Status epilepticus in a patient with fragile X syndrome: electro-clinical features and peri-ictal neuroimaging.

Fragile X syndrome (Fra-X) is a common cause of mental retardation that can be associated with partial epilepsy characterized by a variety of electro-clinical features. A wide spectrum of interictal activities are reported, although no data regarding ictal EEG activity have as yet been published. Drug-resistant seizures are uncommon, and the occurrence of clustering seizures or status epilepticus has only been reported anecdotally. We describe a Fra-X patient with refractory partial epilepsy related to a malformation of cortical development who experienced a partial status epilepticus that was well documented by video-EEG and MRI. We report the electro-clinical features and peri-ictal neuroimaging data.     

Neurological findings in patients with the fragile-X syndrome.

We report two brothers with previously unexplained mental retardation and seizures who had dysmorphic facial features, macro-orchidism, and a fragile site at the X chromosome. This recently described syndrome is the second most common chromosome aberration associated with mental retardation after Down's syndrome. In order to determine the prevalence of seizures and the frequency of specific neurological features, we studied a total of 17 patients with the fragile X syndrome. 41% had grand mal seizures; 41% had extensor plantar responses; 47% had hyperactive behaviour and 65% exhibited stereotypics; 59% had incoordination and 35% had blepharospasm. We emphasise the need for chromosome analysis of patients with unexplained mental retardation, specific phenotypic abnormalities, and large testes.     

Homicidality in a woman with a 47,XXX karyotype

The 47,XXX karyotype is a rare sex chromosome anomaly. A female with this karyotype is called a triple X or superfemale. This karyotype is usually not associated with a characteristic mental or physical phenotype. A 19-year-old female who committed homicide and was found to have a 47,XXX karyotype is described, and the possible correlation between sex chromosome anomalies and psychopathology or criminality is discussed.     

Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene.

Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy.     

Electroencephalographic and epileptic patterns in X chromosome anomalies.

Although epilepsy and mental retardation are commonly observed in individuals with chromosomal aberrations, the identification of EEG/epileptic profiles in those with specific chromosome anomalies remains difficult. A few syndromes seem to show peculiar clinical and EEG associations. The authors report an electroclinical investigation on a group of patients carrying X chromosome anomalies: 16 patients with Turner's syndrome, 17 with Klinefelter's syndrome, 1 with an X-autosomal rearrangement, 2 with Xq isochromosome [Xq(i)], and 7 with triple X syndrome. Epilepsy and/or EEG anomalies were found in three of the patients with Klinefelter's syndrome, in one patient with an X-autosomal rearrangement, and in five of those with triple X syndrome. No epilepsy or EEG anomalies were detected in the other patients. Epilepsy may be associated with Klinefelter's syndrome. In addition, the authors found that an electroclinical pattern, represented by paroxysmal activity in the posterior regions (temporo-parieto-occipital areas) with complex partial seizures and easily controlled by antiepileptic drugs, may be present in patients with triple X syndrome. In contrast, gross X-autosomal rearrangements are associated with polymorphic EEG/epileptic findings. Although further studies are needed to validate these observations, they clearly confirm the strict relationship between X chromosome anomalies and epilepsy.     

Symptomatic generalized epilepsy associated with an inverted duplication of chromosome 15.

An inverted duplication of chromosome 15 (inv dup[15] chromosome) is the most common supernumerary marker chromosome in humans. Inv dup(15) chromosomes are commonly associated with mental retardation, epilepsy, behavioral problems and structural malformations. Though epilepsies associated with inv dup(15) chromosomes are often intractable, there have been very few reports regarding the seizure manifestations or types. We report a patient with severe mental retardation and intractable epilepsy, associated with an inv dup(15) chromosome. The seizures recorded with EEG-VTR monitoring were axial and generalized tonic seizures, and our case was diagnosed as symptomatic generalized epilepsy. Molecular and cytogenetic analysis showed an inv dup(15) chromosome containing the Prader-Willi syndrome/Angelman syndrome region mapped within bands 15q 11-q13.     

Epilepsy in fragile X syndrome

Epilepsy is reported to occur in 10 to 20% of individuals with fragile X syndrome (FXS). A frequent seizure/EEG pattern in FXS appears to resemble that of benign focal epilepsy of childhood (BFEC, benign rolandic epilepsy). To evaluate seizure frequency and type in a Chicago FXS cohort, data regarding potential seizure history were reviewed for 136 individuals with FXS (age range 2 to 51 years: 113 males and 23 females). Seizures occurred in 15 males (13.3%) and one female (4.8%): of these, 12 had partial seizures. EEG findings were available for 35 individuals (13 of 16 with seizures and 22 of 120 without seizures) and showed an epileptiform abnormality in 10 (77%) individuals with seizures and five (23%) individuals without seizures--the most common epileptiform pattern being centrotemporal spikes. Seizures were easily controlled in 14 of the 16 individuals with seizures. Many individuals, including all with centrotemporal spikes, had remission of seizures in childhood. The most common seizure syndrome resembled BFEC and this pattern had the best prognosis for epilepsy remission. Deficiency of FMRP (fragile X mental retardation protein) appears to lead to increased neuronal excitability and susceptibility to epilepsy, but particularly seems to facilitate mechanisms leading to the BFEC pattern.     

Sex differences in brain expression of X- and Y-linked genes

The X chromosome plays an important role in brain development and function, as evidenced by its disproportionately high content of genes whose mutations cause mental retardation. These X-linked brain genes may play a role in sexual differentiation if they are expressed at a higher level in XX females than in XY males, due to incomplete X inactivation in females. The expression of several X escapee genes is indeed higher in brain tissues from females when compared to males. In mouse, some of the sex differences are only found in adult brains but not in other tissues. Determining the brain expression pattern of these X escapee genes is important for a better understanding of their role in the neurological phenotypes of XO Turner syndrome.     

Fragile X syndrome: associated neurological abnormalities and developmental disabilities

The fragile X syndrome is a frequent cause of developmental disabilities. It is associated primarily with nonprogressive X-linked mental retardation. The neurodevelopmental abnormalities of 25 males and 3 females are described. Mental retardation was mild in 4, moderate in 11, severe in 6, and profound in 2 patients, while 4 patients had only learning disabilities. The presence or absence of a developmental disability could not be determined in the youngest (8 months). Seven patients had had infantile autism and 7 had epilepsy. Generally no major focal neurological abnormalities were observed but most of the patients exhibited minor signs. The severity of developmental disabilities in our patients varied between and within families and between genders. All adult males had macroorchidism. Unusual facial features were present in 13 males but none were seen in the females. Familial occurrences were found in 18 cases (64%); 10 cases (36%) were sporadic. Overall, males were more severely affected than females. Diagnostic tests including computed tomographic scans, electroencephalograms, and evoked potentials did not disclose any specific abnormalities.     

A de novo 11p12-p15.4 duplication in a patient with pharmacoresistant epilepsy,mental retardation,and dysmorphisms

We report a 22-year-old male patient with pharmacoresistant epilepsy, mental retardation and dysmorphisms. Standard cytogenetic analysis revealed a de novo interstitial duplication of the short arm of chromosome 11 (11p). High density array-CGH analysis showed that the rearrangement spans about 35 Mb on chromosome 11p12-p15.4. Duplications of 11p are rare and usually involve the distal part of the chromosome arm (11p15), being not associated with epilepsy, whereas our patient showed a unique epileptic phenotype associated with mental retardation and dysmorphic features. The role of some rearranged genes in epilepsy pathogenesis in this patient is also discussed.     

Female-to-male transsexual with 47,XXX karyotype.

BACKGROUND: There are few reports describing chromosomal abnormalities in transsexuals. In rare cases, transsexualism and sexual chromosomal multiplicity coexist. Six cases of male-to-female transsexuals with 47,XYY chromosomal pattern have been previously reported. We have not encountered any female transsexual cases with 47,XXX karyotype in the literature. METHODS: A 21-year-old female patient came to our outpatient department with depressive symptoms and suicidal thoughts. On psychiatric interview, she reported that she had feelings of discomfort with her gender identity and had desired to be male since her childhood. Then, we performed cytogenetic investigation using blood culture and G chromosome banding. RESULTS: Histology and DNA histograms of the patient revealed a chromosomal pattern of 47,XXX. CONCLUSIONS: We conclude that sexual chromosomal abnormalities in some transsexuals may cause a vulnerability to development of a gender identity disorder.     

Epilepsy and polymicrogyria in Kabuki make-up (Niikawa-Kuroki) syndrome.

Kabuki make-up syndrome is a rare dysmorphogenic disorder characterized by peculiar facial appearance (resembling the make-up of actors in Kabuki, the traditional Japanese theatre), skeletal anomalies, dermatoglyphic abnormalities, postnatal growth deficiency, and mental retardation. Central nervous system dysfunctions, other than mental retardation, are rarely reported; they include microcephaly, brachycephaly, early hypotonia, feeding disorders, subatrophy of the optic nerves, subarachnoid cyst, cerebellar and brainstem atrophy, and epilepsy. These manifestations appear to be more common in non-Japanese patients. Reported is an Italian child with phenotypical appearance of Kabuki make-up syndrome and partial epilepsy who demonstrated polymicrogyria on neuroimaging. This article is the first report of a gyration disorder in Kabuki make-up syndrome. The relationship between epilepsy and polymicrogyria in this patient is discussed.     

Epilepsy and electroencephalographic findings in pericentric inversion of chromosome 12

Epilepsy, together with mental retardation, represents a common manifestation of chromosomal aberrations. Specific electroencephalographic (EEG) and epileptic patterns have been described in several chromosomal disorders, such as Angelman's syndrome, Miller-Dieker syndrome, Wolf-Hirschhorn syndrome, and ring 20 syndrome. A peculiar electroclinical pattern has also been identified in trisomy 12p syndrome. We report three patients with a pericentric inversion of chromosome 12, with breakpoints localized to p11-q13 and affected by epilepsy or EEG anomalies. Two suffered from epilepsy, which, in the clinical course, was mainly characterized by complex partial seizures with a semiology related to the temporal lobe. In one patient, myoclonic absences, head drop, and massive jerky attacks were also present. In both patients, generalized 3 Hz bursts were registered, together with multifocal and focal paroxysmal activity, which were most prominent in the temporoparietal and temporal areas, respectively. In the other patient, who had no epilepsy, EEG showed bioccipital paroxysmal activity. In all patients, the clinical picture was characterized by the presence of moderate mental retardation and behavioral disorders. The incidence of epilepsy or EEG anomalies among patients with a pericentric inversion of chromosome 12 remains to be ascertained. However, the present study confirms that chromosome 12 anomalies can be associated with epilepsy. Although myoclonic absence-like episodes can occasionally be part of the epileptic phenotype, the electroclinical pattern in pericentric inversion of chromosome 12 seems to be more polymorphic when compared with that observed in trisomy 12p syndrome.     

Occipital encephalocele and epilepsy]

We report the incidence of epilepsy in 7 patients with occipital encephalocele (meningocele: 6 cases, meningoencephalocystocele: 1 case). Two cases had epilepsy and a case without the history of epileptic seizure had an epileptic pattern on the EEG. All these 3 cases had cortical dysplasia(CD) such as schizencephaly and subcortical gray matter, and two of them were associated with mental retardation. The location of the prominent CD was correlated with the EEG abnormalities and clinical epileptic pattern in each case. Associated hydrocephalus and placement of VP shunt had no significant influence on the occurrence of the epilepsy. Thus, complicated CD is thought to be epileptogenic in patients with occipital encephalocele.     

Epilepsy in chromosomal abnormalities: an Italian sample

Epilepsy is common in chromosomal abnormalities, but systematic studies are scanty. We describe an Italian sample of patients with chromosomopathies to establish epilepsy occurrence and clinical electroencephalographic (EEG) features. Forty-five patients with different types of chromosomal abnormalities were analyzed to examine different variables in patients with epilepsy (group 1) and without (group 2) and to compare the types of epilepsy in our cases with respect to a nonselected sample of Italian people with epilepsy. Epilepsy occurred in 51.1% (group 1) of cases and prevailed in autosomal abnormalities but without a statistical significance (P > .05). There was a prevalence of EEG paroxysmal abnormalities in group 1 (P < .0001); continuous spike-waves during sleep were observed in three cases. Profound mental retardation prevailed in group 1 (P < .001) and mild mental retardation in group 2 (P < .05). Generalized epilepsies prevailed significantly (P < .00001). A high-resolution karyotype should be undertaken in all patients with epilepsy presenting with mental retardation when an obvious etiology is not available.     

Choroid plexus hyperplasia and monosomy 1p36: report of new findings

Monosomy 1p36 is a newly delineated multiple congenital anomalies/mental retardation syndrome characterized by mental retardation, growth delay, epilepsy, congenital heart defects, characteristic facial appearance, and precocious puberty. It is now considered to be one of the most common subtelomeric micro-deletion syndromes. This article reports new findings of choroid plexus hyperplasia and dextrocardia with situs solitus in a patient who had deletion of chromosome 1p26.33 with a brief review of the literature.     

The clinical spectrum of focal cortical dysplasia and epilepsy

Focal cortical dysplasia is an important pathologic substrate in patients with epilepsy, but its clinical spectrum has not yet been completely defined. We retrospectively studied 30 epilepsy surgery patients with focal abnormalities of neuronal migration as the only histopathologic finding in resected tissue. Patients comprised two clinical groups. Seventeen patients with extratemporal epilepsy had early (median age, 7.0 years) extratemporal resection or hemispherectomy for severe epilepsy (47% of patients with > 10 partial seizures a day) that began in infancy or early childhood (median age, 1.0 year), usually in the setting of mental retardation or developmental delay (59% of patients), and often with magnetic resonance imaging (MRI) evidence of focal neuronal migration abnormality (44% of patients). In contrast, 13 patients with temporal lobe epilepsy were significantly older at age of seizure onset (median, 8.0 years; p = 0.001) and surgery (median, 22.0 years; p = 0.001), with less severe epilepsy (no patients with an average of > 10 seizures a day; p = 0.004), and without mental retardation or MRI evidence of neuronal migration abnormality (p = 0.001). In both groups, positron emission tomography (PET) was more sensitive than MRI and showed focal hypometabolism in seven patients with normal MRI. Seizure-free outcome tended to be more common after temporal lobectomy (77%) than after extratemporal resection or hemispherectomy (53%). Pathologic abnormalities were more severe in patients with extratemporal epilepsy than in patients with temporal lobe epilepsy. The clinical spectrum of focal cortical dysplasia included not only infants and children with severe extratemporal epilepsy and mental retardation, but also older patients with temporal lobe epilepsy and at least boderline IQ. Preoperative diagnosis may be difficult in cases with less severe pathologic abnormality, but high-resolution MRI and PET can increase the yield.     

Ring 14 chromosome presenting as early-onset isolated partial epilepsy

We report four infants (two males, two females) with ring 14 chromosome presenting with early-onset partial epilepsy. The first seizure occurred between 3 and 6 months (3, 3, 4, and 6mo respectively). In all four cases, diagnosis was based on early focal seizures, rather than on psychomotor retardation or morphological features, which were not prominent at seizure onset. Moreover, despite the young age of the patients and the high frequency of seizures, neither epileptic spasms nor progression to 'epileptic encephalopathy', such as hypsarrhythmia, were observed. Epilepsy remained partial in these patients. At the most recent follow-up, all four children had slight or mild psychomotor delay, and two of them had moderate non-specific dysmorphic traits. Data from the literature about epilepsy in ring 14 chromosome syndrome were also reviewed. Ring 14 chromosome syndrome may be revealed by isolated, early-onset focal epilepsy suggestive of focal lesions with only mild mental retardation and morphological features at the time of diagnosis. The characteristics of these observations differ from classic ring 14 syndrome, and may enlarge this clinical spectrum. Many unanswered questions remain concerning phenotype–genotype correlation and identification of the potential genes and molecular mechanisms responsible for epilepsy in patients with ring 14 syndrome.     

Electro-clinical phenotypes of chromosome disorders associated with epilepsy in the absence of dysmorphism

Chromosome imbalances are associated with epilepsy but electro-clinical phenotypes are lacking for all but the best-known syndromes. Scanty information is contained in older case reports published in genetics journals that describe children with severe patterns of malformation and dysmorphism. From a larger series of children with chromosome abnormalities and epilepsy, we identified 10 patients with associated dysmorphism without malformation. Electro-clinical features are described for each patient. We found that these patients are at greater risk of delayed diagnosis, particularly when there are no learning difficulties at the onset of epilepsy, as in ring chromosome 20 syndrome. Chromosome studies should be ordered on all children with learning difficulties and epilepsy, and on children with atypical non-lesional epilepsy, even in the absence of learning difficulties or dysmorphism.     

Cytogenetic abnormalities in attention-deficit/hyperactivity disorder

OBJECTIVE: To systematically assess the prevalence of fragile X syndrome, velocardiofacial syndrome, and other cytogenetic abnormalities in a group of children with attention-defict/hyperactivity disorder (ADHD). METHOD: Blood samples were obtained from 100 children (64 boys) with combined type ADHD and normal intelligence and analyzed for the presence of fragile X mutation expansions, the 22q11.2 microdeletion associated with velocardiofacial syndrome, and cytogenetic abnormalities that would be detected with high resolution chromosomal banding. RESULTS: One girl with ADHD had a sex chromosome aneuploidy (47,XXX). One boy had a premutation-sized allele for fragile X; no subjects showed the full mutation. Testing for 22q11.2 microdeletion was negative for all subjects with ADHD screened. None of these differences exceeded those expected by chance. CONCLUSIONS: In the absence of clinical signs or positive family history, these relatively expensive laboratory assessments are not clinically indicated for children with ADHD and normal intelligence, and are not recommended as a component of other genetic investigations of this disorder.