Robin M. Bannerman

The familial occurrence of intracranial aneurysms.

INTRACRANIAL saccular aneurysms are usually regarded as congenital in origin but their etiology is unknown. Any clue that might lead to better understanding of their pathogenesis is worth pursuit, and one such clue is their familial occurrence. One of us has recently reported 3 families, each with 2 affected individuals.lP2 We have subsequently studied these families in greater detail and the results are reported here. We have also reviewed other familial cases previously published and personally communicated to us. In addition, we have attempted to collect information on variations in incidence of intracranial aneurysm in different countries and ethnic groups. While the role of genetic factors in most cases of intracranial aneurysm is unknown, aneurysms occasionally may be due to the inheritance of a single mutant gene, such as those occurring as a complication of the dominantly inherited disorders of connective tissue (for instance, the Ehlers-Danlos ~yndrome,~.3,* which is reported in the first pedigree set out here) or in association with polycystic kidneys.5.6 These examples show that intracranial saccular aneurysms are a heterogeneous disorder; i.e., the same clinical and pathological syndrome is produced by more than one cause. We have attempted to discern whether other familial cases could be separated from the larger group.

Hereditary defect of intestinal iron transport in mice with sex-linked anemia

Iron transport by everted duodenal sacs in vitro was studied in mice with sex-linked anemia (gene symbol sla) (an inherited iron deficiency anemia), in normal mice, and in normal mice on iron-deficient and iron supplemented diets. Although the over-all mucosal uptake of iron was the same in sla and normal sacs, transport of iron to the inside of the sac was much decreased in sla. The iron transport defect in sla was emphasized by the fact that genotypically normal mice on an iron-deficient diet demonstrated greatly increased iron transport. Electrophoretic analysis of protein extracted from sla and normal sacs showed only one iron-binding fraction. The sla and normal fractions had the same mobility and corresponded in position to the major band of horse ferritin. It thus appears that the iron deficiency of sla is due to a genetically determined defect in mucosal iron transport and that this defect is not associated with any demonstrable abnormality of a major iron-binding protein.

A new familial syndrome characterized by pigmentary retinopathy, hypogonadism, mental retardation, nerve deafness and glucose intolerance

Three siblings with retinitis pigmentosa, deafness and mental retardation were studied. Physical abnormalities included nystagmus, acanthosis nigricans and multiple keloids. The two male siblings had gynecomastia, small testes and mild subvirilization whereas the only indication of hypogonadism in the female sibling was oligomenorrhea. Testosterone levels in the males, which were in the low to low normal range, were increased by the administration of large doses of chorionic gonadotropin. The two affected males had elevated plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels which were decreased by the administration of testosterone and increased by the administration of clomiphene. One sibling had mild obesity and diabetes mellitus, one had moderate obesity, normal glucose tolerance and hyperinsulinism and the third had abnormal glucose tolerance and hyperinsulinism. This familial syndrome is distinct from either the Laurence-Moon, Bardet-Biedl or Alström disorders and provides further evidence of genetic heterogeneity in this group of autosomal recessive traits.

Sex-Linked Anemia: A Hypochromic Anemia of Mice

This hereditary anemia is most severe in young mice and tends to diminish with increasing age. Erythrocytes show great variation in size and form, with hypochromia and formation of target cells. Though the anemia occurs on a normal diet, it responds rapidly to iron-dextran injection. It may represent an unusual primary disturbance of iron metabolism.

X-linked hypochromic anaemia of mice.

An X‐linked recessive mutant gene (symbol sla) in the mouse causes hypochromic anaemia in hemizygous males and homozygous females; heterozygous carrier females show only slight changes. A detailed assessment of the anaemia is presented here. The red cells show a wide variety of morphological changes, including target cell formation, and the MCV is strikingly reduced. The anaemia and morphological changes tend to regress with increasing age. The anaemia also responds to parenteral iron‐dextran treatment, but not to pyridoxine and other agents.

Hereditary microcytic anaemia in the mouse; studies in iron distribution and metabolism

Summary. Iron distribution and metabolism have been studied in hereditary iiiicrocytic anaemia of tlie mouse (gene symbol mk), an autosonial recessive trait cliaractcrizcd by hypoclironiia and microcytosis. Evidence of iron deficiency was hutid in the forin of depleted body stores, hyposidcraemia, an increased total iron biiiding capacity of tlic plasma and a high free erythrocyte‐protoporyhyrin level. I lowcvcr, the failure to find citlicr rapid clearance and high utilization of tracer doses of 59Fe or a complete response to pareliteral iron treatment indicated that simple iron deficiency was not the cause of tlie anaemia. It is suggested that generalized impairmcn t in tlie cellular uptake of iron involvingthe transfer of iron from the intestinal lumen to tlic mucosa and from tlie plasma to the erythroblast may provide a unitary explaiiation of licreditary microcytic anaemia.

Iron metabolism and absorption studies in the X-linked anaemia of mice.

Summary. The X‐linked anaemia of mice (gene symbol, sla) is hypochromic and microcytic, and the stainable iron stores are reduced. Chemical estimates of total body iron content and serum iron concentration show low values and the total serum iron binding capacity is elevated in anaemic mice. Rapid plasma iron clearance and increased iron utilization provide further confirmation of iron deficiency in anaemic animals. Alterations in activity of haem‐containing enzymes have been sought in the heart, liver and kidney of anaemic mice, and slightly decreased activity found only in kidney cytochrome oxidase.

Iron Deficiency Anaemia in Newborn sla Mice: a Genetic Defect of Placental Iron Transport

Summary. . Newborn mice with X‐linked anaemia (gene symbol sla) have lower haemoglobin levels at birth than normal and carrier mice but there is considerable overlap. Serial observations showed that the haemoglobin values of segregating male mice separate into a bimodal distribution by 42 d of age, and 50 d values were used to assign genotypes retrospectively. The anaemia in newborn sla mice is attributable to iron deficiency, since their total body iron is lower than in normal newborn mice, while their birth weights are almost identical.

ABNORMALITIES OF HEME AND PYRROLE METABOLISM IN THALASSEMIA.

The problem of the nature of the biochemical mechanisms by which thalassemia genes act is both puzzling and exciting. The concept of a and P types of thalassemia’ is immensely valuable in systematizing our views on the control of globin production and receives new support from the direct observations of Marks and Burka.’ At the same time a number of abnormalities of heme and pyrrole metabolism have now been reported and we even suggested a few years ago that the primary defect might be in heme synthesis.s It seems appropriate, therefore, to consider some of the information available about the heme side of the story.

Pyrrole pigments in normal and congenitally anaemic mice (+/+, W/Wv, ha/ha, nb/nb, mk/mk, f/f and sla/Y)

Abstract 1. Values for faecal urobilinogen (UBG), serum bilirubin, and free erythrocyte protoporphyrin (FEP) are reported for normal and anaemic mice with six different hereditary anaemias. 2. Greatly increased faecal UBG and elevated serum bilirubin were found in mice with severe haemolytic anaemia (nb/nbandha/ha). 3. Mice with microcytosis (mk/mk) and sex-linked anaemia (sla/Y), both showed increased FEP and only moderate increase of faecal UBG. 4. Values for W/Wv mice fell within the normal ranges. 5. FEP levels in normal 15-day foetal red cells were extremely high. Levels for 15-day flexed anaemic foetuses (f/f) were lower, but markedly aboved adult level.