Brief screening questionnaire for determining affected state in fragile X syndrome: a consensus recommendation.

New molecular research has provided strong evidence for different forms of the fragile X mutation. These findings suggest the need to develop a more standardized and sensitive method for determining neurobehavioral effects of the fragile X gene(s), particularly for molecular studies of patients who do not have obvious mental retardation. This report describes a brief screening questionnaire designed to increase the detection of neurobehavioral dysfunction in individuals from fragile X families who are included in new molecular studies. Improved detection of the affected state in fragile X syndrome will allow more valid clinical data to be correlated with the important molecular information currently being collected.     

Comparative genomic hybridization in glioma: a meta-analysis of 509 cases

Much data about genetic imbalances in tumors have been accumulated by comparative genomic hybridization (CGH). In order to distinguish between significantly and coincidentally involved regions in glioma by means of a meta-analysis, we summarized and analyzed the CGH results of 509 cases published in 26 reports between 1992 and 2001. The expansion of all aberrations to the 850-band level impressively visualized distinct patterns in astrocytoma, oligodendroglioma, and ependymoma as well as loci of frequent aberrations. For example, in astrocytoma the frequency of gains culminated at 7p12, 8q24.1, and 12q13-q15 (the loci of EGF-R, C-MYC and CDK4, respectively) and losses at 9p21 (the locus of p15 and p16) and 10q23.3 where PTEN resides. Most chromosomes were variably prone to copy number changes at different scales of aberrations. At the whole chromosome level the analysis showed +7, -10 in astrocytoma and +9, +18 in ependymoma, but +20q, -9p in astrocytoma and +1q, -22q in ependymoma at the p-q arm level. Furthermore, we could confirm the correlation between the average number of copy alterations per patient (average number of copy alterations [ANCA] index) and malignancy for astrocytoma in a refined graduation as well as for oligodendroglioma. As a new parameter, the average number of affected GTG-bands per patient (average number of affected GTG bands [ANAG] index) showed an even more striking correlation with the World Health Organization grade for gains and losses.     

Late diagnosis of Curschmann-Steinert myotonic dystrophy in a female patient with dilated cardiomyopathy and in her son

A 41 year old woman presented with dyspnoea at rest and swollen legs in the emergency room of our centre. She reported a history of slowly progressing dyspnoea and oedema in the legs. Physical examination showed signs of biventricular congestive heart failure and dysmorphia of the face. Routine laboratory examination revealed elevated CK levels without significant elevations of the CK-MB isoform. ECG showed complete left bundle branch block and first degree atrioventricular block. Echocardiography and angiography showed markedly reduced left ventricular systolic function, the ejection fraction was 25%. Coronary angiography excluded CAD and there was no evidence for congenital or valvular heart disease. The patient also reported a history of a serious complication during emergency general anaesthesia and cataracts of both eyes. Because of the clinical and chemical findings, the history of cataracts and complications during general anaesthesia, a systemic congenital disease of the muscular tissue was suspected. Molecular studies revealed a trinucleotide amplification at the myotonic dystrophy locus 19q 13.3, so the diagnosis myotonic dystrophy Curschmann-Steinert was established. The sixteen year old son of the patient suffered from an at this time unknown disease with retardation, muscular weakness and myotonia of the face. The diagnosis myotonic dystrophy was evident because of the clinical signs and the family history.     

Congenital defects of the limbs and alcohol exposure in pregnancy: Data from a population based study

Limb deficiency may occur in offspring prenatally exposed to alcohol. In a study on limb deficiency occurring in 1,213,913 consecutive liveborn infants in British Columbia, born in the years 1952–1984, a total of 659 cases with limb deficiency was identified. Cases with documented maternal alcohol abuse in pregnancy in this group were analyzed separately. We found eight cases with severe prenatal alcohol exposure (6 F, 2 M). In six of the eight cases a terminal transverse defect of the forearm or hand was present. In the remaining two cases ulnar defects were identified. These observations give further support to the hypothesis that intrauterine alcohol exposure may cause limb defects. This has also been demonstrated in experimental animals. Terminal transverse defects made up a larger proportion of cases with known alcohol exposure (6/8) than of cases where alcohol exposure was not noted (217/651) (χ² = 6.13; P < 0.025) in this study. The defects primarily involved the right hand and forearm. This suggests a vascular origin of the limb defects after intrauterine alcohol exposure. © 1992 Wiley-Liss, Inc.     

Molecular genetic analysis of the BIGH3 gene in lattice type I (Biber-Haab-Dimmer) and granular type II (Avellino) corneal dystrophy: is indirect mutation analysis for hot spots recommended?

BACKGROUND: Mutations of the BIGH3 gene were delineated as the underlying gene defect for corneal dystrophy Lattice Type I (CDL1) and corneal dystrophy Avellino type (CDA) in families with different regional provenance. Missense mutations in exon 4 with single base pair substitution which result in amino acid alterations Arg124Cys (CDL1) and ARG124His are described as hot spots. We report on histopathological and molecular genetic investigations in 2 German families and a single patient with CDL1 and CDA. METHOD: In 3 affected family members and 1 unaffected family member and in one single patient with CDL1 and in 3 affected family members and 1 unaffected family member of a family with CDA mutation analysis in exon 4 of BIGH3 gene by direct sequencing of genomic DNA from peripheral blood was performed. Histopathological examination of corneal tissue of both index patients was performed after penetrating keratoplasty. RESULTS: We revealed a heterozygous single base pair substitution 417C-->T in family A and patient B (CDL1) and a heterozygous single base pair substitution 418G-->A in family C (CDA). In all index patient's diagnosis was confirmed by histopathological examination of corneal tissue. The sequencing results were confirmed by restriction digestion with HpyCH4V (NEB; CDL1) restriction endonuclease site and AvaII (NEB; CDA) restriction endonuclease site. The heterozygous 417C-->T transition in family A and patient B alters the amino acid sequence from Arg124Cys while the heterozygous 418G-->A transition in family C alters the amino acid sequence from Arg124His in the keratoepithelin. COMMENT: Codon 124 of the BIGH3 gene appears as a mutation hot spot also in German families with CDL1 and CDA. Indirect mutation analysis with restriction digestion is suggested as first step investigation in families with relevant corneal dystrophies. Direct sequencing of all exons is recommended as a second step if there are no results in restriction digestion.     

Characterization of chromosomal aberrations in a case of glioblastoma multiforme combining cytogenetic and molecular cytogenetic techniques

A case of glioblastoma multiforme (GBM) that was investigated with a broad spectrum of cytogenetic and molecular cytogenetic techniques is reported. The results of cytogenetic studies, interphase fluorescence in situ hybridization, comparative genomic hybridization, and spectral karyotyping (SKY) are reported. Various structural chromosomal aberrations were identified, among which aberrations involving chromosome arm 2p were especially frequent. Using SKY, six translocations not previously described in GBM are reported.     

Familial pericentric inversion of chromosome 1 (p34q23) and male infertility with stage specific spermatogenic arrest.

We report on two infertile brothers presenting with severe oligozoospermia or azoospermia. Testicular biopsy was performed on one of them and showed spermatogenic arrest at the level of primary spermatocytes. Both brothers were found to be heterozygous for a pericentric inversion of chromosome 1 (46,XY,inv(1)(p34q23)). The inversion chromosome was inherited through the maternal line, with no indication of subfertility in the probands' mother.