XPR1 mutations are a rare cause of primary familial brain calcification.

Mutations in XPR1, a gene encoding an inorganic phosphate exporter, have recently been identified in patients with primary familial brain calcification (PFBC). Using Sanger sequencing, we screened XPR1 in 18 unrelated patients with PFBC and no SLC20A2, PDGFB, or PDGFRB mutation. XPR1 variants were tested in an in vitro physiological complementation assay and patient blood cells were assessed ex vivo for phosphate export. We identified a novel c.260T > C, p.(Leu87Pro) XPR1 variant in a 41-year-old man complaining of micrographia and dysarthria and demonstrating mild parkinsonism, cerebellar ataxia and executive dysfunction. Brain (123)I-Ioflupane scintigraphy showed marked dopaminergic neuron loss. Peripheral blood cells from the patient exhibited decreased phosphate export. XPR1 in which we introduced the mutation was not detectable at the cell surface and did not lead to phosphate export. These results confirm that loss of XPR1-mediated phosphate export function causes PFBC, occurring in less than 8 % of cases negative for the other genes, and may be responsible for parkinsonism.

Sleep-related Cognitions Mediate the Impact of Neuroticism on Insomnia.

OBJECTIVES: Our study aimed to explore how neuroticism and neuroticism-related traits as well as sleep-related cognitions (dysfunctional beliefs and subjective quality of sleep) influence the emergence of insomnia using a mediational model. METHODS: A cross-sectional study was conducted in which 159 insomniac patients paired with 159 normal sleepers in sex and age (N = 318) completed an online questionnaire. RESULTS: At the global level, dysfunctional beliefs and poor subjective quality of sleep mediated the neuroticism-insomnia path; at the trait-specific level, these variables mediated the anxiety-insomnia path and partially mediated the effects of vulnerability and self-consciousness on insomnia; some other relations were essentially indirect effects (between depression and insomnia). CONCLUSIONS: These findings extend our understanding of how neuroticism is a predisposing factor of insomnia. This knowledge could be helpful to shape prevention and intervention programs to treat insomnia.

Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness.

OBJECTIVE: Narcolepsy is a rare disabling sleep disorder characterized by excessive daytime sleepiness and cataplexy (sudden loss of muscle tone). Drugs such as pitolisant, which block histamine H3 autoreceptors, constitute a newly identified class of stimulants because they increase brain histamine and enhance wakefulness in animal and human adult narcolepsy. METHODS: We report our experience with the off-label use of pitolisant in 4 teenagers with narcolepsy/cataplexy with severe daytime sleepiness, refractory to available treatments (modafinil, methylphenidate, mazindol, sodium oxybate, and D-amphetamine). RESULTS: All teenagers developed their disease during childhood (11.3 ± 2.4 years; 50% boys) and were 17.3 ± 0.8 years old at the time of pitolisant therapy. Pitolisant treatment was increased from 10 to 30 mg (n = 1) and 40 mg (n = 3). The adapted Epworth Sleepiness Score decreased from 14.3 ± 1.1 to 9.5 ± 2.9 (P = 0.03) with pitolisant alone to 7 ± 3.4 when combined with mazindol (n = 1), methylphenidate (n = 1), or sodium oxybate plus modafinil (n = 1). Mean sleep onset latency increased from 31 ± 14 minutes to 36 ± 8 minutes (P = 0.21) on the maintenance of wakefulness test. The severity and frequency of cataplexy were slightly improved. Adverse effects were minor (insomnia, headache, hot flushes, leg pain, and hallucinations) and transitory, except for insomnia, which persisted in 2 teenagers. The benefit was maintained after a mean of 13 months. CONCLUSIONS: Pitolisant could constitute an acceptable alternative for the treatment of refractory sleepiness in teenagers with narcolepsy.