Andrew Norman

Medical genetics: advances in brief: Charcot-Marie-Tooth disease type 1A: association with a spontaneous mutation in the PMP22 gene

Mutations of mitochondrial (mt) DNA have recently been identified in patients with sensorineural deafness and diabetes mellitus. Last year, the description in this Journal of a six generation pedigree (including 55 affected subjects) with exclusively maternally transmitted deafness further strengthened the link between hearing loss and mt disease (3 Med Genet 1992;29:86-90). The present paper describes the sequencing of the mtDNA in two subjects from this pedigree, together with the investigation of three Chinese families segregating for maternally inherited, aminoglycoside induced deafness. Many sequence alterations were identified, most of which could be explained as natural polymorphisms or previous sequencing

Medical genetics: advances in brief The psychological consequences of predictive testing for Huntington's disease

This paper documents some of the psychological consequences of predictive testing for HD. All 135 participants in the Canadian programme of genetic testing to predict the risk of HD were followed prospectively in three groups divided according to their test result: high risk (37 participants), low risk (58), and a group for whom no change in risk could be given (40). Standard measures of psychological distress, depression, and wellbeing were administered before genetic testing and again at intervals of a week, six months, and 12 months after participants received their test result. At each assessment, the low risk group had lower scores for distress than before testing. The high risk group showed no significant change from baseline on any measure, but over the year there were small declines for distress and depression. The group with no change in risk had scores lower than baseline on the index of general wellbeing at each follow up. At 12 months both high risk and low risk groups had lower scores for depression and higher scores for wellbeing than the no change group. A predictive test for HD has potential benefits for psychological health of people who receive results that indicate either an increase or a decrease in risk.

Medical genetics: advances in brief Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus

Approximately 10% of infants have haemangiomas and the vast majority of these are isolated, benign lesions that resolve without treatment. The authors of this paper present nine infants with large, unilateral facial haemangiomas and an abnormality of the posterior fossa central nervous system and review previously reported cases with similar findings. The most striking thing about the vascular lesions in these nine children was their aggressive nature, with seven of nine cases requiring active treatment. The intracranial lesions were also interesting with five of nine showing Dandy-Walker malformations and the remainder having ipsilateral cerebellar hypoplasia associated with their facial haemangioma. Significant ocular findings were present in five of the children (three of nine had choroidal haemangiomas and two cases had microphthalmos) and complex cardiac defects were present in two of nine. Eight of nine were female and all were isolated cases. The authors reviewed 19 previously reported cases with facial haemangiomas and posterior fossa abnormalities and these cases also had commonly associated ocular and cardiac defects with a marked excess of female cases. Although these cases are interesting, the frequency of haemangiomas in the population makes identification of a significant malformation association difficult without systematic study. There is also too little known about the developmental biology of either of these systems to make an informed guess about the embryopathogenesis of this proposed developmental field defect. However, the authors make the reasonable suggestion that cranial ultrasound and ophthalmological examination should be performed on children with large unilateral facial haemangiomas.

Medical genetics: advances in brief: Diagnosis of susceptibility to malignant hyperthermia with flanking DNA markers

The potential to analyse over 300 conditions using molecular genetic methods is now available. In this third edition, these authors summarise the exponential rise in reports dealing with such analysis up to the end of 1990. For a given condition, McKusick number, available probes, distance between probes and disease locus, method of detection, mutation type, and references are listed. Of 304 conditions, 152 are dominant, 82 recessive, and 70 X linked. For single gene defects the vast majority of lesions are point mutations or deletions; gene insertions, duplications, and rearrangements are so far relatively minor components. For 80 conditions, direct analysis is not available and linkage analysis by RFLPs cannot be avoided. Like previous editions, this article provides a valuable quick reference to the relevant reports on a given disease and thereby to the groups who might be able to assist in the analysis of a genetic condition. A quarterly update by computer printout or floppy disk is available on request.

Comments on important genetic topics from papers in other journals: Review of neonatal screening programme for phenylketonuria.

The mouse Pax gene family all code for a protein domain, the paired box, originally identified in the Drosophila mutation Paired. It is a DNA binding element important in gene regulation and embryonic pattern formation, similar in many ways to the homeobox. Pax-1 is expressed in the segmented prevertebral column from day 9 in the mouse embryo, and later in the thymus and sternum. Pax-1 maps to mouse chromosome 2, near to the un (undulated) locus. Undulated mutants show abnormal development of the vertebral column and sternum, and have alterations in Pax-1. In this paper the authors show that the DNA sequence change in one un mutant, which results in a glycine-serine replacement in a highly conserved region of the molecule, changes the DNA binding activity of the Pax-l protein. Affinity for normal receptor sequences is greatly reduced, consistent with a recessive loss-of-function mutation. In addition, the affinity for certain other sequences is much increased, suggesting there may also be dominant gain-of-function effects. Since human counterparts are known for this and some other Pax genes, it is clear that this represents an important avenue of investigation into human dysmorphic syndromes.

Medical genetics: advances in brief: Antenatal maternal serum screening for Down's syndrome: results of a demonstration project

The involvement of chromosome 15ql 1-13 mutations in two clinically distinct syndromes, those of Angelman (AS) and PraderWilli (PWS), has provided several new insights in human genetics over the past few years, and represents perhaps the best example of imprinting effects in human disease. Most cases of PWS result from de novo paternal deletion or maternal uniparental disomy; about 60% of AS is caused by de novo maternal deletion, with a small contribution from paternal uniparental disomy. In the remaining 40% of AS, however, neither of these mechanisms seems to occur: the identification of this group is particularly important because the recurrence risk may be higher, approaching 50%. Wagstaff et al now describe a very instructive family in which three clinically normal sisters have between them borne four offspring with AS, together with three healthy children. A fourth sister has had two healthy children. The authors show that the four affected children all share a 15qll-13 haplotype inherited from the matemal grandfather; the unaffected children have either inherited a grandmaternal haplotype, or (in a child of the fourth sister) the opposite haplotype from the maternal grandfather. As well as serving as a beautiful example of imprinting (the mutation must be transmitted through the female to be manifest), the family provides further evidence that non-deletion AS may be linked to 15q11-13 and that the locus is distinct from that for PWS.