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Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk., (© 2011 Wiley Periodicals, Inc.)

Background and Purpose: It has previously been demonstrated that comparison of signal intensity (SI) between selected brain structures on T1-weighted images enables distinction between the absence or presence of hypoxic-ischemic (HI) brain injury in young infants. The aim of the present study was to assess whether this method of brain structure T1-weighted SI comparison also enables prediction of outcome., Materials and Methods: Survivors of a group of 57 children with neonatal HI encephalopathy (HIE) grade 2 or 3 according to Sarnat and Sarnat and controls who underwent neonatal MR imaging were retrospectively assigned to 1 of 3 outcome groups at 5 years of age, depending on developmental outcome: 1) normal, 2) mildly abnormal, and 3) definitely abnormal. Gestational age was not significantly different between the HIE group (range, 35 + 5-42 + 5 weeks; mean, 39 + 4 weeks) and control group (range, 35 + 0-42 + 1 weeks; mean, 39 + 2 weeks). We calculated the predictive values of the neonatal clinical HIE classification according to Sarnat and Sarnat for outcome (neonatal death and developmental outcome in survivors). We assessed which brain structure T1-weighted SI comparison scored best for outcome prediction. Predictive values of that comparison for outcome were calculated for the entire group and for the HIE grade 2 group only, a patient group with highly variable outcome., Results: Of the 57 children, 6 died. Outcome group 1 consisted of 31; group 2, of 14; and group 3, of 6 children. The positive predictive value of the neonatal clinical classification for adverse outcome (outcome group 3 and death) was 52%; and negative predictive value, 100%. These were respectively 45% and 0% in children with HIE grade 2. Of all brain structure T1-weighted SI comparisons, that of the posterior limb of the internal capsule versus the posterolateral putamen scored best for outcome prediction. The positive predictive value for adverse outcome was 69%; and negative predictive value, 98%. In children with HIE grade 2, the positive predictive value and negative predictive value for adverse outcome were 67% and 88%., Conclusions: Brain structure T1-weighted SI comparisons are helpful to predict outcome in (near) term neonates with HIE. This finding adds to the current knowledge and clinical practice. If the SI in the posterolateral putamen is less than the SI in the posterior limb of the internal capsule, favorable outcome is very likely, whereas if the SI in the posterolateral putamen is equal to or greater than the SI in the posterior limb of the internal capsule, adverse outcome is very likely. In neonates with HIE grade 2 according to Sarnat and Sarnat, prediction of outcome is substantially improved by using these brain structure T1-weighted SI comparisons.

Background and Purpose: Hypoxic-ischemic cerebral changes can be difficult to distinguish from normal myelination on T1-weighted images. We hypothesized that comparing signal intensity (SI) of brain structures on T1-weighted images enables differentiation of myelination from hypoxic-ischemic brain damage., Materials and Methods: T1-weighted images, obtained in 57 infants aged 1-104 days and born after a gestational age of 35 weeks or older, were retrospectively evaluated. Subjects were assigned to a patient (n = 23, with perinatal hypoxic-ischemic encephalopathy [HIE] stage 2/3) or a control group (n = 34). In each subject, an SI score was assigned to 19 brain structures on the basis of pairwise comparisons with the other 18 structures. In both groups, mean total SI scores were calculated for the 19 structures. Independent samples t tests assessed whether the mean total score of a structure differed significantly between the 2 groups. Logistic regression assessed which comparison was best to distinguish between the groups and to predict the presence of hypoxic-ischemic injury., Results: In patients, mean total SI scores for posterolateral putamen (PP) and peri-Rolandic cortex (PC) were significantly higher (P = .000 for both). Mean total SI scores of the posterior limb of internal capsule (PLIC) and the corona radiata (CR) were significantly lower in patients (P = .000 and 0.005, respectively). Two comparisons (PLIC versus CR, PP versus PC) were best to distinguish patients and controls and to predict absence or presence of HIE (P < .0001)., Conclusion: SI changes due to hypoxia-ischemia can be differentiated from normal myelination by comparing SI of 4 brain structures on T1-weighted images.

High-resolution analyses of complex chromosome rearrangements (CCR) have demonstrated in individuals with abnormal phenotypes that not all seemingly balanced CCRs based on G-banding are completely balanced at breakpoint level. Here we report on an apparently balanced de novo CCR involving chromosomes 2, 3 and 5 present in a 6-month-old girl. She was referred for genetic evaluation because of severe psychomotor retardation, distinctive dysmorphic features and microcephaly. A 1Mb resolution array-CGH analysis of DNA from the patient revealed a deletion of about 6Mb for chromosome 2. FISH analysis showed that the deletion interval found in band 2q22 mapped at the translocation breakpoint, and that the ZFHX1B gene, which is known to be involved in the Mowat-Wilson syndrome, is located within the deletion interval. To our knowledge this is the first case of a complex chromosomal rearrangement associated with Mowat-Wilson syndrome. Our data illustrate the important role for high-resolution investigation of apparently balanced chromosome rearrangements in patients with unexplained psychomotor retardation and/or other clinical features, and should contribute to our understanding of the mechanisms involved in chromosome rearrangement.

Alternating hemiplegia of childhood (AHC) is a severe brain disorder, mainly characterised by episodes of hemiplegia, progressive mental retardation, and other severe paroxysmal and permanent neurological symptoms. Clinically and genetically, there is some overlap with sporadic (SHM) and familial (FHM) hemiplegic migraine, a severe monogenic subtype of migraine. Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2 ATP1A2 gene in a family with AHC. Recently, a missense mutation was found in the SLC1A3 gene that encodes the glutamate transporter EAAT1, in a patient with alternating hemiplegia, episodic ataxia, seizures, and headache. Because of the remarkable clinical similarities and the potential role of glutamate in AHC, we analysed six sporadic patients with AHC for mutations in the SLC1A3 gene. No mutations were found. The SLC1A3 EAAT1 glutamate transporter gene does not seem to be involved in the pathogenesis of AHC.

In 1995, a consensus statement was published for the purpose of summarizing the salient clinical features of Angelman syndrome (AS) to assist the clinician in making a timely and accurate diagnosis. Considering the scientific advances made in the last 10 years, it is necessary now to review the validity of the original consensus criteria. As in the original consensus project, the methodology used for this review was to convene a group of scientists and clinicians, with experience in AS, to develop a concise consensus statement, supported by scientific publications where appropriate. It is hoped that this revised consensus document will facilitate further clinical study of individuals with proven AS, and assist in the evaluation of those who appear to have clinical features of AS but have normal laboratory diagnostic testing.

A 4-year-old previously healthy boy presented with a non-traumatic right parietal hemorrhage. A second life-threatening left cerebral hemorrhage occurred three weeks later and was decompressed with a craniotomy. Transthoracic echocardiography revealed a hypermobile elongated tumor of the mitral valve. The cardiac tumor was successfully resected three weeks after the craniotomy. Histological examination of the cardiac tumor revealed a papillary lesion of spindle cells with smooth muscle cell differentiation. In view of the histological findings and the clinical symptoms, a cellular myofibroblastic tumor was considered the most likely diagnosis in our patient. Although a cardiac tumor is a rare cause of a cerebral hemorrhage, a cardiac evaluation is recommended in pediatric patients with a cerebral hemorrhage of unknown etiology.

Objective: To describe the clinical features of children with chronic daily headache (CDH) and examine the usefulness of the International Classification of Headache Disorders-II., Background: Few data are available on chronic daily headache and analgesic overuse in children and adolescents and there are no specific criteria for headache in children., Methods: We retrospectively reviewed all charts of 79 children and adolescents (<16 years) with headache on > or =15 days/month presenting to the outpatient clinic of the Department of Neurology of the Leiden University Medical Center between 1994 and 2001. We classified their headaches according to the International Classification of Headache Disorders-II., Results: Fifty-seven (72%) children had chronic daily headache for more than 6 months, with a duration of more than 4 hours a day in 60% of them. Quality, severity, and location of pain varied. Sixty patients (76%) used analgesics, 10 patients more than one type. Thirteen patients (16%) used analgesics daily. In one-third of patients, headache led to frequent school absenteeism and sleeping problems. Twenty-eight (35%) patients could be classified, 17 patients (22%) as chronic tension-type headache, 5 patients (6%) as chronic migraine, and 6 patients (8%) as probable medication overuse headache. Fifteen patients (19%) did not fit into any category and 36 (46%) could not be classified due to insufficient data., Conclusions: Chronic daily headache in children is a serious disorder. A relatively large number of patients overuse medication and it leads to frequent school absenteeism and sleeping problems. It remains difficult to classify their headaches with the new criteria for headache disorders.

Angelman syndrome (AS) is a genetic disorder characterised by severe mental retardation, subtle dysmorphic facial features, a characteristic behavioural phenotype, epileptic seizures and EEG abnormalities. AS can be caused by various genetic mechanisms involving the chromosome 15q11-13 region. Neurophysiological studies report a variety of EEG abnormalities seen in AS patients. The objective of this article was to analyse whether there are characteristic EEG changes in AS, whether this varies with age and what the differential diagnosis is. Most of the authors agree about the existence of three main EEG patterns in AS which may appear in isolation or in various combinations in the same patient. The pattern most frequently observed both in children and in adults has prolonged runs of high amplitude rhythmic 2-3 Hz activity predominantly over the frontal regions with superimposed interictal epileptiform discharges. High amplitude rhythmic 4-6 Hz activity, prominent in the occipital regions, with spikes, which can be facilitated by eye closure, is often seen in children under the age of 12 years. There is no difference in EEG findings in AS patients with or without epileptic seizures. AS patients with a deletion of chromosome 15q11-13 have more prominent EEG abnormalities than patients with other genetic disturbances of the chromosome 15 region. The EEG findings are characteristic of AS when seen in the appropriate clinical context and can help to identify AS patients at an early age when genetic counselling may be particularly important.

Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterised by attacks of hemiplegia and mental retardation. AHC has often been associated with migraine. Previously, we have excluded the involvement of the familial hemiplegic migraine (FHM) CACNA1A gene in four patients with AHC. A second gene for FHM was discovered recently: the ATP1A2 gene on chromosome 1q23, coding for the alpha 2 subunit of Na+,K+-ATPase. We performed a mutation analysis of the ATP1A2 gene in six patients, using direct sequencing, but found no mutations in any of the 23 exons. Other cerebral ion channel genes remain candidate genes for AHC.

Background: The course of central nervous system systemic lupus erythematosus (CNS-SLE) is largely unknown. New imaging techniques are available to assist in monitoring the disease course., Objective: To report a case of juvenile CNS-SLE, in which magnetic resonance imaging (MRI) was used to assess disease activity., Case Report: A 10-year-old female patient with SLE presented with convulsions; MRI and computed tomography (CT) of the cerebrum disclosed abnormalities. Despite adequate treatment, two years later she had a generalised convulsion, and MRI showed new lesions. MR spectroscopy (MRS) indicated neuronal loss, inflammation, and metabolically compromised tissue; magnetisation transfer imaging (MTI) showed an increase in whole brain lesion load. After exclusion of a malignancy, CNS-SLE was the most likely diagnosis, and cyclophosphamide pulses were administered. Initially, multiple sclerosis (MS)-like lesions regressed, but despite maximal immunosuppressive drugs, new lesions formed and disappeared. When immunosuppressive drugs had been stopped for six months MRI showed improved lesions and MTI histograms., Discussion: In this case report, the anatomical substrate, metabolic aspect, neuroimaging, and clinical course of MS-like lesions in a child with CNS-SLE are described. The way in which radiological techniques can support clinical decision making in this young patient with progressive CNS-SLE is illustrated.

Purpose: To draw attention to the phenomenon that EEG characteristics of both Angelman syndrome (AS) and Rett syndrome (RS) can be found in the same patient, as evidenced by the description of one case. There are specific EEG patterns in AS patients, in which the most frequently occurring EEG characteristics are rhythmic triphasic 2- to 3-Hz, high-voltage (200-500 microV) activity, mixed with spikes or sharp waves, with a maximum over the frontal regions. EEG changes in RS patients are less specific and can show multifocal, mostly central or centrotemporal epileptiform discharges in combination with slow background activity., Methods: A 6-year-old girl with RS and a proven MECP2 mutation was described., Results: She had an EEG pattern at age 2 years comparable with the clinical diagnosis of RS, and an EEG at age 6 years comparable with an AS EEG., Conclusions: We wish to draw attention to this phenomenon, although there is as yet no evident explanation for it. We advise MECP2 examination in AS patients of unknown genetic etiology whose EEG examinations are/were pathognomonic for AS to exclude RS.

A female patient, the first child of healthy non-consanguineous parents, presented at the age of 16 months with delayed motor development and facial dysmorphism. In addition she displayed a palatoschizis and multiple skeletal abnormalities as hypoplastic scapulae, hypoplastic os ilea, and an extreme cervical kyphosis. Biochemical investigation of urine revealed no abnormalities except for the presence of large amounts of reducing sugars. The sugar was identified as L-arabinose, which mainly originated from fruit formula in her diet. In addition highly elevated levels of L-arabitol were found in urine, plasma, and cerebrospinal fluid. Although little is known about human arabinose metabolism, we presume that L-arabitol dehydrogenase is deficient in our patient. As polyols are potentially toxic to the central nervous system there could be deleterious long-term effects of this disorder. Withdrawal of dietary fruit led to normalization of polyol levels. The above-mentioned clinical abnormalities are probably not related to this new inborn error of metabolism and should be considered as a separate entity.

We describe two sisters (ages 10 and 3 years, respectively) with a normal development and a combination of congenital sensorineural hearing loss, partial agenesis of the corpus callosum, arachnoid cyst, and hydrocephalus. Neither girl has distinctive physical anomalies. In the oldest girl, there was a hearing loss of 80 dB bilaterally, and the most severe loss on audiogram was seen at 2,000-4,000 Hz. In the youngest girl, there was a hearing loss of 100 dB bilaterally. Above 2,000 Hz no neural reactions were seen. Cerebral magnetic resonance imaging in one girl and computed tomography in the other showed a partial agenesis of the corpus callosum and a cyst in the pineal region, causing an aqueduct stenosis by compression and consequent hydrocephalus. The parents have normal hearing, and brain magnetic resonance imaging showed no abnormalities. They are nonconsanguineous but from the same small village. This is the first report of a combination of congenital sensorineural hearing loss, partial agenesis of the corpus callosum, and an arachnoid cyst. The pattern of inheritance is probably autosomal recessive., (Copyright 1999 Wiley-Liss, Inc.)

This paper reviews Angelman syndrome (AS) with regard to the clinical features in childhood and adulthood, epileptic seizures and EEG findings, neuroimaging studies and the present knowledge on the genetic mechanisms underlying this syndrome. Different clinical phenotypes and genotypes of AS are described, including chromosome 15q11-13 deletion, uniparental disomy, methylation imprinting abnormalities and mutations in the UBE3A gene.

We determined the diagnostic value of the EEG in young children with Angelman syndrome (AS) and Rett syndrome (RS). EEGs, recorded before 5 years of age, of 10 patients with AS, 10 with RS and 10 with mental retardation of other origin were studied blindly by two examiners for the presence of the following items: (A) 4-6 Hz rhythmic activity of over 200 microV; (B) 2-3 Hz frontal activity of 200-500 microV; (C) posterior spikes; (D) triphasic frontal waves; (E) central and/or centro-temporal spike-wave complexes; and (F) other epileptic discharges. Based on these items the EEGs were scored as AS (A-D); RS (E-F); or other. Examiners never made a mistake between AS and RS. One examiner labeled 6 of 10 AS cases correctly, the other 5; 4 (5) were characterized as 'other.' In RS cases 5 were labeled as 'other' by the first examiner and 3 by the second one. We conclude that EEG patterns of AS and RS are sufficiently different to help differentiate between AS and RS at a young age, which has a bearing on genetic counseling.

The clinical findings in 12 Angelman syndrome (AS) patients (4 sib pairs and 4 sporadic cases, aged 12-55 years) without a cytogenetic or molecular detectable defect at the AS locus were compared to those of 28 AS patients (aged 11-50 years) with a deletion, in order to determine whether the clinical spectrum differed between the two groups. There were only two minor differences, i.e., mandibular prognathism was always found in the patients with a defect (100% vs. 58%), whereas truncal hypotonia was found less frequently in the group with a detectable genetic defect (54% vs. 91%). All other clinical and physical characteristics were equally represented in the two groups. Epileptic seizures occurred in 93% and 75%, respectively, of patients with and without a detectable chromosome 15 defect. Specific EEG patterns were found in 90% of both groups. The clinical signs and symptoms of our patients closely resemble those in familial AS cases reported in the literature, with the exception of scoliosis, which was present in 55% of the patients in our study. We conclude that the absence of a detectable cytogenetic or molecular defect at the AS locus is not associated with a strikingly different AS phenotype, compared to those with such a defect. Mutation analysis of the UBE3A gene in our patients without a detectable genetic defect, especially in the familial cases, is currently underway.

Purpose: To evaluate the evolution of epileptic seizures and EEG features in a large group of patients with Angelman syndrome (AS)., Methods: Thirty-six patients with AS with a proven chromosome 15q11-13 deletion were retrospectively analyzed with regard to their epilepsy and EEG findings by examination of patient files and EEGs. AIJ EEGs were reviewed by one of the authors. A logistic regression model, with a follow-up from 1 to 39 years (mean, 15 years), was used for statistical analysis., Results: Epileptic seizures had occurred in 30 (83%) patients. In 43% of them, the initial symptoms of epilepsy were febrile convulsions in infancy. In childhood, epilepsy could start with almost any type of seizure. Atypical absences and myoclonic seizures prevailed in adulthood. Epileptic seizures were present in 92% of the adult patients. The most typical EEG findings were rhythmic triphasic delta waves of high amplitude with a maximum over the frontal regions, identified in 99 (66%) of 150 EEGs, and continuously or intermittently, in 30 (83%) of 36 patients with AS. In 47% it was present even before a clinical diagnosis of AS was considered. High-amplitude rhythmic 4-6/s slow activity, seen in 44 (29%) of 150 EEGs, was not present after the age of 12 years., Conclusions: In contrast to previous reports suggesting a decreasing frequency of epileptic seizures with age, we found that 92% of the adult patients with AS continued to have epileptic seizures. The most typical EEG finding in AS, in both children and adults, was the presence of frontal triphasic delta waves. In mentally retarded patients, this EEG pattern should point the physician in the direction of AS.

We studied the clinical and EEG-findings in 28 adult patients (aged 20-53 years) with Angelman syndrome (AS). Twenty-three showed a maternal chromosome 15q11-13 deletion; in 5, the diagnosis was based on a combination of typical clinical findings. Compared to the clinical manifestations present in childhood, "coarsening" of facial traits (100%), thoracic scoliosis (71%), and being wheelchair-bound (39%) were found more frequently. Paroxysms of laughter were still observed in adulthood (79%), but less frequently than in childhood. Most adult patients could feed themselves, but needed help with many daily activities. The majority (82%) had epileptic seizures. Abnormal EEG-activity consisting of 2-3/s rhythmic triphasic waves of high amplitude with a maximum over the frontal regions, which has been identified in many AS children, was found in 67% of these adult patients.

Objective: We performed neurodevelopmental assessment in children born with an umbilical artery pH < 7., Study Design: All infants born with an umbilical artery pH < 7 from a 19-month period were retrieved from the obstetric database. Obstetric, neonatal, and pediatric records were reviewed. At an age of 1 to 3 years, children were visited at home for semi-structured questioning of the mother and a Denver Developmental Screening Test of the child., Results: During the study period 1614 umbilical artery pH measurements were entered in the database. Thirty (1.9%) were < 7. From this group 23 infants were admitted to the neonatal intensive care unit, and 8 of them required intubation. Twenty-eight children survived the neonatal period. Three children experienced an episode of mild hypertonia. One child had a mild motor developmental delay., Conclusion: Babies born with an umbilical artery pH < 7 are at greater risk to experience considerable short-term morbidity. Those who leave the neonatal intensive care unit without major problems have good outcomes, and pessimism in counseling their parents in unwarranted.

Four patients with an absence status induced by drugs, are described. In three patients the use of neuroleptics was the probable cause, in the other indomethacin could be incriminated. As yet an absence status after treatment with these medicaments has not been described. Clinically, the diagnosis was not unequivocal. The EEG gave clear results, rapidly indicating the cause of the patient's clinical condition.