Mitochondrial ND5 T12338C, tRNA(Cys) T5802C, and tRNA(Thr) G15927A variants may have a modifying role in the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in three Han Chinese pedigrees

We report here on the clinical, genetic, and molecular characterization of three Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing loss. Clinical evaluation revealed the variable phenotype of hearing impairment including severity, age-at-onset, audiometric configuration in these subjects. The penetrance of hearing loss in WZD8, WZD9, and WZD10 pedigrees were 46%, 46%, and 50%, respectively, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrance of hearing loss in these pedigrees were 23%, 31%, and 37.5%, respectively. Mutational analysis of the complete mitochondrial genomes showed the homoplasmic A1555G mutation and distinct sets of mitochondrial DNA variants belonging to haplogroups D4b2b, B5b1, and F2, respectively. Of these, the tRNA(Cys) T5802C, tRNA(Thr) A15924C, and ND5 T12338C variants are of special interest as these variants occur at positions which are highly evolutionarily conserved nucleotides of tRNAs or amino acid of polypeptide. These homoplasmic mtDNA variants were absent among 156 unrelated Chinese controls. The T5802C and G15927A variants disrupted a highly conserved A-U or C-G base-pairing at the anticodon-stem of tRNA(Cys) or tRNA(Thr), while the ND5 T12338C mutation resulted in the replacement of the translation-initiating methionine with a threonine, and also located in two nucleotides adjacent to the 3' end of the tRNA(Leu(CUN)). Thus, mitochondrial dysfunctions, caused by the A1555G mutation, would be worsened by these mtDNA variants. Therefore, these mtDNA mutations may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated 12S rRNA A1555G mutation in those Chinese pedigrees.     

Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy

Febrile seizures (FS) and temporal lobe epilepsy (TLE) were found in four of the seven siblings born to healthy Moroccan consanguineous parents. We hypothesized autosomal recessive (AR) inheritance. Combined linkage analysis and autozygosity mapping of a genome-wide single nucleotide polymorphism genotyping identified a unique identical by descent (IBD) locus of 9.6 Mb on human chromosome 8q12.1-q13.2. Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6). Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients. Structural modeling of CPA6 indicated that both mutations are located near the enzyme's active site. In contrast to wild-type CPA6, which is secreted and binds to the extracellular matrix where it is enzymatically active, Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix. This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases.     

Effect of meditation on intracerebral EEG in a patient with temporal lobe epilepsy: A case report

Meditation has been deemed a miracle cure for a wide range of neurological disorders. However, it is unclear whether meditation practice would be beneficial for patients suffering from epilepsy. Here we report on the comparison of the effects of focused-attention meditation and a control task on electroencephalographic (EEG) activity in a patient undergoing stereoencephalographic (SEEG) investigation for drug-resistant epilepsy. The patient routinely practiced focused-attention meditation and reported that she found it beneficial. During the SEEG investigation, intracerebral EEG data were recorded during meditation as well as during mind-wandering task. The EEG data were analyzed for type of electrical activity (labeled) by two expert epileptologists. We found that the proportion of EEG segments containing activity classified as interictal epileptiform discharges (IEDs; abnormal electrical activity that occurs between seizures) increased significantly during meditation practice. Although the finding was surprising, this increase in IEDs may not correlate with an increase in seizure frequency, and the patient might still benefit from practicing meditation. The finding does, however, warrant further studies on the influence of meditation on epileptic activity.     

A reevaluation of sustained attention performance in temporal lobe epilepsy.

Reports of normal Continuous Performance Test (CPT) accuracy in patients with temporal lobe epilepsy (TLE) stand in contrast to a demonstration of nonspecific absolute reaction time (RT) deficits in this population. In this study, we examined CPT data from a TLE sample for potential RT deficits across three consecutive blocks of time during the vigil. Seventeen patients with medically intractable epilepsy of temporal lobe origin and 17 healthy volunteers participated. The Conners CPT was used to assess sustained attention over a 14-min vigil. There were no significant group differences in accuracy. There was, however, a significant interaction between groups and time intervals, with disproportionate RT increases for patients at the end of the vigil. These findings are consistent with a report of nonspecific RT deficits in TLE despite normal accuracy scores, and further indicate impaired RT performance over time.     

Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation.

A mitochondrial A 3243 G mutation in the tRNA(Leu(UUR)) gene was first described as a common cause of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome). This same mutation is also the cause of a totally different disorder, a subtype of diabetes mellitus which is inherited maternally and often associated with sensorineural hearing loss. In this paper, we report on a Japanese boy with A 3243 G who developed a previously undescribed combination of symptoms, nephropathy and growth hormone deficiency. The patient first presented with short stature and moderate mental retardation. Growth hormone (GH) provocation tests showed deficient growth hormone secretion. During the course of follow up, he presented with progressive nephropathy followed by the development of diabetes mellitus. The results of laboratory tests and renal biopsy were against incidental association of known types of nephropathy. On PCR-RFLP analysis, the percentage of mutated mtDNA was higher in the renal biopsy specimen than 12 peripheral blood leucocytes. Our case suggests that mitochondrial diseases should be taken into account when there is nephropathy of unknown cause. In addition, the presence of growth hormone deficiency may account for part of the mechanism leading to short stature commonly seen in these patients.     

Object naming and semantic knowledge in temporal lobe epilepsy.

Object-naming impairment is common among temporal lobe epilepsy (TLE) patients, but other aspects of semantic memory have received limited attention in this population. This study examined object-naming ability and depth of semantic knowledge in healthy controls (n = 29) and patients with early onset TLE (n = 21). After administration of the Boston Naming Test (BNT), the authors asked participants to provide detailed definitions of 6 BNT objects. The TLE group demonstrated a significant deficit relative to controls in both object-naming ability and semantic knowledge for the target objects, even after controlling for IQ. In a multiple regression analysis that included other neuropsychological test scores as independent variables, the semantic knowledge score was the only significant predictor of patients' object-naming performance. Thus, at the group level, early onset TLE patients have a semantic knowledge deficit that contributes to dysnomia.     

A mathematical model of internal time processing in temporal lobe epilepsy.

Based on known relationships between epileptic and nonepileptic cortical cerebral blood flow, electrocorticographic factors and epileptogenicity, a mathematical model for internal time processing is derived. The model suggests that the human brain has mechanisms for internal processing of real, reverse and imaginary time.     

A novel mutation (V191G) in a German-British type 1 Gaucher disease patient. Mutations in brief no. 131. Online

Gaucher disease results from mutations in the glucocerebrosidase gene located on human chromosome 1q21. Three clinical forms of Gaucher disease have been described: type 1, nonneuropathic; type 2, acute neuropathic; and type 3, subacute neuropathic. We have identified a novel mutation in a German-British patient with type 1 Gaucher disease which results in V191G of the glucocerebrosidase polypeptide. Because the mutation abolishes a HphI cleavage site, its presence was confirmed by HphI RFLP analysis of PCR-amplified genomic DNA. In the second allele of the patient, the mutation identified was g.5841A G(N370S). Sequence analysis of the remainder of the coding region of the gene as well as the exon-intron boundaries showed identity to normal controls. Because mutation N370S has so far been found only in type 1 Gaucher disease and postulated to result in mild clinical presentation, and since the clinical course of this patient has been relatively mild with minimal skeletal involvement, we speculate that the V191G/N370S genotype may also result in good prognosis.     

Fatal hypertrophic cardiomyopathy associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene

We describe an 8-day-old baby girl presenting a fatal infantile form of hypertrophic obstructive cardiomyopathy, associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. She was born from a healthy unrelated couple, and was the first infant of dizygotic twins. Soon after birth, she was noted to have tachypnea and generalized hypotonia. She had high levels of lactate and pyruvate, and was diagnosed as having hypertrophic cardiomyopathy using echocardiography. She died by cardiac failure. Mitochondrial DNA analysis was performed by sequencing after PCR-subcloning methods, and the percentage of mutation was measured using PCR-RFLP methods. In various tissues obtained at autopsy, analysis showed a heteroplasmic population of A8296G mutation in the mitochondrial tRNA(Lys) gene in all the tissues examined. Maternal inheritance was demonstrated in the family members. Our data demonstrated that an A8296G mutation in the mitochondrial tRNA(Lys) gene showed clinical heterogeneity from a milder form previously reported as mitochondrial diabetes mellitus, to a more severe form as hypertrophic obstructive cardiomyopathy, according to the spatial distribution of this mutation. Hum Mutat 15:382, 2000.     

颞叶的局部解剖与癫痫的手术治疗（颞叶切除术的一些改进）

目的:复习颞叶的局部解剖,探讨颞叶切除方法的改进。方法:(1)手术技巧的改进:①首先寻找侧脑室颞角;②经颞上回切除颞叶外侧皮质;③在直视下切除颞叶内侧结构(杏仁核、海马、勾回及海马旁回等)。(2)在ECoG监测下,反复描记ECoG,尽可能切除致痫组织。结果:结果满意者38％,显著改善者占40％,良好者占10％,效差6％,无改善者6％。并发症:偏瘫加重1例,无菌性脑膜炎3例,记忆力下降4例,无手术死亡。结论:熟悉颞叶解剖应用改进的颞叶切除法,术后的并发症少,控制癫痫效果好。     

An fMRI case study of visual memory in a patient with epilepsy: comparison before and after temporal lobe surgery

We report fMRI activation data for a female patient with epilepsy, who was tested before and 2 years after resection surgery, to assess changes in fMRI activation. Areas within her right ATL/MTL were removed during surgery, including the right hippocampus. A visuo-spatial task was used in which novel and familiar pictures of objects, animals, scenes and buildings were randomly presented. Half of the pictures were novel to the patient, while half of the pictures were familiar pictures from the same stimulus categories. Despite unchanged visuo-spatial IQ-scores and equal performance on the fMRI task pre- and post-surgery, there was evidence of changes in functional organization of the brain as seen in the pre- versus post-surgery fMRI data. It is suggested that maintenance of memory performance from pre- to post-surgery might be due to functional reorganization in the brain, as evidenced in the fMRI data.     

Association between survivor motor neuron 2 (SMN2) gene homozygous deletion and sporadic lower motor neuron disease in a Korean population

The association between survivor motor neuron (SMN) gene deletions and motor neuron diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) suggest that sporadic lower motor neuron disease (LMND) may be related to SMN gene deletion. We examined the association between copy numbers of SMN and the risk of LMND among Koreans. We genotyped the copy number of SMN1 and SMN2 in 18 patients diagnosed with sporadic LMND and 100 neurologically healthy subjects using the multiplex ligation-dependent probe amplification (MLPA) method. A total of eight SMN1:SMN2 genotypes (1:1, 1:3, 2:0, 2:1, 2:2, 2:3, 3:2, and 2:2/3:1 of exon7/exon8) were found. We found that homozygous deletion of SMN2 was significantly related to LMND (OR 20.7; 95% CI 2.8-150.5; p = 0.003). There was no significant difference in the distribution of the SMN1 copy number between the LMND patients and controls. In contrast to ALS, the risk of which is influenced by various factors other than SMN copy number itself, the association studies in LMND show a consistent finding that homozygous deletion of SMN2 may be specifically related to LMND, despite the small number of subjects.     

A novel mutation (G233D) in the glycogen phosphorylase gene in a patient with hepatic glycogen storage disease and residual enzyme activity

We identified a novel mutation in the glycogen phosphorylase gene (PGYL) in a Chinese patient with glycogen storage disease (GSD) type VI. The patient presented with gross hepatomegaly since the age of two without history of any hypoglycemic attack. Otherwise, he was largely asymptomatic. Liver tissue enzyme assays revealed a mild deficiency of total glycogen phosphorylase. Both PGYL and PHKA2 genes were sequenced. The patient was homozygous of a missense mutation G233D in PGYL. This location forms a hairpin turn secondary structure and the small glycine residue is completely conserved in all the orthologous proteins from Escherichia coli to mammals. This is the sixth reported mutation of this form of GSD.     

von Willebrand disease with G4022A mutation (vWd Sungnam): a case report

A 10-year-old male patient affected by type 2 von Willebrand disease (vWD) and his family members were investigated by hemostatic and molecular genetic studies. The propositus, who experienced frequent bleeding episodes, was characterized by a normal level of von Willebrand factor (vWF) antigen (54%), reduced vWF ristocetin cofactor activity (5%), decreased factor VIII clotting activity (25%) and absent high molecular weight multimers in the plasma. An exon 28 fragment coding for the A1 and A2 domains was amplified by polymerase chain reaction and sequenced. We found a heterozygous mutation (G4022A), producing an additional PstI restriction site, which resulted in the substitution of Arg578Gln. Family studies, including the parents and a brother, were negative for this mutation and vWF abnormalities were not observed. We confirmed that G to A mutation in the region of the platelet glycoprotein Ib binding domain of vWF causes the qualitative type 2 defect in von Willebrand disease.     

颞叶癫痫患者语言相关功能区的fMRI研究

目的：通过功能磁共振成像（fMRI）检查,了解颞叶癫痫（TLE）患者语言相关功能区的分布,初步探讨影响其不典型分布的因素,评价fMRI对癫痫患者进行无创语言功能定位检查的临床可操作性。方法：健康对照组和成人发病的左、右一侧性TLE患者组各6例,均为右利手。所有受试者进行动词产生任务fMRI检查,以按键记录受试者的反应。使用统计参数图2（statisticalparametricmap-ping2,SPM2）对fMRI的图像进行个体和组分析。结果：所有受试者顺利完成任务,fMRI的结果显示左侧组较对照组有明显差异,语言激活出现不典型化表现,优势侧有向右侧转移的趋势,其偏侧化指数（1ateralityindex,LI）与病程呈相对的负相关。结论：左侧TLE患者的语言功能区出现不典型分布,偏侧化程度可能与病程有关。fMRI检查评价语言功能相关区结果基本可靠,受试者耐受性好,具有一定的临床可操作性。