2q24-q31 deletion: report of a case and review of the literature.

We report a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q24.3-q31.1. The patient shows postnatal growth retardation, microcephaly, ptosis, down-slanting palpebral fissures, long eyelashes and micrognathia. Halluces are long, broad and medially deviated, while the other toes are laterally deviated and remarkably short with hypoplastic phalanges. She also showed developmental delay, seizures, lack of eye contact, stereotypic and repetitive hand movements and sleep disturbances with breath holding. Prenatal and three independent postnatal karyotypes were normal. Array-CGH analysis allowed us to identify and characterize a "de novo" 2q interstitial deletion of about 10.4Mb, involving segment between cytogenetic bands 2q24.3 and 2q31.1. The deletion was confirmed by quantitative PCR. About 30 children with 2q interstitial deletion have been reported. The deletion described here is overlapping with 15 of these cases. We have attempted to compare the clinical features of our patient with 15 overlapping cases. The emerging phenotypes include low birth weight, postnatal growth retardation, mental retardation and developmental delay, microcephaly, and peculiar facial dysmorphisms. Peculiar long and broad halluces with an increased distance between the first and the second toe are ("sandal gap" sign) present in most of the described patients. The gene content analysis of the deleted region revealed the presence of some genes that may be indicated as good candidates in generating both neurological and dysmorphic phenotype in the patient. In particular, a cluster of SCNA genes is located within the deleted region and it is known that loss of function mutations in SCNA1 gene cause a severe form of epilepsy.

Intractable reflex audiogenic seizures in Aicardi syndrome.

Aicardi syndrome (AS) is a rare disorder which includes the triad of total or partial agenesis of the corpus callosum, infantile spasms, and chorioretinal anomalies. Seizures and electroencephalogram findings observed in AS are polymorphic with both focal and generalized seizures. We first report on a patient affected by AS who presented with reflex audiogenic seizures specifically triggered by the starting tune of a popular television news. No other type of stimuli, either simple or complex, were able to precipitate the seizures in the patient. The severe cortical-subcortical lesions commonly observed in AS are associated with hyperexcitability of the cortices and may well account for the broad electroclinical patterns noted in this group of patients. From our report, the context of these patterns should be extended to include reflex audiogenic seizures.

Efficacy and safety of topiramate in infants according to epilepsy syndromes.

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravet's syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravet's syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Chromosome 18 aberrations and epilepsy: a review.

Epilepsy is commonly observed in patients with chromosomal aberrations. We evaluated epilepsy and electroencephalographic (EEG) features in a group of patients carrying aberrations of chromosome 18. Fourteen patients were recruited: five with an 18p deletion syndrome (18pDS); six with an 18q deletion syndrome (18qDS); two with trisomy 18p syndrome; and one with a 45,XY,t(17-18) (cen-q11.2) karyotype. Patients with 18pDS had neither epilepsy nor EEG anomalies; four patients with 18qDS had epilepsy with partial seizures occurring during infancy or early childhood. Partial seizures were also present in both patients with trisomy 18p. By contrast, mixed seizures were observed in the patient carrying a translocation between chromosomes 17 and 18. Our data and a re-evaluation of the literature suggest that epilepsy is infrequent in patients with 18pDS. Conversely, partial seizures and focal EEG anomalies may be observed in those with patients with 18qDS. Our observations suggest that the haplo-insufficiency of genes located on the long arm of chromosome 18 is more likely to be associated with epilepsy, than is haplo-insufficiency of genes located on the short arm. While further EEG/clinical investigations are needed to validate these observations, this study indicates a possible relationship between chromosome 18 genes and epilepsy.

Facial hemangioma and malformation of the cortical development: a broadening of the PHACE spectrum or a new entity?

Facial hemangioma is usually isolated but its association with craniocervical arterial anomalies and structural brain malformations is well known. The acronym PHACE syndrome (posterior fossa malformation, facial hemangiomas, arterial anomalies, cardiac/aortic anomalies, and eye abnormalities) has been used to indicate that disorder in which brain anomalies are mainly represented by the Dandy-Walker malformation. We report on a 10-month-old boy affected by facial hemangioma and a complex cortical dysplasia located in the left frontal region. The lesion was characterized by a deeply infolding pachygyric cortex and a band of gray matter lining the wall of the lateral ventricle. The entire left cerebral hemisphere appeared hypoplastic. No anomalies of the posterior fossa structures or cardiac/aortic malformations were present. An overlapping clinical/pathological pattern was previously reported in another patient with facial hemangioma and cerebrovascular anomalies. These observations seem to indicate that the facial hemangiomas may be associated with disorders of the cortical development.

Malformations of cortical development in neurofibromatosis type 1.

The authors report three patients with neurofibromatosis type 1 and different types of malformations of cortical development: Patient 1 had a possible transmantle cortical dysplasia involving the right temporoinsuloparieto-occipital areas; Patient 2 had a periventricular band of heterotopic gray matter with an overlying pachygyric cerebral cortex; and Patient 3 had a left perisylvian polymicrogyria. Because all of these lesions result from different pathogenetic mechanisms, neurofibromin may play a role during several stages of cortical development.

Familial Axenfeld-Rieger anomaly, cardiac malformations, and sensorineural hearing loss: a provisionally unique genetic syndrome?

Axenfeld-Rieger anomaly (ARA) is an autosomal dominant disorder of the anterior chamber of the eye that includes a prominent and anteriorly displaced Schwalbe line and an iridocorneal synechiae, and is associated with iris hypoplasia, corectopia, and hole formation. Extraocular developmental abnormalities, especially of the teeth, facial bones, and periumbilical skin, have also been reported with ARA, in the context of the so-called Axenfeld-Rieger syndrome (ARS). Genetic heterogeneity exists, as ARA maps to chromosome 6p25, whereas ARS can be linked to both chromosome 4q25 and chromosome 13q14. Here we describe a new family in which ARA is associated with cardiac malformations and sensorineural hearing loss. No abnormalities of the teeth, facial bone, or periumbilical skin, which are considered of paramount importance in the diagnosis of ARS, were observed in our patients. Genetic studies will clarify if these patients represent a unique phenotypic expression of ARS or constitute the clinical presentation of a new genetic syndrome.

Operative results without invasive monitoring in patients with frontal lobe epileptogenic lesions.

PURPOSE: To further explore the still controversial issues regarding whether all or most candidates for epilepsy surgery should be investigated preoperatively with invasive long-term video-EEG monitoring techniques (ILTVE). METHODS: We studied five patients with intractable seizures since early childhood using the same protocol: clinical evaluation, magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) sequences, long-term video-EEG (LTVE) monitoring with scalp electroencephalogram (EEG), interictal single photon emission computed tomography (SPECT), positron emission tomography (PET), and neuropsychological testing. The patients' seizures had clinical features suggesting a frontal lobe (FL) origin. MRI scans revealed focal cortical dysplasia (CD) in four patients and a probable gliotic lesion in the fifth. The findings in both PET and SPECT images were congruent with those of the MRI. Scalp LTVE failed to localize the ictal onset, although the data exhibited features suggestive of both CDs and FL seizures. On the basis of these results, surgery was performed with intraoperative corticography, and the cortical area exhibiting the greatest degree of spiking was ablated. RESULTS: Histopathologic study of four of the resected specimens confirmed the presence of CD, whereas in the fifth, there were features consistent with a remote encephaloclastic lesion. There were no postoperative deficits. Seizures in three of the patients were completely controlled at 2-3.5 years of follow-up; a fourth patient is still having a few seizures, which have required reinstitution of pharmacotherapy, and the fifth has obtained > or =70% control. All patients have had significant improvement in psychosocial measures. For comparison, five patients with generally similar clinical and neuroradiologic features to the previous group underwent preoperative ILTVE monitoring. The surgical outcomes between the two groups have not differed significantly. CONCLUSIONS: We conclude that patients with FL epilepsies may be able to undergo successful surgery without preoperative ILTVE monitoring, provided there is high concordance between neuroimaging tests (MRI, SPECT, PET) and the seizure phenotypes, even when routine EEGs and scalp LVTE fail to localize ictal onset unambiguously. The surgical outcomes of these patients generally paralleled those of the other subjects who also had FL epilepsy but who were operated on only after standard ILTVE monitoring.

Multiple neuroendocrine disorder in Salla disease.

Salla disease represents the slowly progressive adult form of the sialic acid storage diseases, a group of autosomal-recessive neurodegenerative disorders in which psychomotor development, ataxia, axial hypotonia, and spasticity in the lower limbs occur. No skeletal dysostosis or organomegaly is present, and life expectancy is normal. Short stature can also be observed. Progressive cerebral and cerebellar atrophy associated with dysmyelination and corpus callosum hypoplasia have been shown by magnetic resonance imaging studies. We report the first patient with Salla disease in whom combined growth hormone and gonadotropin deficiencies, hypothalamic pituitary in origin, have been demonstrated by neuroendocrine studies. We believe that the multiple neuroendocrine disorder may be the consequence of the abnormalities of common neuronal pathways regulating growth hormone and gonadotropin synthesis or secretion related to the brain storage of free sialic acid and/or to the neurodegenerative process occurring in Salla disease. Therefore, a complete endocrinologic evaluation of these patients is both warranted and useful.

The syndrome of inv dup (15): clinical, electroencephalographic, and imaging findings.

The clinical and laboratory data of four pediatric patients and one adult patient with inverted duplication (inv dup) (15) are reported. The most evident findings were dysmorphic features with frontal bossing; genital abnormalities, such as macropenis or hypospadias; mental retardation; autistic behavior; and seizures. Two additional adults with inv dup (15) from other institutions were also diagnosed in our laboratory. Seizures and mental retardation were the reasons for their referral. The clinical picture of inv dup (15) seems to be quite variable since the phenotype can also be normal. However, karyotyping and fluorescent in-situ hybridization, focused in particular on chromosome 15, appear to be indicated in patients with dysmorphic phenotypes, such as the one present in our patients, and in subjects with early-onset seizures and psychomotor retardation with autistic features.

Celiac disease with cerebral calcium and silica deposits: x-ray spectroscopic findings, an autopsy study.

An increased incidence of seizures and cerebral calcifications, usually bilateral and located in the occipital cortex, has been reported in celiac patients. The histology of cerebral lesions is not well defined, and their pathogenesis is only speculative. We report the autopsy results of a patient with celiac disease, seizures, and cerebral calcifications who died following a cerebral hemorrhage caused by Fisher-Evans syndrome. Calcifications were restricted to the cortical gray matter and composed of aggregates of small calcified spicules. Calcium deposition was present as psammoma-like bodies, along small vessels, and within neurons. X-ray spectroscopy of the calcified areas revealed that calcium (43%) and silica (57%) were present in the lesions. High silica content was also found in the cerebral hemorrhagic fluid. Silica toxicity has to be considered in regard to the pathogenesis of the cerebral lesions and of the seizures.

EEG, PET, SPET and MRI in intractable childhood epilepsies: possible surgical correlations.

Magnetic resonance imaging (MRI), single photon emission tomography (SPET), and positron emission tomography (PET) using [18F]fluorodeoxyglucose were used in combination with scalp and scalp-video EEGs in a group of 30 pediatric patients with drug resistant epilepsy (DRE) in order to identify patients who could benefit from neurosurgical approach. Seizures were classified according to the consensus criteria of The International League Against Epilepsy. In three patients infantile spasms (IS) were diagnosed; 13 subjects were affected by different types of generalized seizures, associated with complex partial seizures (CPS) in three. In the other 14 patients partial seizures, either simple (SPS) or complex, were present. A localized abnormality was demonstrated in one patient with IS and in three patients with generalized seizures. Of the group of 14 subjects with CPS, MRI and CT were normal in 7, but SPET or PET indicated focal hypoperfusion or hypometabolism concordant with the localization of the EEG abnormalities. In 5 of the other 7 patients anatomical and functional imaging and EEG findings were concordant for a localized abnormality. It can be concluded that functional imaging combined with scalp EEGs appears to be superior to the use of only CT and MRI for selecting children with epilepsy in whom a surgical approach can be considered, in particular when CPS resistant to therapy are present.

Progressive cerebral calcifications, epilepsy, and celiac disease.

A case with progressive cerebral calcifications, white matter involvement, and drug-resistant epilepsy in a 9-year-old boy is described. The final diagnosis was celiac disease (CD). The relationship of CD with epileptogenic lesions is considered, and the possible significance of this association is discussed.

Biochemical diagnosis of Canavan disease.

Canavan disease (CD) is a rare autosomal recessive disorder characterized by macrocephaly and progressive leukodystrophy. Up to now biopsy or necropsy were required to define the diagnosis. Recently the disease has been related to N-acetylaspartic aciduria and deficiency of aspartoacylase, an enzyme possibly involved in the myelin synthesis. These biochemical findings have provided a diagnostic marker for the disease. We report a new case of infantile CD in which the demonstration of N-acetylaspartic aciduria and a marked deficiency of aspartoacylase activity confirmed the diagnosis.