Alena Zumrova

Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism

Abstract.The aim of the study was to investigate the potential association of epilepsy and EEG abnormalities with autistic regression and mental retardation. We examined a group of 77 autistic children (61 boys, 16 girls) with an average age of 9.1 ± 5.3 years. Clinical interview, neurological examination focused on the evaluation of epilepsy, IQ testing, and 21-channel EEG (including night sleep EEG recording) were performed. Normal EEGs were observed in 44.4% of the patients, non-epileptiform abnormal EEGs in 17.5%, and abnormal EEGs with epileptiform discharges in 38.1% of the patients. Epilepsy was found in 22.1% of the subjects. A history of regression was reported in 25.8% of the patients, 54.8% of the sample had abnormal development during the first year of life, and 79.7% of the patients were mentally retarded. Autistic regression was significantly more frequent in patients with epilepsy than in non-epileptic patients (p = 0.003). Abnormal development during the first year of life was significantly associated with epileptiform EEG abnormalities (p = 0.014). Epilepsy correlated significantly with mental retardation (p = 0.001). Although the biological basis and possible causal relationships of these associations remain to be explained, they may point to different subgroups of patients with autistic spectrum disorders.

Large de novo expansion of CAG repeats in patient with sporadic spinocerebellar ataxia type 7

Sirs: Spinocerebellar ataxia type 7 (SCA7) is a rare neurodegenerative disorder caused by CAG repeat expansion within the 5’-translated region. Ataxia is usually combined with pigmentary macular degeneration [1, 3]. The locus for SCA7 has been mapped to chromosome 3p14-p21.1 [1]. Expanded alleles in SCA7 patients range from 37 to > 200 repeats, whereas in normal alleles the number of trinucleotides varies from 4 to 35 [4, 7]. The repeat sequence in SCA7 gene is extremely unstable, therefore the age of onset may be shifted in descendent generations as many as decades. SCA7 repeat is liable to expand in particular when transmitted by males [2, 5]. We report an unusual case of sporadic SCA7 with de novo CAG expansion. Initially the patient was misdiagnosed as having Friedreich’s ataxia (FRDA) due to sporadic occurrence in the family and early age of onset. DNA analysis of FRDA was performed first to confirm the clinical diagnosis but the proband showed to be a heterozygous with both alleles in normal range (15/21 GAA). Later we have analysed SCA7 CAG repeat number in the patient and 4 relatives. DNA analysis was performed using a modified PCR method [6] (primers 7ALT/4 U716) either with direct incorporation of α32P dCTP, or by PCR fragment analysis using ABI PRISM 377 Automated Sequencer (Perkin Elmer). To resolve the multiple bands in the expanded allele, we diluted the DNA samples to about 10 genome copies of DNA/ PCR reaction (Fig. 1). We found a large de novo expansion in the proband, where the 51 CAG allele expanded from a normal range 10 CAG (Fig. 2). PCR fragments were gel-purified, subcloned into pGEMT Easy Vector (Promega), and the number of CAG in each allele was confirmed by sequencing using BigDyeTM Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems). For the paternity testing, we genotyped also multiallelic microsatellite markers using LETTER TO THE EDITORS

Absence of spinocerebellar ataxia type 3/Machado-Joseph disease within ataxic patients in the Czech population

Although spinocerebellar ataxia type 3 (SCA3)/Machado–Joseph disease is the most common type of SCA worldwide, we did not identify any cases of the disease amongst SCA patients in the Czech population. It has been proposed that the prevalence of large normal alleles correlates with the frequency of various types of SCA. We have therefore attempted to resolve the absence of SCA3 in our population by investigating, within 204 normal chromosomes, the frequency and nature of CAG repeats as well as two intragenic polymorphisms. We found that large normal alleles with more than 33 CAG repeats were observed at a frequency of only 0.49%. Whereas most of the expanded alleles worldwide have the CA haplotype, this was the least common (5.4%) variant observed in our study, although it was associated with a larger mean CAG repeat length (26.9). We postulate that the absence of SCA3 in the Czech population might be explained by the lack of large normal alleles and consequently a relatively small reservoir for aberrant CAG expansions at the SCA3 locus.

An Electrophysiological Study of Visual Processing in Spinocerebellar Ataxia Type 2 (SCA2)

Reports of visual functional impairment in spinocerebellar ataxia type 2 (SCA2) have been studied previously using pattern reversal visually evoked potentials (VEPs) with contradictory results. To provide additional evidence to this area, visual functions were studied using VEPs and event-related potentials (ERPs) in a group of ten patients with genetically verified SCA2. The electrophysiological examination included pattern reversal and motion-onset VEPs as well as visually driven oddball ERPs with an evaluation of a target and a pre-attentive response. In six patients, we found abnormal visual/cognitive processing that differed from normal values in latency, but not in the amplitude of the dominant VEP/ERP peaks. Among the VEPs/ERPs used, the motion-onset VEPs exhibited the highest sensitivity and showed a strong Spearman correlation to SCA2 duration (from r = 0.82 to r = 0.90, p < 0.001) and clinical state assessed by Brief Ataxia Rating Scale (from r = 0.71 (p = 0.022) to r = 0.80 (p < 0.001)). None of the VEP/ERP latencies showed a correlation to the triplet repeats of the SCA2 gene. In three patients, we did not find any visual/cognitive pathology, and one subject showed only a single subtle prolongation of the VEP peak. The observed visual/cognitive deficit was related to the subjects’ clinical state and the illness duration, but no relationship to the genetic marker of SCA2 was found. From the VEP/ERP types used, the motion-onset VEPs seems to be the most promising candidate for clinical state monitoring rather than a tool for early diagnostic use.

Spinocerebellar Ataxias Type 8, 12, and 17 and Dentatorubro-Pallidoluysian Atrophy in Czech Ataxic Patients

Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders currently associated with 27 genes. The most frequent types are caused by expansions in coding CAG repeats. The frequency of SCA subtypes varies among populations. We examined the occurrence of rare SCAs, SCA8, SCA12, SCA17 and dentatorubro-pallidoluysian atrophy (DRPLA), in the Czech population from where the data were missing. We analyzed causal gene expansions in 515 familial and sporadic ataxic patients negatively tested for SCA1–3 and SCA6–7. Pathogenic SCA8 and SCA17 expansions were identified in eight and five patients, respectively. Tay–Sachs disease was later diagnosed in one patient with an SCA8 expansion and the diagnosis of multiple sclerosis (MS) was suspected in two other patients with SCA8 expansions. These findings are probably coincidental, although the participation of SCA8 expansions in the susceptibility to MS and disease progression cannot be fully excluded. None of the patients had pathogenic SCA12 or DRPLA expansions. However, three patients had intermediate SCA12 alleles out of the normal range with 36 and 43 CAGs. Amyotrophic lateral sclerosis (ALS) was probable in the patient with 43 CAGs. This coincidence is remarkable, especially in the context with the recently identified predisposing role of longer SCA2 alleles in ALS. Five families with SCA17 represent a significant portion of ataxic patients and this should be reflected in the diagnostics of SCAs in the Czech population. SCA8 expansions must be considered after careful clinical evaluation.

Cerebellar Symptoms Are Associated With Omission Errors and Variability of Response Time in Children With ADHD.

Objective: We examined the presence of cerebellar symptoms in ADHD and their association with behavioral markers of this disorder. Method: Sixty-two children with ADHD and 62 typically developing (TD) children were examined for cerebellar symptoms using the ataxia rating scale and tested using Conners’ Continuous Performance Test. Results: Children with ADHD had significantly more cerebellar symptoms compared with the TD children. Cerebellar symptom scores decreased with age in the ADHD group; in the TD group remained stable. In both groups, cerebellar symptoms were associated with parent-rated hyperactive/impulsive symptoms, variability of response time standard error (RT-SE) and increase of RT-SE as the test progresses. More variables were associated with cerebellar symptoms in the ADHD group including omission errors, overall RT-SE and its increase for prolonged interstimulus intervals. Conclusion: Our results highlight the importance of research into motor functions in children with ADHD and indicate a role for cerebellar impairment in this disorder.