Gillian Lockitch

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.

Perspectives on lead toxicity

Lead toxicity causes hematological, gastrointestinal, and neurological dysfunction in adults and children. Symptoms are usually noted with blood lead greater than 1.93 mumol/L. Severe or prolonged exposure may also cause chronic nephropathy, hypertension, and reproductive impairment. Lead inhibits enzymes; alters cellular calcium metabolism; stimulates synthesis of binding proteins in kidney, brain, and bone; and slows nerve conduction. Less severe exposure to lead, designated by blood lead levels of 0.48-0.96 mumol/L, has been implicated in poor pregnancy outcome, impaired neurobehavioral development, reduced stature in young children, and higher blood pressure in adults. Biochemical and systemic effects of high and low level lead toxicity are described. Dust, water, and paint chips are still major sources of lead but lead from folk remedies, cosmetics, food supplements, food preparation utensils, and improperly prepared infant formula has caused epidemic and sporadic severe lead toxicity. Screening for pediatric low level lead exposure requires measurement of blood lead.

Natural history of juvenile haemochromatosis

Summary. 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.

Selenium: Clinical Significance and Analytical Concepts

Selenium is an essential trace element in humans and animals. Its only established function in humans is the antioxidant activity of glutathione peroxidase, a selenoenzyme. Severe prolonged deficiency may cause a fatal cardiomyopathy. Iatrogenic causes of selenium deficiency include parenteral and enteral nutrition. Low plasma selenium is also found in malabsorption, cystic fibrosis, rheumatoid arthritis, neoplasia, and other varied clinical disorders. Death has resulted from a single massive ingestion of selenium, while chronic excessive intake causes skin, nail, and hair pathology. Extreme geographical variation in population blood and urine selenium levels and a marked age-specific variation in population reference intervals are important factors in understanding selenium nutrition. Nutritional requirements, biological availability, and metabolism are discussed in relation to geographical, age, and method variability. Sampling, processing procedures, and methods for selenium quantitation are reviewed. Selenium content in different biological matrices and reference values for pediatric, adult, and obstetric populations are provided.

Selenium deficiency in low birth weight neonates: An unrecognized problem

To determine whether selenium deficiency is common among low birth weight infants in our neonatal intensive care unit, we surveyed blood samples from healthy full-term and preterm infants born in our hospital over a 3-month period. Selenium was measured by electrothermal atomic absorption spectrometry. Glutathione peroxidase was measured in plasma by an automated method. Baseline (less than 72 hours postnatal) selenium concentration and glutathione peroxidase activity were significantly lower in low birth weight infants than in full-term babies. Sequential selenium analyses were obtained in 16 sick low birth weight neonates who remained in the intensive care nursery for up to 6 weeks because of lung disease. All were fed parenterally without supplemental selenium, with or without oral intake, for periods varying from 3 to 60 days. All had a marked decrease from baseline selenium levels, and values below the detection limit of our assay were found in seven infants. Selenium deficiency is much more common in small infants than is generally realized, but the clinical significance in neonates is poorly understood.

Clinical Biochemistry of Pregnancy

Major adaptations in maternal physiology and metabolism are required for successful pregnancy outcome. Hormonal changes initiated even before conception significantly alter maternal biochemistry early in pregnancy. Steroid hormones, peptide hormones, and prostaglandins interact to expand blood and plasma volume and modulate the maternal capacity to supply energy and nutrients to the fetoplacental unit. As gestation progresses, reference ranges for the concentration of many biochemical parameters change significantly from those found in the nonpregnant state. Gestation-specific reference ranges are essential for correct interpretation of tests used in screening, diagnosis, and monitoring during pregnancy. The use of clinical laboratory tests in the management of high-risk pregnancy are discussed from the perspective of testing before conception and during pregnancy.

Thiamine, riboflavin, and pyridoxine deficiencies in a population of critically ill children

The unexpected autopsy finding of Wernicke encephalopathy in three children who died after prolonged enteral feeding prompted us to examine the incidence of thiamine deficiency in three high-risk pediatric populations. We also measured riboflavin and pyridoxine activity in the same groups. We used activated enzyme assays (erythrocyte transketolase, glutathione reductase, aspartate aminotransferase) to assess tissue stores of the dependent vitamin cofactors (thiamine (vitamin B1), riboflavin (vitamin B2), and pyridoxine (vitamin B6), respectively). Using our own reference ranges based on data from 80 healthy adults and children, we prospectively investigated the B vitamin status of three groups of children: (1) 27 patients who were fed solely by nasogastric tube for more than 6 months, (2) 80 children admitted to a pediatric intensive care unit for more than 2 weeks, and (3) 6 children receiving intensive chemotherapy. The upper limits for stimulated enzyme activity in control subjects were unaffected by age or gender (16% for transketolase, 63% for glutathione reductase, 123% for aspartate aminotransferase). Using these limits, 10 (12.5%) of 80 patients receiving intensive care and 4 of 6 patients receiving chemotherapy were thiamine deficient. Elevated levels returned to normal after thiamine supplementation. No patients were pyridoxine deficient, but 3 (3.8%) of the 80 patients receiving intensive care and 1 of the 6 patients receiving chemotherapy were also riboflavin deficient. We conclude that unrecognized thiamine deficiency is common in our pediatric intensive care and oncology groups. This potentially fatal but treatable disease can occur in malnourished patients of any age and is probably underdiagnosed among chronically ill children. Our findings may be applicable to other high-risk pediatric groups.

A new mutation (G51C) in the iron-responsive element (IRE) of L-ferritin associated with hyperferritinaemia-cataract syndrome decreases the binding affinity of the mutated IRE for iron-regulatory proteins

Hereditary hyperferritinaemia–cataract syndrome is an autosomal dominant disorder characterized by a constitutively increased synthesis of l‐ferritin in the absence of iron overload. The disorder is associated with point mutations in the iron‐responsive element (IRE) of l‐ferritin mRNA. We report a new mutation, G51C, identified in two members of a Canadian family, presenting a moderate increase in serum ferritin and a clinically silent bilateral cataract. Gel retardation assays showed that the binding of the mutated IRE to iron‐regulatory proteins (IRPs) was reduced compared with the wild type. Structural modelling predicted that the G51C induces a rearrangement of base pairing at the lateral bulge of the IRE structure which is likely to modify IRE conformation.

Blood serotonin concentrations and fenfluramine therapy in autistic children

Whole-blood serotonin concentrations of 31 autistic children, aged 2 1/2 to 16 years, 10 non-autistic retarded children, and 18 children with Down syndrome were measured by a fluorometric method and compared with those of normal children of similar age range. No significant difference in the serotonin concentration per milliliter of whole blood or per 1000 platelets was found between groups for autistic, retarded, or normal children, but the values for those with Down syndrome were significantly lower. A double-blind cross-over study on the effect of fenfluramine versus placebo in seven autistic boys over a period of 8 months demonstrated a significant decrease in blood serotonin levels during the fenfluramine phase in all subjects. Slight improvements were found in short-term auditory memory and some measures of receptive language skills, particularly in children functioning at a high level. There was no significant change in global psychometric measurements of general intelligence during therapy. No adverse clinical effect was observed other than weight loss of 6% in one child. We conclude that fenfluramine may have some selective favorable effects on increasing attention in high-functioning autistic children. Blood serotonin concentration may be followed as an indication of drug compliance during fenfluramine therapy, but does not appear to reflect clinical efficacy.

Infection and immunity in Down syndrome: A trial of long-term low oral doses of zinc†

To determine whether orally administered zinc supplements could correct the abnormal humoral and cell-mediated immunity of Down syndrome, we randomly assigned 64 children with Down syndrome, aged 1 to 19 years and living at home, to receive either zinc gluconate or placebo daily for 6-month periods with crossover from one regimen to another. Control subjects were siblings and age-matched, unrelated children. Serum zinc, copper, and measures of immune system competence were tested at 3- or 6-month intervals. Parents kept daily logs of clinical symptoms such as cough and diarrhea and of physician visits. Mean serum zinc concentrations increased to about 150% of baseline during zinc supplementation, but we found no effect on serum levels of copper, immunoglobulins, or complement; on lymphocyte number or subset distribution; or on in vitro response to mitogens. Children with Down syndrome who were receiving zinc had a trend toward fewer days or episodes of cough and fever but no change in other clinical variables. Long-term, low-dose oral zinc supplementation to improve depressed immune response or to decrease infections in children with Down syndrome cannot be recommended.