Investigation of the 15q13.3 CNV as a genetic modifier for familial epilepsies with variable phenotypes

Incomplete penetrance and variable phenotypic expression are characteristic of a number of syndromes of familial epilepsy. The purpose of the present investigation is to determine if the 15q13.3 copy number deletion functions as a locus modifying the epilepsy phenotype caused by other known or presumed pathogenic mutations segregating in families with epilepsies. No 15q13.3 microdeletions were detected in 756 affected or definite obligate carrier individuals across 151 families selected on the basis of having multiple members affected with epilepsy and showing a range of seizure types. Therefore, the 15q13.3 microdeletion does not act as a genetic modifier in this cohort of families and is not responsible for any of the genetic heterogeneity hypothesized to account for failure to detect linkage in previous genome-wide scans in five of the larger families included in this study.     

A further critical evaluation of requests for electrodiagnostic examinations

Abstract The aim of this study was to evaluate the impact of electrophysiological (EDX) tests in the clinical management and diagnosis of patients, and the appropriateness of the referral diagnosis. A study was carried out in three electrodiagnostic services in the Torino area, over a 12-month period. In our study 3,900 individuals (2,340 females, 1,560 males) were evaluated. Patients underwent EDX examinations including nerve conduction study, electromyography and repetitive stimulation test. Most patients had been sent for EDX tests by specialists. Specialists suspected mainly polyneuropathy, whilst general practitioners suspected mainly carpal tunnel syndrome. Seventy-two percent of the requests were correctly formulated, 55% by general practitioners and 77% by specialists. There was a concordance between the results of the EDX tests and diagnostic hypothesis 40% of the time. This study confirms the usefulness and diagnostic impact of EDX examinations and evidences the amount of time and resources wasted as a result of incorrect or incomplete requests.     

A major locus for several phenotypes of myoclonus--dystonia on chromosome 7q

Myoclonus--dystonia is a genetically heterogeneous autosomal dominant disorder caused by a mutation in the D2 dopamine receptor on chromosome 11 and a locus on chromosome 7q21-q31. The authors tested linkage to the chromosome 7q candidate region in four families with either myoclonic dystonia (n = 3) or essential myoclonus (n = 1). Age at onset ranged from 0.5 to 38 years. Only four patients from two families had a positive response to alcohol. Lod scores were positive in all four families, suggesting that chromosome 7q21-q31 is a major locus for myoclonus-dystonia with several phenotypes.     

A novel candidate region for ALS on chromosome 14q11.2

Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.     

Early onset myoclonic epilepsy and 15q26 microdeletion: Observation of the first case

The authors report the study of a 30-month-old girl with refractory myoclonic epilepsy associated with mental retardation, growth delay, peculiar facial appearance, and minor physical anomalies. Extensive genetic studies were performed, including an array-based comparative genomic hybridization (array-CGH) that showed a cryptic interstitial deletion of 15q (5 Mb) affecting the 15q26.1–26.2 region. Partial deletions of the long arm of chromosome 15, including the 15q26 region, were observed in syndromic associations that typically include congenital diaphragmatic hernia, but neurologic features were poorly described and epileptic seizures were never reported. Our findings suggest that genes for seizures could be included in the 15q26.1q26.2 deletion interval.     

Role of UBE3A and ATP10A genes in autism susceptibility region 15q11-q13 in an Italian population: A positive replication for UBE3A

The aetiology of autism is still largely unknown despite analyses from family and twin studies demonstrating substantial genetic role in the aetiology of the disorder. Data from linkage studies and analyses of chromosomal abnormalities identified 15q11-q13 as a region of particular aetiopathogenesis interest. We screened a set of markers spanning two known imprinted, maternally expressed genes, UBE3A and ATP10A, harboured in this candidate region. We replicated evidence of linkage disequilibrium (LD) at marker D15S122, located at the 5' end of UBE3A and originally reported by Nurmi et al. (2001). The potential role of UBE3A in our family-based association study is further supported by the association of two haplotypes that include one of the alleles of D15S122 and by the transmission disequilibrium test (TDT) evidence of the same allele in a parent of origin effect analysis. In a secondary analysis, we provided the first evidence of a significant association between first word delay and psychomotor regression with the 15q11-q13 region. Our data support a potential role of UBE3A in the complex pathogenic mechanisms of autism.     

Support for EKN1 as the susceptibility locus for dyslexia on 15q21

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.     

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.     

Pursuit gaze and the occipitoparietal region. A case report

A patient lost smooth pursuit gaze to the side opposite a right occipitoparietal hemorrhage. Saccadic gaze was preserved. Pursuit gaze broken by saccades was present toward the side of the lesion. Optokinetic nystagmus (OKN) was defective when a tape was moved toward the patient from the hemianopic fields. Within two weeks, the contralateral pursuit gaze defect had cleared; however, the visual field and OKN defects and the ipsilateral pursuit gaze abnormality persisted.     

Mutation analysis of the zinc transporter gene SLC30A4 reveals no association with periodic catatonia on chromosome 15q15

Summary. The zinc transporter gene SLC30A4, located on chromosome 15q15-q21, has previously been reported to show altered expression patterns in post mortem analysis of the brains of schizophrenic patients. As a positional candidate we investigated SLC30A4 in the chromsome 15q15-linked schizophrenic phenotype periodic catatonia (MIM 605419), by means of a systematic mutation screening in affected individuals from exceptionally large pedigrees with perfect co-segregation of a chromosomal segment between marker D15S1042 and D15S659 in all affected individuals. The mutation scan revealed no genetic variants within the coding and the putative promoter region of SLC30A4 and, thus, excludes a genetic association of SLC30A4 with catatonic schizophrenia.Received January 30, 2003; accepted September 4, 2003     

A case of IgM antibodies which inhibit the contact activation of blood coagulation

The relationship between the concentration of sulfinpyrazone circulating in the plasma and its effects on platelet function $\text{in}$$\text{vivo}$ is not well understood. We have studied the relationship between inhibition of $\text{in}$$\text{vivo}$ collagen-induced platelet aggregation and the sulfinpyrazone plasma concentration. Sulfinpyrazone was shown to inhibit $\text{in}$$\text{vivo}$ collagen-induced platelet aggregation in a dose-related manner and the inhibitory effects were directly related to the concentration of sulfinpyrazone in the plasma. In addition, with high doses, platelet aggregation $\text{in}$$\text{vivo}$ was inhibited for up to 18 hours after drug administration which was 14 hours after the sulfinpyrazone had been cleared from the plasma. These data suggest that a previously unidentified sulfinpyrazone metabolite is formed $\text{in}$$\text{vivo}$ which exerts a potent inhibitory effect on platelet function.     

A case of a giant cavernoma located in the temporal region

We present a case of a 21-year-old female with a giant cavernoma (5 cm x 3.1 cm x 3.6 cm) located in the left temporal region. Giant cavernomas are very rarely diagnosed. In our research we wanted to focus on the occurrence of these vascular malformations and diagnostic problems related to this matter.     

Albinism and developmental delay: the need to test for 15q11-q13 deletion

We report on a 17-month-old African girl with cutaneous and ophthalmologic features of oculocutaneous albinism type 2 as well as microcephaly, absent speech, and tremulous movements. Mutations of the P gene within the Angelman/Prader-Willi syndrome critical region at 15q11-q13 cause oculocutaneous albinism type 2. Comorbid oculocutaneous albinism and Angelman syndrome were suspected and confirmed by cytogenetics. Phenotypic features of Angelman syndrome or Prader-Willi syndrome in a patient with albinism should prompt further investigation.     

A case of glioblastoma multiforme which indicated the early stage on brain MRI]

A 57-year-old male was urgently carried to our hospital because of sudden loss of consciousness, lasting about 10 minutes. He had resumed consciousness before he arrived at our hospital. Neurologically, he had mild muscle weakness of the right arm. Deep tendon reflexes in the right upper extremity were reduced. In high level functions, speech disturbance, dysgraphia (disturbed ability to write Hiragana), and constructive apraxia were noted. A brain MRI upon admission showed a poorly demarcated, high signal intensity area in the cortical and subcortical layers of the left temporal and parietal lobes. This was visible on T 2 weighted images(T 2 WI), although no abnormalities were visible on T 1 weighted images(T 1 WI). No contrast enhancement was effected by Gd-DTPA. The patient was therefore suspected of having a tumor or degenerative disease and was monitored closely. About 4 months later after onset, his symptoms became aggravated, and brain MRI disclosed a marked low signal intensity area on T 1 WI and a heterogeneous high signal intensity area on T 2 WI. The abnormal signal intensity area was surrounded by extensive edema and mass effect. Ring-shaped, irregular, contrast enhanced areas were also visible. Cerebral angiography revealed a poorly demarcated tumor stain in the area supplied by the middle cerebral artery. The tumor was removed surgically and was histopathologically rated as glioblastoma multiforme(GBM). Because this case represents a valuable example of early stage of GBM, it will be discussed in this paper, along with differential diagnoses.