Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.

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.

Chronic daily headache in children and adolescents.

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: is there a characteristic EEG?

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.

A Rett patient with a typical Angelman EEG.

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.