Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions.

BACKGROUND: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have been associated with variably overlapping phenotypes of Leber's hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads also to a Leigh-like phenotype. CASE PRESENTATION: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1 mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6) subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H background, were also present. CONCLUSION: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the primary LHON mutation.

Quality of life in patients with craniocervical dystonia: Italian validation of the "Cervical Dystonia Impact Profile (CDIP-58)" and the "Craniocervical Dystonia Questionnaire (CDQ-24)".

Dystonia is a disabling and disfiguring disorder that can often affect many aspects of patients' daily lives, and lower their self-esteem. To date, quality of life (QoL) has been assessed in dystonic patients using generic measures that do not address the specific problems of this diagnostic group. Recently, two disease-specific scales "The Cervical Dystonia Impact Profile (CDIP-58)" and the "Craniocervical Dystonia Questionnaire (CDQ-24)" were validated for measuring QoL in craniocervical dystonia patients. No disease-specific scales for QoL for dystonic patients are currently available in Italian. The aim of our study was to produce and validate the Italian version of the CDIP-58 and CDQ-24. We obtained the Italian version of CDQ-24 and CDIP-58 with a back-translation design. Both scales were applied to a population of 94 craniocervical dystonia patients along with the Short Form 36 health-survey questionnaire (SF-36), both before and 4 weeks after botulinum toxin therapy. A group of 65 controls matched for sex, age and comorbidity underwent the SF-36. Internal consistency was satisfactory for all subscales. Both the CDIP-58 and CDQ-24 showed moderate to high correlations with similar items of the SF-36. Sensitivity to change was confirmed by highly significant improvements in all CDQ-24 subscales and by moderate improvements in three out of eight CDIP-58 subscales and total score. This is the first Italian study on QoL in dystonia patients. We validated the Italian version of two disease-specific questionnaires to evaluate QoL in craniocervical dystonia patients. These scales could be useful for both clinical practice and clinical trials.

The Indirect Impact of COVID-19 on Major Clinical Outcomes of People With Parkinson's Disease or Parkinsonism: A Cohort Study.

Background: The indirect impact of the COVID-19 epidemic on major clinical outcomes of people with Parkinson's disease (PD) or other parkinsonism is unknown. Objectives: The study aimed to (1) describe changes in healthcare services during the first epidemic bout in people with PD or parkinsonism; (2) compare the occurrence of hospitalization for any PD-related major clinical outcomes in 2020 with 2019; (3) investigate the factors, including changes in healthcare services, associated with major clinical outcomes and death. Methods: All healthcare services of the province of Bologna and major clinical outcomes were assessed through a record linkage study (ParkLink Bologna) using clinical data and health databases. Same analyses were performed in a random cohort of controls matched for age, sex, district of residence, and comorbidities with the ParkLink cohort (ratio of 1:10). Results: A cohort of subjects with PD (759) or other parkinsonism (192) was included together with a cohort of controls (9,226). All indicators of healthcare services dropped at least below 50% during the lockdown period in all cohorts, mostly impacting physiotherapy in people with PD (-93%, 95% CI 88-96%). In 2020, compared to 2019, a three-fold risk of major injuries (RR 3.0, 95% CI 1.5-6.2) and infections (RR 3.3, 95% CI 1.5-7.2), excluding COVID-19, was observed only in people with PD, and neither in people with parkinsonism nor in controls. Decreased physiotherapy was associated with the occurrence of at least one major clinical outcome (OR 3.3, 95% CI 1.1-9.8) in people with PD. Experiencing at least one major clinical outcome was the strongest risk factor for death (OR 30.4, 95% CI 11.1-83.4) in people with PD. Conclusions: During the first COVID-19 epidemic peak, healthcare services were drastically reduced in a province of northern Italy, regardless of the disease condition. However, compared to 2019, in 2020, only people with PD had a higher risk of major clinical outcomes, that were associated with higher mortality. Strategies to maintain physical activity in people with PD should be implemented in possible future health emergencies.

Premotor antidepressants use differs according to Parkinson's disease subtype: A cohort study.

BACKGROUND: Depression is more frequently associated with akinetic-rigid/postural instability gait difficulty subtypes of Parkinson's disease than with tremor-dominant subtype. OBJECTIVES: The aim of the study is to investigate the frequency of exposure to antidepressant drugs, as proxy of depression, before motor onset according to Parkinson's disease subtypes. METHOD: Based on a historical cohort design, the exposure to antidepressant drugs before Parkinson's disease motor onset was obtained from the drug prescription database and assessed in the resident population of the Local Healthcare Trust of Bologna (443,117 subjects older than 35 years). Diagnosis of Parkinson's disease and subtype (tremor dominant, non-tremor dominant) at onset were recorded by neurologists and obtained from the "ParkLink Bologna" record linkage system. Exposure to antidepressants was compared both to the general population and between the two subtypes. RESULTS: From 2006 to 2018, 198 patients had a tremor dominant subtype at onset whereas 450 did not. Comparison with the general population for antidepressant exposure showed an adjusted hazard ratio of 0.86 (95% CI 0.44-1.70) for the tremor dominant subtype and 1.66 (1.16-2.39) for the non-tremor dominant subtype. Comparison of non-tremor dominant with tremor dominant subtypes showed an adjusted odds ratio of 1.86 (1.05-3.95) for antidepressant exposure. CONCLUSIONS: In our study, non-tremor dominant Parkinson's disease at onset was significantly associated with exposure to antidepressants in comparison to the general population and in comparison with the tremor dominant subtype. These results support the hypothesis of different biological substrates for different Parkinson's disease subtypes even before motor onset.

Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation.

None: Mutations in exons 21 and 20 of the DMNT1 gene have been associated with two multisystem neurodegenerative diseases that involve central and peripheral nervous system ADCADN (Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy) and HSAN 1E (Hereditary Sensory and Autonomic Neuropathy IE). We describe a new case of ADCADN that was referred to us in the suspicion of secondary narcolepsy. A 44-year-old female with personal and familiar longstanding history of progressive bilateral sensorineural deafness, and sensitive cerebellar ataxia, presenting with brief episodes of falls while laughing and excessive diurnal somnolence. Clinical and neurophysiological evaluations reveled signs of cerebellar, pyramidal, peripheral, cognitive involvement, and optical atrophy. A 48-hour continuous polysomnography (PSG) and Multiple Sleep Latency Test at first evaluation revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency without sleep onset REM periods (SOREMPs). Normal level of cerebrospinal fluid (CSF) hypocretine 1 was detected. Given the reminiscence with DNMT 1 spectrum a direct sequencing of exons 20 and 21 of the DNMT1 gene was performed revealing the p.Glu575Lys mutation in exon 21 in the proband and her mother. During the 4 years of follow-up her walking ability declined, she became more somnolent and repeated PSG documented REM sleep latency shortening, and finally the evidence of de novo spontaneous SOREMPs, although normal CSF hrct-1 at second revaluation. This case highlights the progressive course of disease although a full-blown picture of classical narcolepsy type 1 was never reached.

Clinical pharmacokinetics of pramipexole, ropinirole and rotigotine in patients with Parkinson's disease.

INTRODUCTION: Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non-ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. METHODS: The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. RESULTS: Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients >65 years than ≤65 years (158 vs 94, p < 0.001), while was not affected by age in ROP and ROT subgroups. No sex-mediated differences in C/D ratios were observed in any group. CONCLUSION: These are the first observations on DAs pharmacokinetics in PD patients' everyday clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients.

Rotigotine Objectively Improves Sleep in Parkinson's Disease: An Open-Label Pilot Study with Actigraphic Recording.

Sleep disturbances represent important predictors of poor quality of life (QoL) in Parkinson's disease (PD). This open-label pilot study aimed to objectively assess, by means of actigraphic recording, effect of rotigotine on sleep in PD patients with self-reported sleep complaints. 15 PD patients underwent one-week actigraphic recording before (T0) and during (T1) rotigotine treatment, which was titrated to the dose subjectively improving motor symptoms (4-8 mg/24 h). Sleep disturbances, daytime sleepiness, cognitive performance, QoL, and depression were also evaluated with questionnaires. Actigraphic recordings showed a significant reduction in nocturnal motor activity and mean duration of wake episodes after sleep onset during rotigotine treatment compared to baseline. In 10 patients presenting objective evidence of poor sleep quality at T0 (sleep efficiency ≤ 85%), rotigotine also significantly improved other sleep parameters and further reduced nocturnal motor activity and mean duration of wake episodes. A significant decrease in number and duration of daytime sleep episodes was also observed at T1. Finally we confirmed that rotigotine significantly improves perceived sleep quality and QoL. Our study showed for the first time that rotigotine is associated with an objective improvement of nocturnal and diurnal sleep disturbances in PD patients with self-reported sleep complaints. This study is registered with AIFA-observational study registry number 12021.