Many chromosomal anomalies are associated with childhood-onset epilepsy with distinctive features. Accurate electroclinical delineation helps identify chromosomal anomalies in infants classified with cryptogenic epilepsy. Chromosomal disorders carry distinct risks of recurrence making accurate classification important for proper genetic counseling.

Chromosome anomalies may result from abnormalities in number or structure. Abnormalities of chromosome number include polyploidy and autosomal and sex chromosome aneuploidy. Aneuploidy refers primarily to “monosomy” (the presence of only one copy of a chromosome in an otherwise diploid cell) and “trisomy” (three copies of a chromosome). Abnormalities of chromosome structure consist primarily of translocations (interchange of genetic material between nonhomologous chromosomes); deletions (caused by a chromosome break and subsequent loss of genetic material); and duplications (i.e., partial trisomy of genetic material).¹ The classic belief that karyotype is sufficient to rule-out chromosomal anomalies applies only to chromosomal anomalies related to number. Structural anomalies do not fit this scenario and often require more detailed investigation. Therefore, for some syndromes, it is important to first recognize the disorder clinically in order to facilitate correct genetic testing.

This chapter summarizes some of the relevant aspects of epilepsy, electroencephalography (EEG) and genetic data that may guide the identification of chromosomal disorders in early postnatal life, when the phenotype does not confer the diagnosis.

1p36 DELETION

The 1p36 deletion syndrome is a disorder with multiple congenital anomalies and mental retardation characterized by growth delay, epilepsy, congenital heart defects, a characteristic facial appearance, and precocious puberty^2,3 (Fig. 34–1).

Monosomy 1p36 is a contiguous gene syndrome considered to be the most common subtelomeric microdeletion syndrome, with an estimated prevalence is 1–5.000. 1p36 deletions account for 0.5%–1.2% of idiopathic mental retardation.³

CLINICAL DIAGNOSIS

PHENOTYPE

The most common features include suggestive facial traits (epicanthus, straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin), microbrachycepahly, large late-closing anterior fontanelle, posteriorly rotated low-set abnormal ears (Fig. 34–2). In addition, motor-delay hypotonia, moderate to severe mental retardation, growth delay, sensorineural deafness, and eye/visual abnormalities with visual inattentiveness, epilepsy, brachy/camptodactyly, and/or short fifth finger(s) are also observed. The majority of patients have heart defects, and some present with a rare congenital cardiomyopathy that results from failure of myocardial development during embryogenesis (noncompaction cardiomyopathy). Associated malformations include central nervous system (CNS) and skeletal and renal abnormalities and abnormal genitalia, Affected patients have abusive behavior, hypotonia, and developmental delay with poor or absent speech.^3,4,5,6,7

ELECTROCLINICAL FEATURES

Epilepsy occurs in approximately 50%–75% of patients.^2,3,5,8 Seizures begin in infancy or early childhood (mean age of 3 months) with tonic, tonic–clonic, myoclonic, and partial motor seizures. At a mean age of 5 months, seizures may evolve into infantile spasms (IS) (40%–45%) with a hypsarrhythmic pattern.⁵

Epilepsy evolves with a wide variety of seizure types, including tonic–clonic seizures, IS, partial seizures—complex and simple—and myoclonic and atypical absence seizures.⁹

Epilepsy presents two patterns of clinical outcome: (1) patients experience few seizures in infancy and (2) have a normal electroencephalogram. After transient therapy with antiepileptic drugs, there are no seizure recurrences until after the age of 1 year. Patients may also experience more severe epilepsy starting in early life with an abnormal EEG and difficult-to-control epilepsy.

DIAGNOSIS

Monosomy 1p36 may result from terminal deletions or interstitial deletions at various sizes and different breakpoints¹⁰ on chromosome 1 or more complex rearrangements.¹¹ Conventional cytogenetic studies may not detect all rearrangements, particularly ones on derivative chromosomes. To date, the parental origin of this anomaly is controversial.^10,11 Standard cytogenetics, fluorescence in situ hybridization (FISH) of the subtelomeric regions or array comparative genomic hybridization are used for diagnosis.

TREATMENT

Early treatment of IS is mandatory for better clinical outcome.³ According to Bahi–Boulisson,⁵ spasms with or without hypsarrhytmia (West syndrome) may be refractory to vigabatrin but respond well to corticosteroids. The epilepsy may evolve toward different types of seizures. Treatment is related to seizure type, although medically refractory epilepsy is common.^3,9

GENOTYPE–PHENOTYPE CORRELATION

Although haploinsufficiency of the potassium channel beta-subunit (KCNAB2) is thought to be responsible for intractable seizures in some cases of 1p36-deletion syndrome,¹² this was not found in 3 of 11 patients by by Kurosawa et al.⁸ Therefore, further investigation of the 1p36 region may be necessary to allow identification of the genes responsible for the 1p36-deletion syndrome.

4p DELETION: WOLF–HIRSCHHORN SYNDROME AND PITT–ROGER–DANKS SYNDROME

Wolf–Hirschhorn syndrome (WHS) is characterized by severe growth retardation and mental defect, microcephaly, “Greek helmet” facies, and closure defects (cleft lip or palate, coloboma of the eye, and cardiac septal defects).

Molecular analysis reveals that the Wolf–Hirschhorn and Pitt–Roger–Dank syndromes which were, previously regarded to be distinct clinical entities, result from the absence of similar, if not identical, genetic segments and the observed clinical differences likely result from allelic variation in the remaining homolog.¹³

4p deletion is an uncommon disorder with an estimated incidence of 1 per 50,000–20,000 births and a sex ratio of 2 females to 1 male.^1,14,15,16

CLINICAL DIAGNOSIS

PHENOTYPE

Cases of the 4p-deletion syndrome may be subdivided into “classical” and “mild” forms. Only the minimal diagnostic criteria are expressed in milder cases. The minimal diagnostic criteria are: severe mental retardation; hypotonia; marked growth retardation and failure to thrive; epilepsy; and microcephaly with Greek warrior helmet face (Fig. 34–3)¹⁷ In the classical cases, systemic manifestations such as closure defects (cleft lip or palate, coloboma of the eye, and cardiac septal defects) occur.¹⁷ Epilepsy in this disorder often has a favorable prognosis and a good outcome is a frequent finding; prenatal onset growth deficiency followed by short stature and slow weight gain, skeletal anomalies, heart lesions, abnormal tooth development, and hearing loss are common findings in classical cases. Structural CNS anomalies occur in 80%. Global developmental delay of varying degrees is present in all patients, although almost 50% will walk either alone or with support. Hypotonia is a feature in virtually all patients.¹⁸

EPILEPSY

The existence of a characteristic electroclinical profile in 4p- is recognized clinically and the high frequency of generalized epilepsy is a prominent feature. Epilepsy represents a major clinical challenge in WHS patients but may have a good prognosis.

Prevalence

There is a high frequency of epilepsy in this syndrome, ranging from 80%–90%.¹⁸ For this reason, epilepsy is as an important criterion for clinical diagnosis and may be especially helpful in cases with a milder phenotype.

Age of Onset

Seizures typically begin within the first 3 years of life.^18,19 The age of onset ranges from 5 to 23 months, with a peak incidence from 9 to 10 months.²⁰ Neonatal onset is rare but may occur in patients with larger deletions.^18,20 Generalized seizures are most frequent at onset. Partial motor seizures (unilateral clonic or tonic), with or without secondary generalization, are also common at onset. The first seizure may be triggered by fever¹⁹ which may evolve to status epilepticus (SE). Tonic spasms, complex partial seizures,¹⁸ and myoclonic seizures, evolving to SE are less frequent.²¹

Seizure Types

There is a wide range of seizure types in the 4p-syndrome including: generalized tonic–clonic seizures (GTC) seizures, tonic spasms, myoclonic seizures, atypical absences variably associated with eyelid myoclonia, eye deviation and perioral jerks, partial motor seizures, and complex partial seizures.^9,18,21,22

Generalized epilepsy is more frequent,^18,19,23,24 with myoclonic, atypical absences, and GTC being the most frequently encountered.^19,20 Atypical absences tend to occur after the first year of life and may be accompanied by a myoclonic component involving the eyelids and hands.¹⁸ Partial motor seizures or “unilateral convulsive seizures” are also frequent.^19,25 An association between convulsive (generalized or unilateral) seizures, atypical absences, and segmental myoclonic seizures has also been described.^18,25

Status Epilepticus and Epilepsy Aggravated by Fever

Two distinguishing features of this syndrome are (1) the presence of epilepsy aggravated by fever and SE and (2) their frequent recurrence in some patients.^9,20,23,26 Status epilepticus may occur in 40% of patients, occasionally facilitated by fever and tending to disappear by ages 3–8 years. In early life, SE occurs despite adequate treatment.¹⁸ All seizure types may occur during episodes of SE and the recognition of nonconvulsive episodes is often challenging. A predominance of myoclonic SE has been reported.¹⁹ Myoclonic and atypical absence SE may persist for days or weeks accompanied by impairment of consciousness and remained underdiagnosed.

SE may be associated with hemiparesis or death.²¹ The use of sodium bromide is particularly effective for preventing SE. The mean age of last SE in patients receiving sodium bromide was significantly younger than that in those not treated with sodium bromide.

Fever or even moderate temperatures may trigger the first seizure Furthermore, seizure worsening during febrile episodes is frequent and may lead to SE. These events may be recurrent in some patients.^19,20,26

Evolution of Epilepsy

The first year of life is typically characterized by generalized or unilateral motor seizures. Subsequently, absence seizures accompanied by eyelid myoclonia appear between ages 1 and 5 years.^16,19,20 Epilepsy often remits after a period of daily disabling seizures during early childhood. Therefore, the prognosis of epilepsy is favorable for both seizure control and evolution despite the initial course.^20,23

EEG FEATURES

The EEG in the 4p-syndrome may demonstrate several characteristic findings, especially during childhood (Fig. 34–4).²⁰ Features frequently reportedinclude:

1. 
   

   Presence of sharp-wave transients superimposed on a background of diffuse, high-voltage 3- to 4-Hz slow-wave discharges^22,27 (Fig. 34–5A).

   
   
2. 
   

   Posterior discharges characterized by high amplitude sharp theta activity in the posterior head regions or repetitive spikes²² (Fig. 34–5B).

These patterns share some similarity with the EEG patterns observed in patients with Angelman syndrome (AS).

GENETIC TESTING

The 4p-depletion syndrome is associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3) (Table 34–1). It is unclear whether a single locus is involved in the phenotype. One locus that may contribute to the phenotypic features of WHS and the allelic and milder Pitt–Rogers–Danks syndrome is the WHS candidate-1 gene (WHSC1).²⁸ There is evidence that the HOX7 gene may be involved in determining the WHS phenotype. Wright et al (1999) characterized a novel gene in the 165-kb critical region in 4p16.3, which they designated WHS candidate-2 (WHSC2). It is considered a contiguous gene syndrome, since no single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype.²⁹

De novo deletions occur in 8% of patients (preferentially paternally derived) and in 13% of cases are secondary to familial translocation (often maternally derived). The size of the deletion varies from cytogenetically visible deletions to undetectable cytogenetic deletions. The diagnosis is based on standard cytogenetics in approximately 50%. FISH can be used to detect deletions of 4p16.3, the critical region for the phenotype.³⁰

The testing strategy to confirm the clinical diagnosis requires (www.ncbi.nlm.nih.gov):

1. 
   

   Conventional cytogenetic studies to detect large deletions and more complex cytogenetic rearrangements (ring chromosome, unbalanced chromosome translocations).

   
   
2. 
   

   FISH analysis to detect smaller deletions involving the WHSCR.

   
   
3. 
   

   Genome-wide chromosomal microarray analysis to detect deletions involving the WHSCR or imbalances resulting from more complex arrangements associated with 4p16.3 deletion (unbalanced translocations).

Early diagnosis and treatment of atypical absences and myoclonic seizures is mandatory. In general, seizures in patients with the 4p-syndrome are not refractory and seizure control is possible with sodium valproate and phenobarbital.^18,23 Ethosuximide is also reportedly effective.¹⁸ Benzodiazepines may be used as add-on therapy.²³

There is a strong genotype–phenotype correlation in 4p syndrome.^16,17,31,32 The characteristic facial phenotype is less pronounced in patients with a smaller deletion, and microcephaly is not observed in patients with certain cryptic unbalanced translocations.¹⁶ Therefore, there is also a correlation between deletion size and severity of epilepsy. Global improvement occurs over time.¹⁸

The mortality rate for patients with the 4p-syndrome correlates with deletion size and overall risk of death in de novo deletion cases. Approximately 35% of patients die during the first 2 years of life, and survival into adulthood is rare. Shannon et al³³ studied 159 cases of WHS and estimated a minimum birth incidence of 1 in 95,896. The crude infant mortality rate was 23 of 132 (17%), and in the first 2 years of life the mortality rate was 28 of 132 (21%).

ANGELMAN SYNDROME

AS is a neurogenetic disorder with multiple genetic mechanisms involving the maternal chromosome 15q11–1q13. Estimates of the prevalence of AS range from 1:10,000 to 1.2000^34,35,36,37 and is similar to Rett syndrome (1.12.000), suggesting that AS remains underdiagnosed.

PHENOTYPE

AS is characterized by severe mental retardation, speech disorder, stereotyped jerky movements, and a peculiar behavioral profile characterized by a happy disposition and outbursts of laughter. Eighty to ninety percent of patients manifest epilepsy and abnormal electroencephalographic patterns which may be used as diagnostic criteria, and become important when the phenotype is not suggestive enough, as in infants. Other features such as hyperactivity, hypopigmentation, ataxia, sleep disorder, and peculiar facial traits (macrostomia, wide-spaced teeth, prognathism, and macrognathism) have variable occurrence, ranging from 20% to 80%.^38,39,40

EPILEPSY

Prevalence

Epilepsy in AS patients ranges from 80%³⁹ to 90%.⁴¹ There is evidence that different genetic groups may present different profiles, with distinct degrees of severity, and that a more severe form of epilepsy occurs in patients with the deletion.⁴¹ Patients with the deletion have a higher prevalence, estimated at close to 100%.^41,42,43

Although less frequently documented and reported, there are variations regarding prevalence and seizure type. The prevalence ranges from 36.1%⁴² to 75%⁴⁴ and is even higher when analyzing patients with the deletion (84.2%).⁴³

Age of Onset

One of the most important aspects of AS is the late onset of the clinical phenotype, especially the diagnostic facial traits. However, in these developmentally delayed infants, epilepsy has an early onset,^{42,43,45,46,47} preceding the clinical diagnosis in most patients, and may anticipate the diagnosis in children with developmental delay and early “cryptogenic” epilepsy. Epilepsy with a later onset (age 5) are encountered rarely.⁴² Atypical absences and myoclonic seizures are the most frequent seizure types at onset.^42,43,45

Seizure Types

Major seizure types include atypical absence, myoclonic, and GTC.^42,43

All seizure types have been reported in AS but generalized seizures, especially atypical absences^42,43,45 and myoclonic seizures predominate.^46,48 Atypical absences and subtle myoclonic seizures are the most frequent seizure types documented by video-EEG (V-EEG), but not by parents who mostly report motor phenomena.⁴³ Atypical absences and myoclonic seizures may be prolonged events lasting weeks or months, reported as periods of decreased contact with the environment.⁴⁵

Viani et al⁴⁹ reported complex partial seizures of occipital lobe origin as a frequent event, an observation not corroborated by others.^25,28,29 IS is reported rarely in AS.^45,49 Other less frequently reported seizure types are atonic, myoclonic absence, hemigeneralized, and partial.^41,44 It is possible that the frequency of myoclonic seizures, atypical absences, or even pure atonic seizures may be higher in AS patients.

Status Epilepticus and Epilepsy Aggravated by Fever

Seizure worsening during fever is as frequent as 52.6%^42,43,49 a high rate in comparison to age-matched controls. In some cases, fever triggers the first seizure^43,49 and may occur even with moderate temperatures.^43,48

The higher incidence of SE in this syndrome may be related to the use of V-EEG monitoring to detect nonconvulsive status. By the same token, myoclonic status is higher in studies utilizing polygraphic recordings and back-averaging techniques.^46,48,49

Evolution of Epilepsy

Patients with AS often evolve into a milder course of epilepsy with increasing age or less commonly achieve complete control.^42,43,48 Severity typically occurs during early life^42,43 and may improve during late childhood and puberty^44,46,50 or adulthood.⁵¹

There is little information on epilepsy in adults with AS. Atypical absences and myoclonic seizures may persist into adulthood.^41,51 Therefore, despite improvement in epilepsy severity, complete seizure control is obtained in approximately 30% of all patients.⁴³

The diagnosis of AS is based on phenotype, electroclinical profile and genetic data. The electroclinical profile may represent the only clue to diagnosis since the clinical phenotype is not relevant in early ages.

EEG PATTERNS

Suggestive EEG patterns were reported in AS^52,53 regarding morphology, burst duration, occurrence, frequency, amplitude, and distribution:

1. 
   

   Delta patterns: Runs of generalized, rhythmic delta activity, usually with frontal emphasis, and of high amplitude, sometimes associated with epileptiform discharges (often more than 300 mV) (Fig. 34–6A).

   
   
2. 
   

   Theta patterns: High amplitude (about 200 mV), 4–6 Hz activity, generalized or over the posterior head regions, noted throughout the tracing (Fig. 34–6B).

   
   
3. 
   

   Posterior discharges: Spike- and sharp-waves mixed with high amplitude 3–4 Hz activity over the posterior regions. These discharges are sometimes asymmetrical and occasionally triggered by passive eye closure (Fig. 34–6C).

The existence of a particular EEG profile, not a common finding in chromosomal disorders, is important to rule-out mimicking conditions such as Rett syndrome, alpha-thalassemia retardation syndrome (ATR-X), and Gurrieri syndrome. Symptom complexes include cerebral palsy, static encephalopathy, Lennox–Gastaut syndrome, autism spectrum disorder, pervasive developmental disorder, and mitochondrial disorders.⁵⁴