Contractile reserve and contrast uptake pattern by magnetic resonance imaging and functional recovery after reperfused myocardial infarction.

OBJECTIVES: We hypothesized that contrast-enhanced and dobutamine tagged magnetic resonance imaging (MRI) could investigate microvascular integrity and contractile reserve of reperfused myocardial infarction (MI) in one examination. BACKGROUND: In reperfused MI, microvascular integrity and contractile reserve are important determinants of functional recovery. METHODS: Twenty-three patients with a reperfused first MI were studied. On day 3+/-1 after MI, patients underwent tagged MRI at baseline and during infusion of 5 and 10 microg/kg/min of dobutamine followed by contrast-enhanced MRI (first pass and delayed imaging) after a bolus infusion of gadolinium-diethylenetriaminepenta-acetic acid. Tagged MRI was performed 9+/-1 weeks later (follow-up). Eighty-four transmural regions with hyperenhancement on delayed contrast-enhanced images were defined as COMB (first pass hypoenhancement) or HYPER (normal first pass signal enhancement). Percent circumferential segment shortening was measured within the subendocardium and subepicardum of each region of HYPER or COMB at baseline, peak dobutamine and follow-up. RESULTS: Shortening improved in COMB regions from 4+/-1% at baseline to 10+/-1% at peak dobutamine and 10+/-1% at follow-up, respectively (p<0.0003 vs. baseline for both). The HYPER regions likewise improved from 10+/-1% at baseline to 16+/-1% and 17+/-1%, respectively (p<0.0004 vs. baseline for both). Function within COMB regions was less than that of HYPER at baseline, peak dobutamine and follow-up (p<0.0003 for all). CONCLUSIONS: Dobutamine magnetic resonance tagging and contrast enhanced MRI are complementary in assessing functional recovery after reperfused MI. Regions of delayed contrast hyperenhancement demonstrate both contractile reserve and late functional recovery. However, if these regions demonstrate first pass contrast hypoenhancement, they are associated with greater myocardial damage.

Vitamin D receptor translation initiation codon polymorphism and markers of osteoporotic risk in older African-American women.

A polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene defined by the FokI restriction endonuclease has been associated with reduced bone mineral density (BMD) among Caucasian, Asian, and Mexican-American women. We tested the hypothesis that the FokI polymorphism is related to markers of osteoporotic risk in 104 community-dwelling African-American women aged 65 years and older. Six percent of the African-American women had the ff genotype, 32% were heterozygous, and 63% had the FF genotype. FokI genotype frequencies did not differ from Hardy-Weinberg expectations. Hip and calcaneal BMD, calcaneal ultrasound attenuation and hip geometry from pelvic radiographs did not differ significantly by FokI genotypes or between women with and without the rare FokI allele. There was also no association between the FokI polymorphism and biochemical markers of bone turnover or fractional calcium absorption. We conclude that the VDR start codon polymorphism does not have a major influence on osteoporotic risk in older African-American women.

Early contrast-enhanced MRI predicts late functional recovery after reperfused myocardial infarction.

BACKGROUND: We have observed 3 abnormal patterns on contrast-enhanced MRI early after reperfused myocardial infarction (MI): (1) absence of normal first-pass signal enhancement (HYPO), (2) normal first pass signal followed by hyperenhanced signal on delayed images (HYPER), or (3) both absence of normal first-pass enhancement and delayed hyperenhancement (COMB). This study examines the association between these patterns in the first week after MI and late recovery of myocardial contractile function by use of magnetic resonance myocardial tissue tagging. METHODS AND RESULTS: Seventeen patients (14 men) with a mean age of 53+/-12 years were studied after a reperfused first MI. Contrast-enhanced images were acquired immediately after bolus administration of gadolinium and 7+/-2 minutes later. Tagged images were acquired at weeks 1 and 7. Circumferential segment shortening (%S) was measured in regions displaying HYPER, COMB, or HYPO contrast patterns and in remote regions (REMOTE) at weeks 1 and 7. At week 1, %S was depressed in HYPER, COMB, and HYPO (9+/-8%, 7+/-6%, and 5+/-4%, respectively) and were less than REMOTE (18+/-6%, P<0.003). However, in HYPER, %S improved at week 7 from 9+/-8% to 18+/-5% (P<0.001 versus week 1). In contrast, HYPO did not improve significantly (5+/-4% to 6+/-3%, P=NS) and COMB tended to improve 7+/-6% to 11+/-6% (P=0.06). CONCLUSIONS: HYPER has partially reversible dysfunction and represents predominantly viable myocardium. COMB shows borderline improvement and likely contains an admixture of viable and necrotic myocardium. HYPO shows little functional improvement at 7 weeks, presumably because of irreversible myocardial damage.

Regional myocyte hypertrophy parallels regional myocardial dysfunction during post-infarct remodeling.

After large myocardial infarction (MI), left-ventricular (LV) remodeling is characterized by cavity dilatation, eccentric hypertrophy, and regional mechanical dysfunction. We wished to correlate cellular hypertrophy chronically after MI with in vivo function on a regional basis within non-infarcted myocardium. Twelve sheep were studied. Seven underwent coronary ligation to create an anteroapical MI. Magnetic resonance imaging (MRI) was performed once in controls, and prior to and 8 weeks after infarction, for measurement of LV mass, volumes, ejection fraction, and regional intramyocardial circumferential shortening (%S). Myocyte morphometric indices (cell volume, length, cross-sectional area, width, and length/width ratios) were measured from myocytes isolated from regions adjacent to (within 2 cm of the infarct border) and remote from the infarct and at corresponding loci in the control animals. From baseline to 8 weeks after infarction in the infarcted animals, end-diastolic volume increased from (mean+/-s.d.) 1.9+/-0.4 ml/kg to 2.6+/-0.4 ml/kg (P<0.02) and EF fell from 49+/-6 to 35+/-6% (P<0.02). LV mass trended upwards from 2.2+/-0.4 to 2.6+/-0.4 g/kg (P=n.s.). Regionally, %S in the region adjacent to the infarct fell (from 19+/-3 to 13+/-3%, P<0.003) while remote %S did not change. Cell volume in adjacent non-infarcted regions was greater than that in remote non-infarcted regions (3.8+/-0.9x10(4) micrometer3 v 2.6+/-0. 8x10(4) micrometer3, P<0.006) and this difference (+1.2+/-0.7x10(4) micrometer3) was greater than the corresponding regional difference in controls (+0.4+/-0.2x10(4) micrometer3, P<0.05). Similarly, myocytes in adjacent non-infarcted regions were longer (138.0+/-10.1 micrometer) than in remote regions (123.7+/-10.1 micrometer, P<0.002), and this difference (+14.3+/-7.2 micrometer) was greater than that in controls (-1.4+/-5.6 micrometer, P<0.003). Adjacent %S correlated inversely with adjacent myocyte cell volume (r=-0.72, P<0.009) and cell length (r=-0.70, P<0.02). In mechanically dysfunctional non-infarcted regions adjacent to chronic transmural myocardial infarction in the remodeled LV, disproportionate cellular hypertrophy occurs, predominantly due to an increase in cell length. Mechanical dysfunction in these regions correlates with cell lengthening and hypertrophy.

Quantitative assessment of myocardial viability after infarction by dobutamine magnetic resonance tagging.

BACKGROUND: The assessment of return of function within dysfunctional myocardium after acute myocardial infarction (MI) using contractile reserve has been primarily qualitative. Magnetic resonance (MR) myocardial tagging is a novel noninvasive method that measures intramyocardial function. We hypothesized that MR tagging could be used to quantify the intramyocardial response to low-dose dobutamine and relate this response to return of function in patients after first MI. METHODS AND RESULTS: Twenty patients with a first reperfused MI (age, 53+/-12 years; 16 male; 11 inferior MIs) were studied. Patients underwent breath-hold MR-tagged short-axis imaging on day 4+/-2 after MI at baseline and during dobutamine infusion at 5 and 10 microg x kg(-1) x min(-1). At 8+/-1 weeks after MI, patients returned for a follow-up MR tagging study without dobutamine. Quantification of percent intramyocardial circumferential segment shortening (%S) was performed. Low-dose dobutamine MRI was well tolerated. Overall, mean %S was 15+/-11% at baseline (n=227 segments), increased to 16+/-10% at 5 microg x kg(-1) x min(-1) dobutamine (P=NS), 21+/-10% at peak (P<0.0001 versus baseline and 5 microg x kg(-1) x min(-1), and 18+/-10% at 8 weeks (P<0.004 versus baseline and peak). The increase in %S with peak dobutamine was greater in dysfunctional myocardium (103 segments, +9+/-10%) than in normal tissue (124 segments, +4+/-12%, P<0.0001). In dysfunctional regions, %S also increased from 6+/-7% at baseline to 14+/-10% at 8 weeks after MI (P<0.0001). In dysfunctional regions that responded normally to peak dobutamine (> or =5% increase in %S), the increase in %S from baseline to 8 weeks after MI (+9+/-9%) was greater than in those regions that did not respond normally (+5+/-9%, P<0.04). Midmyocardial and subepicardial response to dobutamine were predictive of functional recovery, but the subendocardial response was not. CONCLUSIONS: The response of intramyocardial function to low-dose dobutamine after reperfused MI can be quantified with MR tagging. Dysfunctional tissue after MI demonstrates a larger contractile response to dobutamine than normal myocardium. A normal increase in shortening elicited by dobutamine within dysfunctional midwall and subepicardium predicts greater functional recovery at 8 weeks after MI, but the response within the subendocardium is not predictive.

Black-white differences in hip geometry. Study of Osteoporotic Fractures Research Group.

Previous studies have demonstrated that reduced thickness of the femoral neck and shaft cortex, a wider intertrochanteric region and a longer hip axis length were predictive of hip fracture among Caucasian women. We hypothesized that racial differences in these features of hip geometry may contribute to explaining the differences in hip fracture incidence between women of African origin and Caucasian women. We measured the cortical thickness and bone widths in 132 African-American women and 43 Nigerian women who were pair-matched on height (+/- 3 cm), age (+/- 5 years) and weight (+/- 3 kg) to 175 Caucasian women. Measures of cortical thickness were greater among women of African origin than Caucasian. Women of African origin had smaller bone widths and a shorter hip axis length than Caucasians. Several of these differences were independent of bone mineral density except for the cortical thickness of the femoral shaft. We conclude that women of African origin have thicker cortical bone of the hip, a shorter hip axis length and smaller intertrochanteric widths than Caucasians. Based on a model developed from hip fractures among Caucasian women, we predict that these observed racial differences could contribute to approximately a 25% decrease risk of hip fracture among blacks.

Dissociation between changes in intramyocardial function and left ventricular volumes in the eight weeks after first anterior myocardial infarction.

OBJECTIVES: We sought to examine the relation between regional changes in intramyocardial function and global left ventricular (LV) remodeling in the first 8 weeks after reperfused first anterior myocardial infarction (MI). BACKGROUND: Because of limitations in imaging methods used to date, this relation has not been thoroughly evaluated. METHODS: We studied 26 patients (21 men, 5 women; mean age 51 years) by magnetic resonance imaging (MRI) on day 5 +/- 2 (mean +/- SD) and week 8 +/- 1 after their first anterior MI. All patients had single-vessel left anterior descending coronary artery disease and although they had received reperfusion therapy, all had regional LV dysfunction and an initial ejection fraction (EF) < or = 50%. Short-axis magnetic resonance tagging was performed spanning the LV. Percent intramyocardial circumferential shortening (%S) on a topographic basis, LV mass index, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index and LV ejection fraction (LVEF) were measured. RESULTS: Left ventricular mass index tended to decrease, whereas the LVEDVI increased from 82 +/- 24 to 96 +/- 27 ml/m2 (p = 0.002). Left ventricular end-systolic volume index remained unchanged, whereas LVEF increased from 39 +/- 12% to 45 +/- 14% (p = 0.002). Apical %S improved from 9 +/- 6% to 13 +/- 5% (p < 0.0001), as it did in the midanterior (6 +/- 6% to 10 +/- 7%, p < 0.02) and midseptal regions (8 +/- 7% to 12 +/- 6%, p < 0.02). Early dysfunction in remote midinferior and basal lateral regions resolved by 8 weeks. By multivariate analysis, the only significant predictor of an increase in LVEDVI over the study period was peak creatine kinase (p = 0.04). CONCLUSIONS: In the first 8 weeks after a large, reperfused anterior MI, %S improved in the apex, midanterior and midseptal regions and normalized in remote noninfarct-related regions, but LV end-diastolic volumes also increased. This increased LVEDVI correlated with infarct size by peak creatine kinase and was not related to changes in global and regional LV function.

Breath-hold dobutamine magnetic resonance myocardial tagging: normal left ventricular response.

Analysis of the changes in myocardial deformation produced by adrenergic stress has been limited by the imaging techniques used. We used rapid magnetic resonance imaging (MRI) myocardial tagging to map the dose-dependent response to incremental dobutamine in the normal human left ventricle. Thirteen volunteers underwent breath-hold tagged cine MRI during dobutamine infusion. Images were acquired throughout systole to a peak dose of 20 microg/kg/min. End-systolic percent circumferential shortening (%S) was measured at 3 transmural locations and 4 circumferential locations at 3 long-axis positions. Mean circumferential shortening velocity (CSV) was also calculated at each location and dose. Mean %S reached a maximum of 26 +/- 3% at 10 microg/kg/min compared with 21 +/- 4% at baseline (p <0.003). Peak %S was reached by 10 microg/kg/min before a significant increase in heart rate or blood pressure and was unchanged at higher doses. In contrast, CSV increased linearly with dobutamine dose from 4.4 +/- 0.9 mm/s at baseline to 9.8 +/- 1.4 mm/s at 20 microg/kg/min (p <0.0001). Breath-hold tagged dobutamine MRI is safe and effective in detecting regional and transmural changes in function during incremental dobutamine. CSV increased continuously across the dobutamine dose range. At low dose (< or =10 microg/kg/min) %S increased without any change in blood pressure or heart rate. Maintenance of peak %S beyond 10 microg/kg/min in the presence of decreasing systolic intervals resulted from a continued increase in CSV. Thus, CSV may be the preferred measure of contractile function during dobutamine stimulation in human myocardium.

Reduced sympathetic innervation underlies adjacent noninfarcted region dysfunction during left ventricular remodeling.

OBJECTIVES: We examined the association of sympathetic denervation and reduced blood flow with mechanical dysfunction in adjacent noninfarcted regions late after myocardial infarction (MI). BACKGROUND: Using a well characterized ovine model of left ventricular (LV) remodeling after transmural anteroapical MI, we previously showed that histologically normal adjacent noninfarcted regions demonstrate mechanical dysfunction. METHODS: Ten sheep underwent coronary ligation. Magnetic resonance imaging was performed before and 8 weeks after infarction for measurement of LV mass, volumes, ejection fraction and regional intramyocardial circumferential shortening (%S). Iodine-123 metaiodobenzylguanidine (I-123 MIBG) and fluorescent microspheres before and after administration of adenosine were infused before death for measurement of sympathetic innervation, blood flow and blood flow reserve from matched postmortem regions. RESULTS: From baseline to 8 weeks after infarction, LV end-diastolic volume increased from (mean +/- SD) 1.5 +/- 0.3 to 2.6 +/- 0.5 ml/kg (p < 0.001), and LV mass increased from 2.0 +/- 0.3 to 2.6 +/- 0.5 g/kg (p = 0.001). Regionally, the decline in subendocardial %S was greater in adjacent (19 +/- 5% to 8 +/- 5%) than in remote noninfarcted regions (20 +/- 6% to 19 +/- 6%, p < 0.002). No difference in regional blood flow or blood flow reserve was found between adjacent and remote regions, whereas I-123 MIBG uptake was lower in adjacent than in remote myocardium (1.09 +/- 0.30 vs. 1.31 +/- 0.40 nmol/g, p < 0.003). Topographically, from apex to base at 8 weeks after infarction, %S correlated closely with I-123 MIBG uptake (r = 0.93, p = 0.003). CONCLUSIONS: In mechanically dysfunctional noninfarcted regions adjacent to chronic transmural myocardial infarction in the remodeled left ventricle, blood flow and blood flow reserve are preserved, yet sympathetic innervation is reduced. Chronic sympathetic denervation in adjacent noninfarcted regions, in association with regional mechanical dysfunction, may contribute to LV remodeling after infarction.

Usefulness of magnetic resonance imaging early after acute myocardial infarction.

In patients, early after acute myocardial infarction (AMI), rapid magnetic resonance imaging (MRI) techniques have been used to assess left ventricular (LV) structure, global and regional function, infarct artery patency, or contrast uptake individually. We hypothesized that MRI could be used as a comprehensive evaluation of the post-AMI patient, studying all of these parameters in < 1 hour. Twenty-seven patients were studied after first AMI. Complete examinations were performed in 23 patients, 16 with anterior and 7 with inferior wall myocardial infarction, on day 5 +/- 2 after the event. For measurement of LV structure and regional function, a breath-hold segmented k-space gradient echo tagging sequence was used. A fat-suppressed segmented k-space breath-hold sequence was used for coronary artery imaging. MRI contrast-enhanced images during bolus gadoteridol transit through the myocardium were obtained to assess first-pass contrast uptake. No adverse events were noted during the MRI scanning, which was completed in 46 +/- 5 minutes. The LV mass index, end-diastolic and end-systolic volume indexes, and ejection fraction were (mean +/- SD) 107 +/- 13 g/m2, 87 +/- 23 ml/m2, 54 +/- 20 ml/m2, and 39 +/- 12%, respectively. Intramyocardial percent circumferential shortening was 11 +/- 6% at the apex, 14 +/- 4% in the midventricle, and 15 +/- 4% at the base. Flow within all infarct arteries was visualized. Seventeen of 23 patients had regions of reduced contrast uptake on first-pass imaging with mean signal intensity of 47 +/- 24% that of remote regions. In patients with recent AMI, comprehensive assessment of LV structure and function, infarct artery patency, and regional myocardial contrast uptake was safe and feasible with MRI of < 1 hour.

Remote noninfarcted region dysfunction soon after first anterior myocardial infarction. A magnetic resonance tagging study.

BACKGROUND: Previous studies have demonstrated hyperkinetic endocardial motion of noninfarcted myocardium early after myocardial infarction (MI). We wished to substantiate the findings of increased function of remote noninfarcted regions using magnetic resonance (MR) myocardial tagging in patients soon after anterior MI. METHODS AND RESULTS: Twenty-eight patients (25 male; mean age, 52 years) were studied on day 5 +/- 2 after first anterior MI. All had single-vessel left anterior descending coronary artery (LAD) disease and had received reperfusion therapy but had evidence of regional left ventricular (LV) dysfunction and an ejection fraction (EF) < or = 50%. Breath-hold, segmented k-space, gradient-echo MR tagging was performed with short-axis imaging spanning the LV. Percent circumferential shortening (%S) on a topographic basis, LV mass, and EF were measured. Regional %S was compared with that in 10 normal subjects (7 male; mean age, 43 years). We found reduced intramyocardial %S throughout the LV in the patient group. Percent shortening was lower in patients compared with control subjects at all sites along the long axis of the ventricle (9 +/- 5% versus 23 +/- 3% at the apex, P < .0001; 11 +/- 5% versus 21 +/- 3% at the midventricle, P < .0001; 14 +/- 3% versus 17 +/- 5% at the base, P < .02). The basal lateral and midinferior regions, remote from LAD territory, demonstrated reduced %S and a strong trend toward reduced %S, respectively. CONCLUSIONS: Patients on day 5 after first anterior MI with single-vessel disease demonstrate reduced intramyocardial circumferential shortening throughout the LV, including remote noninfarcted regions. Potential mechanisms include altered coronary vasodilatory properties, changes in regional mechanical load, or mechanical tethering to infarcted regions.

Angiotensin-converting enzyme inhibition limits dysfunction in adjacent noninfarcted regions during left ventricular remodeling.

OBJECTIVES: We hypothesized that angiotensin-converting enzyme inhibitors would limit dysfunction in the first 8 weeks after transmural infarction in adjacent noninfarcted regions, as well as attenuate left ventricular remodeling. BACKGROUND: Angiotensin-converting enzyme inhibition limits ventricular dilation and hypertrophy and improves survival after anterior infarction, but its effect on regional function during remodeling is not well characterized. METHODS: Thirteen sheep underwent coronary ligation to create an anteroapical infarction. At postinfarction day 2, eight sheep were randomized to therapy with the angiotensin-converting enzyme inhibitor ramipril, and five sheep received no therapy. Animals were studied with magnetic resonance myocardial tagging before and 8 weeks after infarction. Left ventricular volume, mass and ejection fraction were measured, as were changes in percent circumferential shortening within the subendocardium and subepicardium of infarcted and noninfarcted myocardium, both adjacent to and remote from the infarction. RESULTS: Angiotensin-converting enzyme inhibition limited the increase in end-diastolic volume from a mean (+/- SD) of +1.5 +/- 0.7 ml/kg in control animals to +0.5 +/- 0.8 ml/kg in the treated group (p < 0.04). Segmental function within infarcted and remote noninfarcted tissue did not differ between groups. However, angiotensin-converting enzyme inhibition limited the decline in function in the adjacent noninfarcted region 8 weeks after infarction. Percent circumferential shortening in the subendocardium decreased by -13 +/- 5% in the control group compared with -5 +/- 5% in the treated group (p < 0.03). CONCLUSIONS: In concert with a reduction in left ventricular remodeling after anterior infarction, angiotensin-converting enzyme inhibition limits the decline in function in the adjacent noninfarcted region. Dysfunction in adjacent noninfarcted regions may be an important determinant of left ventricular remodeling after infarction.

"Twins in school". An Australia-wide program.

The multiple birth family is more likely to have a dispute with the education system than with any other service. So many potential areas of conflict exist over the abilities and behaviour of multiples and over such issues as separation or keeping back one twin. One reason for disputes is the lack of good data to adequately reflect the different perspectives of parents and teachers and the differing needs of families: the same solution does not apply to all. To provide the first large-scale data base and building upon an initial survey of 85% of all primary school teachers in South Australia, the LaTrobe Twin Study and AMBA worked with Education Departments to set-up in each state Education Research Teams (ERTs) of parents of multiples who were also teachers. The ERTs were crucial in three phases. 1) Developing and circulating questionnaires and publicising the nationwide survey. 784 families and 1264 teachers of their children completed these questionnaires, many reporting that simply having to address the issues raised in the questionnaire was a valuable learning experience. 2) Exploring the data base. Issues arising included the very different bases on which parents and teachers judged separation desirable, with teachers emphasising the unsubstantiated claim that separation is essential to individual development. Separation became more common over the first three years of schooling but 20-25% of twins separated one year were back together the next. 3) Running regional meetings of parents, teachers and administrators to discuss the results and to pool experiences and plan policies at the local level. A need clearly exists to improve the level of consultation between families and school personnel and to ensure the widespread availability of information which identifies key issues in making decisions for that multiple birth family.

Twin children in volunteer registries: biases in parental participation and reporting.

The biases in voluntary participation by adult twins are well known but less attention has been paid to twin children where parents decide on participation and provide much of the information. Several aspects of reporting including the assessment of zygosity are compared in four large Australian data bases: 1) a nationwide compulsory (and hence representative) survey of literacy and numeracy; 2) a nationwide "Twins in School" survey of parents and teachers of twins run through Education Departments and AMBA, the parents organisation in conjunction with LaTrobe; 3) the LaTrobe Twin Study which is a longitudinal program involving frequent interactions between families and researchers, and 4) the Australian NHMRC Twin Registry which has surveyed a large sample of their families with twin children by mail. One potential bias comes when recruitment is on a continuing basis as in the LaTrobe Twin Study and the Australian Twin Registry when differences between "early" and "late" enrolling families arise. One difference between the four samples arose from parents being much more likely to contrast their twins and to report problems in one but not the other, whereas teachers' and psychologists' assessments of these same children generally reported much smaller intrapair differences. Future studies should have some common questions to provide comparative data on such biases. Key questions are proposed for this area, mainly on the perceived need for different forms of remediation, together with other recommendations about the minimal essential baseline data set for a registry.

Individual variation and specific cognitive deficits in the fra(X) syndrome.

Mental retardation has been associated with fra(X) but comprehensive psychological evaluation has rarely been applied to 2 major behavioral questions 1) the extent of individual variation in IQ among fra(X) males and the possibility of some fra(X) males being of normal IQ; and 2) whether there is a depression in general IQ or whether specific abilities are impaired. The problems of developing an effective battery of tests for assessing fra(X) are discussed. These questions were examined in 54 individuals, comprising fra(X) males, their obligate carrier mothers and those sisters shown to have the fra(X). Among noninstitutionalised males nonverbal IQ as measured on a Block Design test ranged from 100 to 0, and vocabulary scores while generally higher, ranged from 79-33. The males scored low on a digit span memory task, while performance on a memory of objects task was adequate. Despite lower overall scores, a similar pattern and variability emerged in institutionalised males. Daughters were extremely variable in performance and the mothers performed much better, supporting the view that women who have children are a selected subset of fra(X) syndrome individuals. The performance of one male is discussed in detail. His vocabulary and nonverbal IQ scores were normal, despite his having other specific cognitive deficits. The pattern of abilities and behavior seen in fra(X) may result in an overestimation of intelligence and underestimation of penetrance when based on clinical impressions rather than formal psychological assessment. The implications of this for molecular and for population genetic approaches to fra(X) are discussed.