Novel C19orf12 loss-of-function variant leading to neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited disorders characterised by cerebral iron overload mainly in the basal ganglia. Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a form of NBIA caused by pathogenic C19orf12 gene variants. We report on a Romanian patient with MPAN confirmed through exome sequencing, revealing a homozygous nonsense variant in the C19orf12 gene, NM_001031726.3: c.215T>G (p.Leu72*), that co-segregates with disease in tested relatives: the patient`s parents, younger brother and paternal uncle are heterozygous carriers. This is a novel disease-causing variant in the C19orf12 gene and the first reported MPAN case in a Romanian patient.

Effects of nebicapone on levodopa pharmacokinetics, catechol-O-methyltransferase activity, and motor fluctuations in patients with Parkinson disease.

OBJECTIVE: To investigate the effects of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone. METHODS: Randomized, double-blind, placebo-controlled, 4-way crossover study consisting of 4 treatment periods (6-9 days duration each) in 19 patients (65.3 +/- 8.5 years) treated with carbidopa/levodopa 3 to 7 times per day. Nebicapone/entacapone/placebo and carbidopa/levodopa doses were administered concomitantly. At the end of each period, a levodopa test was performed, and levodopa and 3-O-methyldopa levels and COMT activity were assayed. RESULTS: After 75 mg nebicapone, 150 mg nebicapone, and 200 mg entacapone, levodopa area under the plasma concentration time curve significantly increased 28.1, 48.4, and 33.3%, and 3-O-methyldopa area under the plasma concentration time curve significantly decreased 59.2, 70.8, and 59.1%, respectively. Peak COMT inhibition was similar between active treatments, but extent of COMT inhibition was more sustained with 75 and 150 mg nebicapone than with 200 mg entacapone. After the levodopa test doses, ON time significantly increased 29 minutes with 75 mg nebicapone, 45 minutes with 150 mg nebicapone, and 16 minutes with 200 mg entacapone. Patients' diaries showed a decrease in daily OFF time of 109 minutes with 75 mg nebicapone, 103 minutes with 150 mg nebicapone, and 71 minutes with 200 mg entacapone, and an increase in daily ON time of 74, 101, and 74 minutes, respectively. Treatments were generally well tolerated and safe; no relevant changes in liver function tests were reported. CONCLUSIONS: Nebicapone, a new COMT inhibitor, significantly decreased COMT activity, increased systemic exposure to levodopa, and improved motor response. Nebicapone deserves further evaluation in larger samples of patients.