Cobalamin (vitamin B(12)) in subacute combined degeneration and beyond: traditional interpretations and novel theories.
Subacute combined degeneration (SCD) is a neuropathy due to cobalamin (Cbl) (vitamin B(12)) deficiency acquired in adult age. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomized rat, to reproduce the key morphological features of the disease [spongy vacuolation, intramyelinic and interstitial edema of the white matter of the central nervous system (CNS), and astrogliosis], and found new mechanisms responsible for the pathogenesis of SCD: the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumor necrosis factor (TNF)-alpha and the reduced synthesis of the two neurotrophic agents, epidermal growth factor (EGF) and interleukin-6. This deregulation of the balance between TNF-alpha and EGF synthesis induced by Cbl deficiency has been verified in the sera of patients with pernicious anemia (but not in those with iron-deficient anemia), and in the cerebrospinal fluid (CSF) of SCD patients. These new functions are not linked to the coenzyme functions of the vitamin, but it is still unknown whether they involve genetic or epigenetic mechanisms. Low Cbl levels have also been repeatedly observed in the sera and/or CSF of patients with Alzheimer's disease or multiple sclerosis, but whether Cbl deficit plays a role in the pathogenesis of these diseases is still unclear.
Scalabrino
Giuseppe
G
Institute of General Pathology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Mangiagalli 31, I-20133 Milan, Italy. giuseppe.scalabrino@unimi.it
D000818:Animals; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism; D005743:Gastrectomy; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008954:Models, Biological; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014805:Vitamin B 12 / Q000737:chemistry / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000150:complications*
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D014805:Vitamin B 12