Journal of Inherited Metabolic Disease

, Volume 31, Supplement 3, pp 493–496

Amnionless (AMN) mutations in Imerslund–Gräsbeck syndrome may be associated with disturbed vitamin B12 transport into the CNS

  • A. S. Luder
  • S. M. Tanner
  • A. de la Chapelle
  • J. H. Walter
Short Report

DOI: 10.1007/s10545-007-0760-2

Cite this article as:
Luder, A.S., Tanner, S.M., de la Chapelle, A. et al. J Inherit Metab Dis (2008) 31: 493. doi:10.1007/s10545-007-0760-2

Summary

Familial selective vitamin B12 (cobalamin, Cbl) malabsorption (Imerslund–Gräsbeck syndrome, IGS, OMIM 261100) is a group of autosomal recessive disorders characterized by selective malabsorption of Cbl from the terminal ileum in the presence of normal histology. Mutations in the amnionless (AMN) and cubilin (CUBN) genes are known to be causes of IGS. Their gene products combine to form a receptor complex (cubam), which is instrumental in the binding and transport of Cbl in the gut. As opposed to Cbl transport in the terminal ileum, normal transport of Cbl into the CNS is poorly understood and little is known regarding its molecular basis. Studies in adults with neuropsychiatric disease have suggested the presence of an active transport mechanism into the central nervous system constituting a blood–brain barrier (BBB) for Cbl. A child with IGS, compound heterozygous for a missense and a nonsense mutation in the amnionless (AMN) protein gene, was noted to have a high daily cobalamin (Cbl) requirement for neuropsychiatric, but not for systemic metabolic and haematological, remission. Measurements of CSF Cbl revealed evidence that the transport of Cbl into the central nervous system was impaired, and a standard Schilling test was consistent with a dose response of cobalamin transport across the terminal ileum. Amnionless protein is known to be expressed in the fetal and postnatal central nervous system, and is known to be involved in Cbl transport in other tissues such as kidney as well as the gut. It is possible that an active Cbl transport mechanism at the BBB exists, and that the amnionless (AMN) protein may be part of this mechanism, as it is in cobalamin transport in the terminal ileum.

Abbreviations

AMN

amnionless

BBB

blood–brain-barrier

Cbl

cobalamin

CNS

central nervous system

CSF

cerebrospinal fluid

CUBN

cubilin

IF

intrinsic factor

IGS

Imerslund–Gräsbeck syndrome

Copyright information

© SSIEM 2007

Authors and Affiliations

  • A. S. Luder
    • 1
    • 4
  • S. M. Tanner
    • 2
  • A. de la Chapelle
    • 2
  • J. H. Walter
    • 3
  1. 1.Department of Paediatrics, Ziv Medical Center, Safed and Faculty of MedicineTechnionIsrael
  2. 2.Human Cancer Genetics, Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA
  3. 3.Willink Biochemical Genetics UnitRoyal Manchester Children’s HospitalManchesterUK
  4. 4.Department of PaediatricsZiv Medical CentreSafedIsrael