioral disorders, there are few distinctive clinical features that aid identification of this syndrome. Dysmorphic features are not expected. Most cases are sporadic, but familial cases have been reported. Mosaicism is common with intellectual impairment (but not the epilepsy) correlating with the degree of mosaicism. Nocturnal frontal lobe seizures are common. Around 50% of patients report frightening visual hallucinations during their focal seizures. Seizures may manifest as prolonged confusional states, lasting minutes to half an hour, during which the patient may be motionless and staring or may have automatisms and confused wandering. Perioral and eyelid myoclonic jerks may accompany these events. The ictal EEG shows long periods of widespread rhythmic theta and high-amplitude 2-3Hz rhythmic, notched, frontally predominant, slow waves. Interictal EEG may be normal or show focal bi-fronto-temporal spikes. Seizures are usually frequent and intractable to medications. To diagnose this disorder a karyotype should be performed examining 50-100 mitoses, this has to be specifically requested, as it may not be part of routine karyotype assessment. CGH microarray may not detect this disorder if no deletion occurs in the ring formation.

TRISOMY 12p

Trisomy 12p is a chromosomal abnormality that results in developmental delay, intellectual impairment and a number of dysmorphic features including turricephaly, a flattened occiput, short neck, rounded facies with prominent cheeks, high prominent forehead, hypertelorism, epicanthic folds, broad nasal bridge and other facial dysmorphism. Cardiac and limb defects may occur. Structural brain abnormalities include polymicrogyria and focal cortical dysplasia. Seizures are often generalized, with myoclonic absences and myoclonic seizures reported, EEGs have shown 3Hz generalized spike-wave.

WOLF-HIRSCHHORN SYNDROME (DEL 4p)

Wolf-Hirschhorn syndrome results from the partial deletion of the short arm of chromosome 4. The abnormality results in developmental delay, intellectual impairment (severe), hypotonia and epilepsy, and a number of dysmorphic features (microcephaly, micrognathia, short philtrum, epicanthic folds, high forehead, prominent glabella, ocular hypertelorism, dysplastic ears and peri-auricular tags). The nose may have a 'Greek helmet' appearance. There may also be congenital heart defects, hypospadias, colobomata of the iris, renal anomalies, cleft lip and/or palate and deafness. Immune disorders including common variable immunodeficiency and IgA deficiency may occur. Neuroimaging may show abnormalities of the corpus callosum or cerebellum, or other abnormality. Most cases are sporadic, with 10% inherited from a parent with a translocation. Seizures occur in the majority (>90%), typically starting in the first three years of life, with generalized tonic-clonic or hemiclonic seizures facilitated by fever (resulting in seizure clusters or status epilepticus) seen at that time. Epileptic spasms, atypical absences and focal seizures may also occur. EEG patterns of two types are recognized - diffuse, atypical slow sharp/spike-wave complexes in long bursts activated by slow wave sleep or high amplitude fast spike/polyspike-wave with posterior emphasis, triggered by eye closure. Seizures are usually well-controlled with monotherapy and improve with age. Routine karyotype assessment may not allow diagnosis of this syndrome, FISH analysis with sub-telomeric region-specific probes or CGH microarray are usually necessary.