Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.

Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2). Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly. Here we report the positional cloning of the locus associated with juvenile hemochromatosis and the identification of a new gene crucial to iron metabolism. We finely mapped the recombinant interval in families of Greek descent and identified multiple deleterious mutations in a transcription unit of previously unknown function (LOC148738), now called HFE2, whose protein product we call hemojuvelin. Analysis of Greek, Canadian and French families indicated that one mutation, the amino acid substitution G320V, was observed in all three populations and accounted for two-thirds of the mutations found. HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism. Urinary hepcidin levels were depressed in individuals with juvenile hemochromatosis, suggesting that hemojuvelin is probably not the hepcidin receptor. Rather, HFE2 seems to modulate hepcidin expression.

The human cytochrome c oxidase assembly factors SCO1 and SCO2 have regulatory roles in the maintenance of cellular copper homeostasis.

Human SCO1 and SCO2 are metallochaperones that are essential for the assembly of the catalytic core of cytochrome c oxidase (COX). Here we show that they have additional, unexpected roles in cellular copper homeostasis. Mutations in either SCO result in a cellular copper deficiency that is both tissue and allele specific. This phenotype can be dissociated from the defects in COX assembly and is suppressed by overexpression of SCO2, but not SCO1. Overexpression of a SCO1 mutant in control cells in which wild-type SCO1 levels were reduced by shRNA recapitulates the copper-deficiency phenotype in SCO1 patient cells. The copper-deficiency phenotype reflects not a change in high-affinity copper uptake but rather a proportional increase in copper efflux. These results suggest a mitochondrial pathway for the regulation of cellular copper content that involves signaling through SCO1 and SCO2, perhaps by their thiol redox or metal-binding state.

Maternal-fetal risk assessment.

In first-world countries, maternal and infant mortality has significantly decreased over the past 50 years due to factors such as skilled pregnancy care practitioners, aseptic hospital births, antibiotics, safe blood transfusions, and oxytocin. However, international maternal and infant mortality statistics from underdeveloped countries remain high. Pregnancy risk management requires implementation of risk-reduction strategies that have been proven to be effective. Marked physiological alterations in biochemical indices that occur in pregnancy require that laboratories participating in the evaluation of new interventions in pregnancy must ensure that tests are compared to appropriate gestation-specific reference intervals.

Reference limits for copper and iron in liver biopsies.

Using 141 liver biopsy results (103 adults, 38 children) and a rank-order approach, the following reference limits were found: copper 55 microg/g dry weight, iron 1800 microg/g dry weight (adults only), and iron index 1.0. The study was made feasible by the fact that both copper and iron were measured as standard practice in every liver biopsy received for either test. The added analyte tended to contribute more to normal results. Specimens with elevations of both were infrequent (7 of 141) and significant elevations of both (copper >200 microg/g, iron index >2.0) were suggestive of contamination. Advantages of using patient data included studying specimens of limited availability and acquiring information on the distribution of elevated results seen in clinical practice. Disadvantages included increased uncertainty in the reference limits relative to a normal population. Although most of the study population consisted of patients referred for diagnosis of Wilson's disease or hemochromatosis, the reference intervals were similar to those reported from autopsy studies.

Increased levels of mercury associated with high fish intakes among children from Vancouver, Canada.

OBJECTIVE: To assess exposure to mercury (Hg) among children in population subgroups whose traditional dietary practices include fish. STUDY DESIGN: We determined blood Hg, red blood cell phosphatidylethanolamine omega-3 eicosapentaenoic acid as a marker of fish intake, and assessed indexes of childhood behavior in preschool children 1.5 to 5 years of age (n = 228) living in an ethnically diverse neighborhood in Vancouver, British Columbia, Canada. RESULTS: The median blood Hg was 4.6 nmol/L, range 0-67.9 nmol/L. Twelve (6%) children, all of whom were Chinese, had a blood Hg > 28.9 nmol/L. Blood Hg, total fish intake, and eicosapentaenoic acid were higher among Chinese than Caucasian children; however, higher fish intake did not predict blood Hg. Blood Hg was inversely associated with attentional focusing in children over 3 years of age after adjusting for confounding family variables, iron deficiency anemia, and zinc deficiency. Major sources of fish among Chinese children were imported fish rather than local fish. CONCLUSION: Children from population subgroups within populations not considered at risk may be at increased risk of neurotoxicity caused by Hg exposure from fish.

Teaching pediatric laboratory medicine to pathology residents.

CONTEXT: Laboratory data are essential to the medical care of fetuses, infants, children, and adolescents. However, the performance and interpretation of laboratory tests on specimens from these patients, which may constitute a significant component of the workload in general hospitals and integrated health care systems as well as specialized perinatal or pediatric centers, present unique challenges to the clinical pathologist and the laboratory. Therefore, pathology residents should receive training in pediatric laboratory medicine. OBJECTIVE: Children's Health Improvement through Laboratory Diagnostics, a group of pathologists and laboratory scientists with interest and expertise in pediatric laboratory medicine, convened a task force to develop a list of curriculum topics, key resources, and training experiences in pediatric laboratory medicine for trainees in anatomic and clinical pathology or straight clinical pathology residency programs and in pediatric pathology fellowship programs. DATA SOURCES: Based on the experiences of 11 training programs, we have compiled a comprehensive list of pediatric topics in the areas of clinical chemistry, endocrinology, hematology, urinalysis, coagulation medicine, transfusion medicine, immunology, microbiology and virology, biochemical genetics, cytogenetics and molecular diagnostics, point of care testing, and laboratory management. This report also includes recommendations for training experiences and a list of key texts and other resources in pediatric laboratory medicine. CONCLUSIONS: Clinical pathologists should be trained to meet the laboratory medicine needs of pediatric patients and to assist the clinicians caring for these patients with the selection and interpretation of laboratory studies. This review helps program directors tailor their curricula to more effectively provide this training.

A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis.

We report a new mutation, Asn185Asp, in exon 6 of the ferroportin gene (FPN1) in 15 members of three successive generations of a Canadian family of Scandinavian origin with autosomal dominant hemochromatosis. Hyperferritinemia with low transferrin saturation was noted in younger family members, seven of whom were aged 20 years or less at the time of diagnosis. In those individuals first diagnosed with hemochromatosis in later life, marked hyperferritinemia was accompanied by high transferrin saturation. In contrast to the phenotype of high ferritin with low saturation first reported for ferroportin disease, this family demonstrates a phenotype of iron indices that varies with age.

Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation.

Zinc is a common supplement and is widely available as a standard component of many over-the-counter products. A number of reports have identified an association between excessive zinc intake and severe cytopenia. We report a case of zinc-induced copper deficiency in a young adult to illustrate this under-recognized cause of anemia and neutropenia.

Alpha-fetoprotein values in amniotic fluid obtained during early amniocentesis (11-13 weeks).

OBJECTIVES: To determine the normal values of alpha-fetoprotein (AFP) in amniotic fluid between the gestational ages of 11 and 13 weeks and compare these with previously published values. METHODS: Amniotic fluid AFP was analyzed in 149 patients who had undergone amniocentesis between 11 +/- 0 and 13 +/- 6 weeks gestation as part of the pilot study of the Canadian Early and Mid-Trimester Amniocentesis Trial. Analysis was done using the Abbott IMX System (Abbott Laboratories Diagnostic Division, Abbott Park, Ill.). These values were then compared with previously published values. RESULTS: There is a progressive and linear rise in the amniotic fluid AFP concentration from 11 to 13 weeks gestation. The differences between each of the three gestational ages were statistically significant at the 0.05 level. The values differed significantly from those obtained by Crandall et al. [Am J Obstet Gynecol 1989;160:1204-1206], which were also consistently higher. CONCLUSION: Although reference points for 11, 12 and 13 weeks have been established, there are limitations to their clinical application.

Natural history of juvenile haemochromatosis.

Juvenile haemochromatosis or haemochromatosis type 2 is a rare autosomal recessive disorder which causes iron overload at a young age, affects both sexes equally and is characterized by a prevalence of hypogonadism and cardiopathy. Patients with haemochromatosis type 2 have been reported in different ethnic groups. Linkage to chromosome 1q has been established recently, but the gene remains unknown. We report the analysis of the phenotype of 29 patients from 20 families of different ethnic origin with a juvenile 1q-associated disease. We also compared the clinical expression of 26 juvenile haemochromatosis patients with that of 93 C282Y homozygous males and of 11 subjects with haemochromatosis type 3. Patients with haemochromatosis type 2 were statistically younger at presentation and had a more severe iron burden than C282Y homozygotes and haemochromatosis type 3 patients. They were more frequently affected by cardiopathy, hypogonadism and reduced glucose tolerance. In contrast cirrhosis was not statistically different among the three groups. These data suggest that the rapid iron accumulation in haemochromatosis type 2 causes preferential tissue damage. Our results clarify the natural history of the disease and are compatible with the hypothesis that the HFE2 gene has greater influence on iron absorption than other haemochromatosis-associated genes.

Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.

Hereditary hemochromatosis (HH) is classically associated with a Cys282Tyr (C282Y) mutation of the HFE gene. Non-C282Y HH is a heterogeneous group accounting for 15% of HH in Northern Europe. Pathogenic mutations of the transferrin receptor 2 (TfR2) gene have been identified in 4 Italian pedigrees with the latter syndrome. The goal of this study was to perform a mutational analysis of the TfR2 and HFE genes in a cohort of non-C282Y iron overload patients of mixed ethnic backgrounds. Several sequence variants were identified within the TfR2 gene, including a homozygous missense change in exon 17, c2069 A-->C, which changes a glutamine to a proline residue at position 690. This putative mutation was found in a severely affected Portuguese man and 2 family members with the same genotype. In summary, pathologic TfR2 mutations are present outside of Italy, accounting for a small proportion of non-C282Y HH.