Short Report

Journal of Inherited Metabolic Disease

, Volume 31, Supplement 3, pp 493-496

First online:

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

  • A. S. LuderAffiliated withDepartment of Paediatrics, Ziv Medical Center, Safed and Faculty of MedicineDepartment of Paediatrics, Ziv Medical Centre Email author 
  • , S. M. TannerAffiliated withHuman Cancer Genetics, Comprehensive Cancer Center, The Ohio State University
  • , A. de la ChapelleAffiliated withHuman Cancer Genetics, Comprehensive Cancer Center, The Ohio State University
  • , J. H. WalterAffiliated withWillink Biochemical Genetics Unit, Royal Manchester Children’s Hospital

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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.