Nasal potential difference measurements in patients with atypical cystic fibrosis

Abstract

The diagnosis of cystic fibrosis (CF) is based on characteristic clinical and laboratory findings. However, a subgroup of patients present with an atypical phenotype that comprises partial CF phenotype, borderline sweat tests and one or even no common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The aim of this study was to evaluate the role of nasal potential difference (PD) measurements in the diagnosis of CF patients with an atypical presentation and in a population of patients suspected to have CF.Nasal PD was measured in 162 patients from four different groups: patients with classical CF (n=31), atypical phenotype (n=11), controls (n=50), and patients with questionable CF (n=70). The parameter, or combination of nasal PD parameters was calculated in order to best discriminate all CF patients (including atypical CF) from the non-CF group.The patients with atypical CF disease had intermediate values of PD measurements between the CF and non-CF groups. The best discriminate model that assigned all atypical CF patients as CF used: e(response to chloride-free and isoproterenol/response to amiloride)with a cut-off >0.70 to predict a CF diagnosis. When this model was applied to the group of 70 patients with questionable CF, 24 patients had abnormal PD similar to the atypical CF group. These patients had higher levels of sweat chloride concentration and increased rate of CFTR mutations.Nasal potential difference is useful in diagnosis of patients with atypical cystic fibrosis. Taking into account both the sodium and chloride transport elements of the potential difference allows for better differentiation between atypical cystic fibrosis and noncystic fibrosis patients. This calculation may assist in the diagnostic work-up of patients whose diagnosis is questionable.

CFTR biomarkers: time for promotion to surrogate end-point

“…25 studies consistently show a statistically significant difference in chloride and sodium conductance between patients with cystic fibrosis and healthy controls. In patients with ''questionable'' cystic fibrosis, NPD composite scores provided a highly sensitive tool to diagnose patients as ''CF-likely'' and ''CF-unlikely'', with both cohorts having significantly different disease presentation [39,[77][78][79]. Data from studies with ataluren, ivacaftor, the CFTR corrector VX-809 and gene therapy confirm that NPD is a responsive endpoint.…”

Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin

“…In some of these patients (nos. 1, 3, and 4), the normalization of chloride transport was associated with improvement toward normalization of the basal nasal potential difference (NPD) (≥-30 mV) (40). The reason for this improvement in a subset of the patients is unclear.…”

“…It is important to note that in all previous clinical trials in CF patients, aminoglycosides (22,23,29) or other molecules (41-44) affected only the chloride transport All values are expressed as mV. The normal range for basal potential difference in our laboratory is ≥-30 mV, and the normal range of chloride transport is ≤-4 mV (40). A In all previous clinical trials in CF patients, aminoglycosides (22,23,29) or other molecules (41)(42)(43)(44) influenced only the chloride transport abnormality.…”

Biochemical and Molecular Genetic Testing Used in the Diagnosis and Assessment of Cystic Fibrosis

“…The profile of classic CF patients is characterized by hyperpolarization of basal PD, increased Na + channel activity, an amiloride response that is exaggerated, and there is very little or no response to chloride free and isoproterenol solutions. In non-classic CF the nasal PD may be borderline and there is not yet a total consensus as to what exactly constitutes an abnormal result, but a formula which takes into account both sodium and chloride transport has been proposed by Wilschanski and colleagues (Wilschanski et al, 2001). …”

“…Nasal PD measurement has been widely validated in adults (Knowles et al, 1995) and provides an easy, quick and painless tool to discriminate between adults with atypical CF and those presenting some CF symptoms without CF (Delmarco et al, 1997;Wilschanski et al, 2001). Therefore a NPD test showing a significant response to zero-chloride perfusate containing isoproterenol may be useful in ruling out a diagnosis of CF.…”