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GLUTEN ATAXIA

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Definition
Epidemiology
Pathogenesis
Clinical features
Diagnosis

 

Definition

Gluten ataxia  was originally defined as sporadic or idiopathic ataxia with positive serological markers for gluten sensitization. Like Celiac disease, it is an autoimmune disease characterized by cerebellar damage resulting in ataxia.

Epidemiology

A medical research carried out in Sheffield (UK) on a group of 800 patients with progressive ataxia, evaluated over a period of 15 years, found that 148 out of 635 (23%) patients affected by sporadic ataxia had serological evidence of gluten sensitization (M. Hadjivassiliou, personal communication). Studies investigating the prevalence of anti-gliadin antibodies (AGA)in ataxias have been already published. Recurring theme in the main part of these studies is the consistently high prevalence of AGA in sporadic ataxias compared to healthy controls.

Pathogenesis

There is evidence to suggest the existence of antibody cross-reactivity between antigenic epitopes on Purkinje cells and gluten proteins. Widespread deposits of anti-transglutaminase antibodies around brain vessels in patients with Gluten ataxia have been found; most evident deposits are in cerebellum, pons and medulla. In patients suffering from Gluten  ataxia antibodies anti-tTG6, a primarily brain-expressed transglutaminase, have been detected. In Gluten ataxia and Dermatitis Herpetiformis IgA deposits seem to accumulate in the periphery of vessels, where on the other hand these are not usually found in healthy TG6 or TG3 individuals.

Using a mouse model, it has recently been shown that serum from Gluten ataxia patients, as well as monoclonal anti-tTG antibodies derived using “phage display”,  procedure, causes ataxia at intraventricular injection in mice. Therefore, these data provide evidence that anti-tTG antibodies (derived from patients'serum) compromise neuronal function in selected brain areas, suggesting the involvement of an immune-system independent mode of action.

 

 

Clinical features

Gluten ataxia usually presents itself as pure cerebellar ataxia or, less frequently, ataxia associated with myoclonus, palatal tremor and opsoclonus myoclonus. Gluten ataxia is usually characterized by an insidious onset (mean age at onset: 53 years). Ataxia can seldom be rapidly progressive. "Gaze-evoked” nystagmus and other ocular signs of cerebellar dysfunction have been noticed in more than 80% of cases. All patients have gait ataxia, and the majority have limb ataxia. Less than 10% of patients with Gluten Ataxia will develop gastrointestinal symptoms, but a third of them will have evidence of enteropathy on biopsy. Nevertheless, an intestinal biopsy is recommended when serum tTG2 antibodies are elevated. More than 60% of patients have neurophysiological evidence of sensorimotor, length-dependent axonal neuropathy. This is generally mild and does not contribute to ataxia. Moreover, more than 60% of patients with Gluten ataxia have evidence of cerebellar atrophy on magnetic resonance imaging. Even in those patients without cerebellar atrophy, a proton magnetic resonance spectroscopy of the cerebellum will be abnormal.

Response to treatment with gluten-free diet depends on the duration of ataxia before diagnosis. Loss of Purkinje cells in the cerebellum, the end result of prolonged gluten exposure in patients suffering from Gluten ataxia, is irreversible and a prompt treatment is more likely to result in improvement or stabilization of ataxia.

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Diagnosi

Diagnosis of Gluten ataxia is more complicated compared to Celiac disease. Anti-tTG2 IgA antibodies can be found in not more than 38% of patients, but often at lower titers than those detected in celiac patients. Nevertheless, unlike Celiac disease, anti-TG2 IgG antibodies are more copious than IgA. Antibodies against tTG2 and tTG6 combined can be found in 85% of patients with ataxia who are positive for AGA antibodies. Whether combined detection of anti-tTG2 e anti-tTG6 IgA and IgG without using AGA identifies all the patients with Gluten ataxia or not still remains unclear.

According to current recommendation, patients presenting  progressive cerebellar ataxia should be screened for Gluten Sensitivity using AGA IgG and IgA, anti-tTG2 antibodies and, if available, IgG and IgA anti-tTG6 antibodies. Patients with positive anti-tTG2 antibodies should undergo a duodenal biopsy. However, irrespective of the presence of enteropathy, patients who are positive for any of these antibodies with no alternative cause for their ataxia should embrace a strict gluten-free diet ;in addition, regular follow-up should be offered to them in order to ensure the elimination of antibodies, which usually takes 6 to 12 months. Stabilization or even improvement of ataxia after one year would be a strong indicator that the patient actually suffers from Gluten ataxia.

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Pagina aggiornata il: 14/12/2010