All reported mutations in ALAS2, which encodes the rate-regulating enzyme of erythroid heme biosynthesis, cause X-linked sideroblastic anemia. We describe eight families with ALAS2 deletions, either c.1706-1709 delAGTG (p.E569GfsX24) or c.1699-1700 delAT (p.M567EfsX2), resulting in frameshifts that lead to replacement or deletion of the 19-20 C-terminal residues of the enzyme. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. These gain-of-function mutations cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease.

Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension, psychiatric symptoms and, in the worst cases, quadriplegia. Acute attacks, often precipitated by inappropriate drug therapy, are potentially fatal. While earlier workers thought the distal haem biosynthetic enzyme ferrochelatase may be involved in the genesis of VP, it was shown in the early 1980's, and is now accepted, that VP is associated with decreased protoporphyrinogen oxidase activity (PPO) (E.C.1.3.3.4). VP prevalence is much higher in South Africa than elsewhere; probably due to a founder effect with patients descending from a 17th century Dutch immigrant. PPO cDNAs from Bacillus subtilis, Myxococcus xanthus, human placenta and mouse liver have been cloned, sequenced and expressed. Human and mouse cDNAs consist of open reading frames 1431 nucleotides long, encoding a 477 amino acid protein. The human PPO gene contains thirteen exons, spanning approximately 4.5 kb. We have identified a C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W). A protein expressed from an in vitro-mutagenized PPO construct exhibits substantially less activity than the wild type. The R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Since at least one of these families is descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa.

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BackgroundWritten assessments fall into two classes: constructed-response or open-ended questions, such as the essay and a number of variants of the short-answer question, and selected-response or closed-ended questions; typically in the form of multiple-choice. It is widely believed that constructed response written questions test higher order cognitive processes in a manner that multiple-choice questions cannot, and consequently have higher validity.DiscussionAn extensive review of the literature suggests that in summative assessment neither premise is evidence-based. Well-structured open-ended and multiple-choice questions appear equivalent in their ability to assess higher cognitive functions, and performance in multiple-choice assessments may correlate more highly than the open-ended format with competence demonstrated in clinical practice following graduation. Studies of construct validity suggest that both formats measure essentially the same dimension, at least in mathematics, the physical sciences, biology and medicine. The persistence of the open-ended format in summative assessment may be due to the intuitive appeal of the belief that synthesising an answer to an open-ended question must be both more cognitively taxing and similar to actual experience than is selecting a correct response. I suggest that cognitive-constructivist learning theory would predict that a well-constructed context-rich multiple-choice item represents a complex problem-solving exercise which activates a sequence of cognitive processes which closely parallel those required in clinical practice, hence explaining the high validity of the multiple-choice format.SummaryThe evidence does not support the proposition that the open-ended assessment format is superior to the multiple-choice format, at least in exit-level summative assessment, in terms of either its ability to test higher-order cognitive functioning or its validity. This is explicable using a theory of mental models, which might predict that the multiple-choice format will have higher validity, a statement for which some empiric support exists. Given the superior reliability and cost-effectiveness of the multiple-choice format consideration should be given to phasing out open-ended format questions in summative assessment. Whether the same applies to non-exit-level assessment and formative assessment is a question which remains to be answered; particularly in terms of the educational effect of testing, an area which deserves intensive study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12909-014-0249-2) contains supplementary material, which is available to authorized users.