Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome.

Monitoring of optic nerve function in Neurofibromatosis 2 children with optic nerve sheath meningiomas using multifocal visual evoked potentials.

Monitoring optic nerve sheath meningiomas (ONSM) in Neurofibromatosis type 2 (NF2) patients remains difficult. Other ocular manifestations of NF2 may obscure ophthalmic assessment of optic nerve function in these patients. Serial magnetic resonance imaging (MRI) used to assess the optic nerve is not without limitations, being expensive and often requiring general anaesthetic in children, with associated risks.

A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure.

Inactivating mutations of the FSH receptor (FSHR) are known to cause ovarian failure with amenorrhea and infertility in women. The first mutation identified in the FSHR gene was a missense mutation (566C-->T, predicting Ala189Val transition) found in several Finnish patients with primary amenorrhea due to ovarian failure. Only five additional, partially or totally inactivating, mutations of the FSHR have been reported.

Confidentiality.

Issues of confidentiality are complicated by the relationships we have to patients and others who have valid interests in the confidential information. There are no straightforward answers to problems which involve complex relationships and sensitive information. The best we can do is to think thoroughly and carefully about the issues in each case, and use our knowledge of the people involved to reach a decision.

A randomized community intervention trial to increase awareness and knowledge of the role of periconceptional folate in women of child-bearing age.

OBJECTIVES: To determine the effect of a consumer-directed information campaign to increase knowledge of folate for the prevention of neural tube defects among women of child-bearing age, and to measure women's recall of sources of information and knowledge about folate. DESIGN: A community randomized trial. SETTING: Three matched pairs of geographically distinct Local Government Areas in the state of Victoria, Australia.

Fasting medium chain acyl-coenzyme A dehydrogenase--deficient children can make ketones.

Medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency classically presents as hypoketotic hypoglycemia. Under-production of ketones has been presumed to be the cause of hypoketosis, but this has never been proven. Stable isotope dilution studies of ketone kinetics were performed on three well children with homozygous 985G MCAD deficiency using 1,3-13C2 sodium acetoacetate and 1,2,3,4-13C4 sodium 3-hydroxybutyrate to ascertain the rates of ketone production, interconversion, and use.

Towards reliable prenatal diagnosis of mtDNA point mutations: studies of nt8993 mutations in oocytes, fetal tissues, children and adults.

Prenatal diagnosis of mitochondrial DNA (mtDNA) mutations is technically possible, but has only rarely been attempted. This is largely because of uncertainty about the effects of mtDNA heteroplasmy, the mtDNA bottleneck, random segregation or selection of mtDNA species, and difficulty in correlating a particular mtDNA mutant load with clinical outcome. We have investigated the feasibility of prenatal diagnosis for two common mtDNA mutations at nucleotide (nt)8993 by determining mtDNA mutant loads in human oocytes and by reviewing data on 56 pedigrees with these mutations, and by reviewing six studies on mtDNA mutations in human fetuses.

Practical problems in detecting abnormal mitochondrial function and genomes.

Mitochondrial respiratory chain dysfunction causes a wide range of primary diseases in adults and children, with highly variable organ involvement. Diagnosis involves weighing evidence from a number of sources, including the clinical presentation, metabolic measurements in vivo, imaging studies, analysis of respiratory chain function or enzyme activities in vitro, studies of mitochondrial morphology after biopsy, and mitochondrial (mt) DNA mutation analysis. Irrespective of the category of the information, it can be difficult to determine whether abnormal results are due to primary defects of the respiratory chain or to practical problems that complicate the diagnostic methodology.

Sex selection and preimplantation diagnosis: a response to the Ethics Committee of the American Society of Reproductive Medicine.

In its recent statement 'Sex Selection and Preimplantation Genetic Diagnosis', the Ethics Committee of the American Society of Reproductive Medicine concluded that preimplantation genetic diagnosis for sex selection for non-medical reasons should be discouraged because it poses a risk of unwarranted gender bias, social harm, and results in the diversion of medical resources from genuine medical need. We critically examine the arguments presented against sex selection using preimplantation genetic diagnosis. We argue that sex selection should be available, at least within privately funded health care.

Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families.

Leigh disease can be caused by defects of both nuclear and mitochondrially encoded genes. One mitochondrial DNA mutation, G14459A, has been associated with both respiratory chain complex I deficiency and Leber's hereditary optic neuropathy, with or without dystonia. Here, we report the occurrence of this mutation in 3 complex I-deficient patients from 2 separate pedigrees who presented with Leigh disease, with no evidence or family history of Leber's hereditary optic neuropathy or dystonia.

A simple PCR test to detect the common 35delG mutation in the connexin 26 gene.

Background: The most common form of nonsyndromic neurosensory autosomal recessive deafness, DFNB1, is caused by mutations in the connexin 26 gene (GJB2) on chromosome 13. One mutation, in which one guanosine (G) residue is deleted from a run of 6 Gs (35delG), is found in 40% to 70% of DFNB1 cases and has an expected population frequency of one in 40 to one in 100.

Methods And Results: Polymerase chain reaction (PCR)-based tests for the 35delG mutation were developed.

High frequency hearing loss correlated with mutations in the GJB2 gene.

Genetic hearing impairment affects approximately 1/2000 live births. Mutations in one gene, GJB2, coding for connexin 26 cause 10%-20% of all genetic sensorineural hearing loss. Mutation analysis in the GJB2 gene and audiology were performed on 106 families presenting with at least one child with congenital hearing loss.

Identification of the copper chaperone SAH in Ovis aries: expression analysis and in vitro interaction of SAH with ATP7B.

A clone encoding the putative copper chaperone protein Sheep Atx1 Homologue (SAH) was isolated from a sheep liver cDNA library. The 466-bp cDNA encoded a predicted protein of 68 amino acids, with 44 and 81% amino acid identity to the yeast Atx1 and human Atox1 copper chaperone proteins, respectively. The characteristic MTCxxC and KTGK motifs were conserved in SAH.

Cloning, mapping and expression analysis of the sheep Wilson disease gene homologue.

Copper homeostasis in mammals is maintained by the balance of dietary intake and copper excretion via the bile. Sheep have a variant copper phenotype and do not efficiently excrete copper by this mechanism, often resulting in excessive copper accumulation in the liver. The Wilson disease protein (ATP7B) is a copper transporting P-type ATPase that is responsible for the efflux of hepatic copper into the bile.

Centromerization.

Centromere formation is a complex process that involves the packaging of DNA into a centromere-unique chromatin, chemical modification and the seeding of kinetochore and associated proteins. The early steps in this process, in which a chromosomal region is marked for centromerization (that is, to become resolutely committed to centromere formation), are unusual in that they can apparently occur in a DNA-sequence-independent manner. Current evidence indicates the involvement of epigenetic influences in these early steps.

Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization.

Karyotypic studies of aborted fetuses have been used to draw the inference that the proportion of conceptuses with chromosome abnormalities is very high. Fluorescent in situ hybridization (FISH) studies of blastomeres from early cleavage embryos have provided some support for this inference but they are limited to the study of a few chromosomes. We describe the novel application of comparative genomic hybridization (CGH) to the study of numerical and structural abnormalities of single blastomeres from disaggregated 3-day-old human embryos.

Assessment of education and counselling offered by a familial colorectal cancer clinic.

We have evaluated whether or not client expectations, in terms of education and information needs, have been met by a multi-disciplinary familial colorectal cancer clinic. The study used a pre- and post-clinic questionnaire design and 126 (84 women, 42 men) clients of the clinic participated. The most common reason for coming to the clinic is to 'find out whether there is a gene for colorectal cancer in the family', followed by 'to reduce risk for bowel cancer' and 'concern for children's risk'.

The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene.

Most cases of Friedreich ataxia (FRDA) are due to expansions of a GAA trinucleotide repeat sequence in the FRDA gene coding for frataxin, a protein of poorly understood function which may regulate mitochondrial iron transport. However, between 1% and 5% of mutations are single base changes in the sequence of the FRDA gene, causing missense, nonsense, or splicing mutations. We describe three new mutations, IVS4nt2 (T to G), R165C, and L182F, which occur in patients in association with GAA expansions.

Women's knowledge and attitudes about emergency contraception: a survey in a Melbourne women's health clinic.

The aim of the study was to determine the level of awareness of emergency contraception in women seeking pregnancy counselling and to investigate their attitudes towards emergency contraception. All women presenting for pregnancy counselling at a Melbourne women's health clinic in October 1997 were invited to complete a questionnaire detailing their contraceptive practices. One hundred and sixty-six questionnaires were distributed and 153 were completed (92% response rate).

Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice.

Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone H3-like protein that is thought to be involved in the nucleosomal packaging of centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene and demonstrated that the gene is essential. Heterozygous mice are healthy and fertile whereas null mutants fail to survive beyond 6.

Uterine dysfunction and genetic modifiers in centromere protein B-deficient mice.

Centromere protein B (CENP-B) binds constitutively to mammalian centromere repeat DNA and is highly conserved between humans and mouse. Cenpb null mice appear normal but have lower body and testis weights. We demonstrate here that testis-weight reduction is seen in male null mice generated on three different genetic backgrounds (denoted R1, W9.