IMERSLUND-GRÄSBECK SYNDROME; EVIDENCE FOR A FUNCTIONAL BLOOD-BRAIN BARRIER FOR VITAMIN B12

A.S. Luder^{1 2}, A.Rappaport³,

¹Department of Paediatrics and Genetics Unit, Sieff Hospital, Safed, and ²Faculty of Medicine, Technion-lsrael Institute of Technology, Haifa; ³Kupat-Holim HMO, Galilee Region, Israel

OBJECTIVE: Little is known about the mechanisms of vitamin B12 transport into the central nervous system (CNS). The traditional view has been that B12 is carried to the CNS by the B12-transcobolamin II complex, is released, and enters the CNS by diffusion at a rate determined by the serum level. Imerslund-Grasbeck syndrome (IGS) is a group of rare autosomal recessive diseases characterised by congenital malabsorption of vitamin B12, proteinuria and malformations of the genito-urinary tract. In IGS the defective uptake and transport of B12-lntrinsic Factor (IF) complex by enterocytes in the terminal ileum is due to molecular lesions in specific membrane receptors or intra-cytoplasmic transport proteins. The CNS B12 dynamics of children with this syndrome are poorly understood. A patient with IGS provided an opportunity to evaluate gastro-intestinal B12 absorption, and the B12 blood-brain gradient.

METHODS: A 3 year old boy with low serum B12, megaloblastic anaemia, poor wound healing, proteinuria and hypospadias, was diagnosed with IGS. He exhibited severe behavioural problems and personality disorder. Following treatment with i.m. (and later sub-lingual) hydroxycobolamin, all his symptoms and signs disappeared. An isotope study of gastro-intestinal (Gl) absorption (with and without added IF, Schilling test) was carried out. CSF and plasma B12 levels were measured in parallel.

RESULTS: The patient required at least 2000/ig hydroxycobolamin per month to remain neurologically (but not haematologically) asymptomatic (RDA 60µg/month), suggesting a high threshold for blood-brain transport. Gl B12 absorption without added IF was markedly reduced (4%, Schilling test), and was partially corrected to 10% with added IF (expected >20%). This was interpreted as indicating defective ileal enterocyte B12 absorption, with a reduced Km and/or Vmax. Such a result would be expected if a receptor protein component had reduced affinity for B12-IF complex. Direct measurement of CSF showed a low B12 level of 3.3 pmol/L (6-26) with a serum level of 1,620 pmol/L (CSF:plasma ratio of 0.002, normal >0.05).

CONCLUSIONS: A high B12 plasma:CSF gradient exists in IGS, compatible with a functional blood-brain barrier for vitamin B12. Vitamin B12 transport into the CNS is probably mediated by an active, receptor-dependent mechanism. There is reduced gut vitamin B12-IF absorption in IGS, partially correctable with added IF. The co-existence of defective Gl absorption and a blood-brain transport defect in this IGS patient, strongly suggests that a common protein is involved in enterocyte and blood-brain transport. These observations have important implications for the IGS, for vitamin B12 physiology, and the mechanisms controlling transport of B12 into the CNS.