Bao Xh

Association between genetic variation of CACNA1H and childhood absence epilepsy

Direct sequencing of exons 3 to 35 and the exon–intron boundaries of the CACNA1H gene was conducted in 118 childhood absence epilepsy patients of Han ethnicity recruited from North China. Sixty‐eight variations have been detected in the CACNA1H gene, and, among the variations identified, 12 were missense mutations and only found in 14 of the 118 patients in a heterozygous state, but not in any of 230 unrelated controls. The identified missense mutations occurred in the highly conserved residues of the T‐type calcium channel gene. Our results suggest that CACNA1H might be an important susceptibility gene involved in the pathogenesis of childhood absence epilepsy. Ann Neurol 2003

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.

Using a large international sample to investigate epilepsy in Rett syndrome

The aim of this study was to identify characteristics of epilepsy in Rett syndrome (RTT), and relationships between epilepsy and genotype.

Clinical study and PLA2G6 mutation screening analysis in Chinese patients with infantile neuroaxonal dystrophy

Background and purpose:  Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder. The most typical neuropathological finding of this disease is axonal swelling. Before the identification of associated mutations in PLA2G6‐encoding iPLA2‐VIA (cytosolic Ca2+‐independent phospholipids A2, group VIA) in 2006, neuropathological evidence was critical for definitive diagnosis. Only five genetic studies in INAD patients have been published worldwide, wherein 44 mutations were reported. To define the clinical and genetic characteristics of Chinese patients with INAD, 10 cases were analyzed.

T-type calcium channel gene alpha (1G) is not associated with childhood absence epilepsy in the Chinese Han population.

We investigated whether the T-type calcium channel gene alpha (1G) is associated with childhood absence epilepsy (CAE), a form of idiopathic generalized epilepsy. We carried out direct sequencing of exons 1-37 and the exon-intron boundaries of the alpha (1G) gene in 48 Han Chinese patients with CAE and 48 normal controls. We found no mutation in the exons of alpha (1G). However, we did identify six single nucleotide polymorphisms (SNPs). Using two of these as markers, we carried out a case-control study in 192 patients with CAE and 192 normal controls. The allele and genotype distributions of all the SNPs studied were not significantly different between cases and control groups, thus the alpha (1G) gene is not an important susceptibility gene for CAE, at least in the Chinese population.

InterRett, a model for international data collection in a rare genetic disorder.

Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other studies. A literature review compared InterRett with RTT population-based and case-based studies of thirty or more cases that investigated genotype and/or phenotype relationships. Questionnaire data were used to determine case status and to investigate the comparability of InterRett and ARSD. Twenty four case series, five population based studies and a MECP2 mutation database were identified of which twenty one (70%) collected phenotype and genotype data. Only three studies were representative of their underlying case population and many had low numbers. Of one thousand one hundred and fourteen InterRett subjects, nine hundred and thirty five born after 1976 could be verified as Rett cases and compared with the two hundred and ninety five ARSD subjects. Although more InterRett families had higher education and occupation levels and their children were marginally less severe, the distribution of MECP2 mutation types was similar. The InterRett can be used with confidence to investigate genotype phenotype associations and clinical variation in RTT and provides an exemplary international model for other rare disorders.

Follow‐up study of 25 Chinese children with PLA2G6‐associated neurodegeneration

To perform a follow‐up of 25 Chinese children with gene‐confirmed PLA2G6‐associated neurodegeneration (PLAN).

Mutation screen of the GABAA receptor gamma 2 subunit gene in Chinese patients with childhood absence epilepsy

Abstract Childhood absence epilepsy (CAE) is considered to be a genetic disease, the genes responsible for which have not yet been identified. To investigate whether or not GABA A receptor gamma 2 subunit gene (GABRG2) is the susceptibility gene for CAE in the Chinese population, we screened 68 CAE patients of Han ethnicity from North China for mutations in the nine exons of GABRG2. Although we found no mutation in the exons of GABRG2, we did identify two single nucleotide polymorphisms (SNPs) in exon 3 and exon 5. Using the two SNPs as markers, we carried out a transmission/disequilibrium test (TDT) in 68 trios with CAE. TDT results showed that there were no significant discrepancies between the CAE patients and ‘internal controls’ in allele frequencies of the two SNPs. We postulate that the GABRG2 gene might be neither a susceptibility gene for CAE nor in linkage disequilibrium with disease-predisposing sites in the Chinese population.

Alpers syndrome with prominent white matter changes

Alpers syndrome is a fatal neurogenetic disorder caused by the mutations in POLG1 gene encoding the mitochondrial DNA polymerase gamma (polgamma). Two missense variants, c.248T > C (p.L83P), c.2662G > A (p.G888S) in POLG1 were detected in a 10-year-old Chinese girl with refractory seizures, acute liver failure after exposure to valproic acid, cortical blindness, and psychomotor regression. The pathology of left occipital lobe showed neuronal loss, spongiform degeneration, astrocytosis, and demyelination. In addition, there were prominent white matter changes in a series of brain magnetic resonance imaging (MRI) and increased immunological factors in CSF.

Large deletions of the MECP2 gene in Chinese patients with classical Rett syndrome

To the Editor: Rett syndrome (RTT; MIM 312750), an Xlinked disorder that almost exclusively affects girls (1), is caused by mutations in the MECP2 (methyl CpG binding protein 2) gene (2). DNA sequencing identifies mutations in the MECP2 gene in 80% of classic RTT patients. Recently, quantitative analysis has identified large deletions within theMECP2 gene in 20–38% of those RTT patients with no mutation found on sequencing (3–9). We have studied 30 Chinese classical RTT patients without a defined MECP2 mutation using multiplex ligase-dependent probe amplification (MLPA) to detect large deletions of the MECP2 gene. These 30 patients were referred from 11 provinces of China. All patients fulfilled the international diagnostic criteria (10) and did not have a defined MECP2 mutation. Genomic DNA was prepared and purified from peripheral blood (Qiagen, Valencia, CA). Informed consent was obtained. MECP2-MLPA (covering each of the four exons of the MECP2 gene) was performed using kit P015C (MRC-Holland,Amsterdam) (11). X chromosome inactivation (XCI) was tested in all 11patientswith a large deletion in theMECP2 gene by analysing the androgen receptor gene (AR) in peripheral blood DNA (12). X inactivation was considered significantly skewed if the ratio equated or exceeded 80:20. We detected 11 cases with large deletions of the MECP2 gene in the 30 Chinese classical RTT patients (36.6%). Ten of the 11 deletions involved either exon 3 or both exons 3 and 4 (Table 1). In one case (R-111), the flanking IRAK1 gene was deleted along with the exons 3 and 4. The clinical features, the MLPA and XCI results of these 11 patients are summarized in Table 1. This is the first report on the study of large deletions of the MECP2 gene in Chinese patients with classical RTT. A review of the literature showed nine studies on large deletions of the MECP2 gene on Caucasian classic RTT patients with a detection rate of 20–38% in those with no mutation found on sequencing (3–9, 13). Little is known about Chinese patients with RTT. We reported previously the identification of 17 cases with aMECP2mutation among 30 Chinese RTT patients by DNA sequencing (14). The present study identified 11 cases with large deletion in 30 Chinese classical RTT patients without MECP2 gene mutation on sequencing, a detection rate (36.6% or 11/30) comparable to the reported data. In other studies, large deletions frequently involve either exon 4 or both exons 3 and 4 of the MECP2 gene (4, 5, 7–9). Our experience is consistent with previous observations. Archer et al. (8) reported five RTT patients with additional congenital anomalies, accounting for 22.7% of those with large deletions involving the downstream DNA sequences. Deletions involving the adjacent IRAK1 gene and other genes were proposed as the cause of congenital anomalies. Ravn et al. (7) reported larger deletions involving the downstream IRAK1 gene in three patients, who did not display additional congenital anomalies or other clinical features. Our patient (R-111) with a deletion involving exons 3 and 4 ofMECP2 gene as well as the IRAK1 gene does not have congenital anomalies or other clinical features. Based on these data, the cause of the congenital anomalies may not be an IRAK1 gene deletion. Of our 11 patients aged between 3 and 23 years, the severity scores according to Kerr and Archer (8, 15), vary from4 to 8. Because some of the symptoms are age-dependent and the number of subjects in this study is small, we were unable to establish any correlation between phenotype and different exon deletions of the MECP2 gene. In addition, skewed XCI pattern was found in two RTT patients (Table 1). Because of the small number of patients with large deletions in our study, we did not attempt to correlate the degree of XIC with the type/size of the MECP2 deletion. Our experience is that MLPA, as a complement to DNA sequencing, is a useful tool for Rett syndrome molecular diagnosis especially in countries with a big population like China, where the number of patients requiring analysis can be large.