This condition was described simultaneously in Norway by the pediatrician Olga Imerslund (15
) and in Finland (16
). Many names have been used for the condition. The most commonly used name is Imerslund-Gräsbeck syndrome, abbreviated IGS (17
The first case was an 11-year old boy. Since the age of two he had been investigated and treated for megaloblastic anemia and proteinuria at irregular intervals. RG was consulted to elucidate the condition. It was found to be due to poor absorption of practically only Cbl. The case was reported at a pediatric congress in 1958 (18
). At this early stage, it was already assumed that the error was located in the ileal acceptor (receptor) for vitamin B12
and that something similar affected the kidney tubules known to have many properties in common with the intestine (18
The next Finnish case was found under circumstances that could be called serendipity: A student nurse in the ward where RG was a resident presented with identical symptoms. This strongly suggested that the two patients had the same disease or syndrome. That the condition was hereditary was suggested by the fact that the parents of the female patient were double cousins.
The two cases were thoroughly examined using up-to-date methods available to investigate Cbl deficiency because of the current research on tapeworm anemia in the department. Kidney biopsies were also performed. Suspecting that the condition represented a hitherto unknown disease entity a manuscript was drawn up. Just before its submission it was discovered that Olga Imerslund in Norway had collected similar cases and was preparing her dissertation. This confirmed that the syndrome existed and we published the article (16
) where the title indicated the pathogenesis ”selective vitamin B12
malabsorption”. The possible common origin of the intestinal and renal tubular conditions was also pointed out.
Imerslund’s dissertation describing 10 cases in 6 families (15
) demonstrated that the syndrome existed, that the condition was hereditary, autosomal and recessive, that functioning IF was secreted and that the patients did not respond to IF (gastric juice) given together with Cbl by mouth. In spite of the proteinuria, kidney function was and remained good. In addition, Imerslund found anomalies in the urinary tract (double ureters, horseshoe kidney). Such findings have not been made by others. Harald Broch, who has continued Imerslund’s work in Norway, has not found such new cases either (20 and personal communication). Combinations with other anomalies appear to be fortuitous (21
Imerslund’s dissertation did not pass ”probably because too few laboratory investigations had been made” (M. Seip letter to RG in 1994), which apparently means that few attempts at elucidating the pathogenetic mechanism had been made. Thus, it was not certain that the Finnish and Norwegian patients suffered from the same condition. However, using radioactive Cbl and other techniques Imerslund and Bjørnstad (22
) later made the same observations that had been made on the Finnish patients.
These first concrete observations were preceded by reports which may represent the same disease, but at the time of their publication radioactive Cbl absorption and other tests did not exist. The case reported by Najman & Brausil (23
) is usually quoted. These authors suggested that their case was due to low secretion of IF. Also, until recently there was little awareness that an absent or inactive IF could imitate IGS (24
Following the first reports, Lamy and colleagues (25
) quickly reported four similar cases from France. In 1967, we were aware of 47 cases (14
). At present, over 300 have been published worldwide, but in many cases the diagnosis may be uncertain and some represent cases of IFD (24
). In 2006, there were 27 cases from 19 families in Finland and 19 cases from 15 families in Norway (17
). Today, most new cases have appeared in the Middle East, and in Europe and North America about 50% of newly diagnosed cases are detected among recent immigrants from North Africa and the Middle East (unpublished results, S.M.T.). In Finland and Norway, the estimated prevalence is 1:200,000 (17
) but worldwide prevalence is hard to estimate. Most recently, a case from Thailand was confirmed genetically (unpublished results, S.M.T.).
Patient age at diagnosis varies from a few months to puberty. The patients present with diffuse symptoms such as failure to grow and thrive, pallor and fatigue, recurrent respiratory and gastrointestinal infections. Laboratory investigations usually reveal anemia, low serum-Cbl and/or proteinuria. In most cases, the neurological signs appear mild, but exceptions exist. An IGS case compound-heterozygous for two AMN
mutations showed severe psychiatric instability (26
). Only high-dose parenteral Cbl of 1 mg biweekly prevented behavioral relapses, while hematological symptoms were cured by a standard dose of 1 mg/month. The conclusion was that the Cbl receptor may play a role at the blood-brain barrier (26
). Nevertheless, Cbl deficiency may express itself only in the results of laboratory tests or after a meticulous search for clinical symptoms. Especially when the relatives of confirmed cases are examined, new cases may be discovered. Interesting possibilities are that children with mono-symptomatic ”benign” proteinuria or behavioral disturbances may suffer from undiagnosed IGS; therefore assay of serum Cbl of such patients seems advisable.
The combination of megaloblastic anemia and proteinuria attracted both discoverers of the syndrome. However, two of Imerslund’s original cases lacked proteinuria and in 1967, two of our 19 patients lacked proteinuria (14
). In a study of 13 Finnish patients (27
), only three clearly excreted increased amounts of total protein, including albumin and smaller amounts of transferrin, light immunoglobulin chains and alpha1
microglobulins. Three cases excreted only modest amounts of protein and the rest had barely increased excretion levels. One explanation for the finding of more non-proteinuric patients may be that the diagnosis was based on mutational analysis, which may reveal clinically less conspicuous patients among relatives of typical patients.
Olga Imerslund died in 1987 and her patients have been supervised since then by Harald Broch (20
). He and others, including ourselves have performed kidney biopsies on untreated and treated patients (14
). In untreated patients, weak signs of membranous glomerulonephritis were observed in light microscopy. In electron microscopy, mild signs of glomerulopathy of mesangioproliferative type, increased mesangial matrix, thickening of the basal membrane, and mesangial deposits were detected. Some patients have been biopsied before and after the correction of the deficiency state, and following treatment the pathological kidney findings have usually disappeared (14
). Broch recently reported to RG that the oldest Norwegian patient died in an accident. He had been biopsied before treatment and electron-microscopic changes had been observed, but they were absent in the specimens taken at autopsy. Evidently, the changes have been due to the Cbl deficiency, which affects all cells in the body, enterocytes included. But the proteinuria persists following Cbl treatment and is probably due to the malfunction of the receptor in the kidney (31
). There is general agreement that kidney function does not worsen in treated patients, some of which have been observed for more than 50 years.
Intestinal biopsies were performed at an early date and showed no pathology (14
). Considerable efforts were expended to elucidate the structure of the Cbl-IF receptor in the ileum and its defect in IGS. For instance, it was demonstrated that the binding to the receptor required calcium ions (33
) and later that the receptor contained two subunits (31
). The receptor has therefore been called cubam (cub
ilin and am
). Decreased urinary excretion of the receptor was found in the Finnish patients, whereas some Arab patients could even excrete increased amounts (36
). Those patients were probably incorrectly diagnosed and suffered from lack of IF. The overall conclusion was that the disease had subsets, apparently due to different genetic errors (37
). Then it was reported that the kidney receptor was identical with the intestinal one and also bound ligands other than Cbl-IF (38
). That the receptor had several ligands was philosophically satisfying, since it seemed ”luxurious” that evolution has produced one special membrane receptor for each substrate. It seems more likely that membrane transport mechanisms are variants on the same theme (40
). The detailed structure of the receptor was recently described and excellently illustrated by Nielsen & Christensen (41
) and Andersen et al. (42
). The similarity of the kidney and ileal receptors is striking, but the two may not be completely identical. The kidney receptor mediates the reabsorption of many proteins. Uptake of non-human proteins in the intestine would probably elicit an immune response and be an undesirable property perhaps removed during evolution. Incidentally, porcine IF causes an immune response when given by mouth to patients (43