title: The role of hyperhomocysteinemia in neurological features associated with coeliac disease.
abstract: Although a range of neurological and psychiatric disorders are widely reported to be associated with coeliac patients, their pathogenesis remains unclear. Some such disorders are believed to be secondary to vitamin deficiency due to malabsorption, others to immune mechanisms. We hypothesise that hyperhomocysteinemia might, by damaging the blood-brain barrier, expose neuronal tissue to all neuro-irritative metabolites, such as homocysteine itself, a neurotoxic excitatory and proconvulsant amino acid. Neurons respond to these stimuli through hyperexcitability, thereby predisposing subjects to neurological disorders such as epilepsy and headache. Furthermore, persisting endothelial damage may cause blood extravasation and subsequent deposition of calcium salts. We suggest that this might be the pathogenesis of the CEC syndrome, which is characterized by the association of coeliac disease, epilepsy and cerebral calcifications. Indeed, homocysteine plays a well-known role in cardiovascular endothelial dysfunction, with high serum and cerebrospinal fluid levels often being reported in coeliac patients. Moreover, data in the literature show a strong, growing association of homocysteine with epilepsy and migraine in non-coeliac subjects. Despite these findings, homocysteine has never been held directly responsible for neuronal functional features (neuronal hyperexcitability underlying epilepsy and migraine) and structural brain damage (expressed as cerebral calcification) in coeliac patients. Damage to the blood-brain barrier might also facilitate immune reactions against neuronal tissue to a considerable extent. This hypothesis combines the two afore-mentioned theories (vitamin deficiency due to malabsorption and immune mechanisms). We also wish to point out that no studies have yet investigated the prevalence of neuronal hyperexcitability and subclinical electroencephalic abnormalities in children and adults with newly-diagnosed coeliac disease before the introduction of a gluten-free diet, and in particular any changes following the introduction of the diet. We believe that the onset of clinical symptoms such as migraine and convulsions is preceded by a period in which damage is expressed exclusively by subclinical electroencephalic abnormalities; persisting damage to neuronal tissue subsequently leads to clinical manifestations. We propose two types of investigations: the first is to determine whether newly-diagnosed coeliac patients with hyperhomocysteinemia are a subgroup at risk for neurological features (clinical and subclinical); the second is to determine whether appropriate treatment of hyperhomocysteinemia and vitamin B status deficiency improves neurological abnormalities and reduces the risk of cerebral calcifications. The aim of these investigations is to develop new therapeutic strategies designed to prevent neuronal damage and increase the quality of life in children affected by such disorders.
authors.affiliation: Pediatric Sleep Disease Centre, Child Neurology, NESMOS Department, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa 1035-39, 00189 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ferretti
authors.forename: Pasquale
authors.initials: P
authors.lastname: Parisi
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Villa
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology*; D002446:Celiac Disease / Q000150:complications* / Q000188:drug therapy; D002648:Child; D006710:Homocysteine / Q000633:toxicity*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects*; D014804:Vitamin B Deficiency
chemical_list: D006710:Homocysteine