Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

BACKGROUND: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. METHODS: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. RESULTS: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]. CONCLUSIONS: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

EFAS/EAN survey on the influence of the COVID-19 pandemic on European clinical autonomic education and research.

PURPOSE: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe. METHODS: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders. RESULTS: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year. CONCLUSIONS: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design.

Amyloid detection and typing yield of skin biopsy in systemic amyloidosis and polyneuropathy.

OBJECTIVE: Disease-modifying therapies are available for amyloidosis but are ineffective if end-organ damage is severe. As small fiber neuropathy is an early and common feature of amyloidosis, we assessed detection and typing yield of skin biopsy for amyloid in patients with confirmed systemic amyloidosis and neuropathic symptoms. METHODS: In this case-control study, patients with transthyretin and light chain amyloidosis (ATTRv, ATTRwt, and AL) were consecutively recruited. They were sex and age-matched to three control groups (1) non-neuropathic controls (NNC), (2) monoclonal gammopathy of undetermined significance (MGUS), and (3) other neuropathic disease controls (ONC). Patients underwent a double 3 mm skin biopsy in proximal and distal leg. Amyloid index and burden, protein typing by immuno-electron microscopy, intraepidermal nerve fiber density, electroneuromyography, and clinical characteristics were analyzed. RESULTS: We studied 15 subjects with confirmed systemic amyloidosis, 20 NNC, 18 MGUS, and 20 ONC. Amyloid was detected in 100% of patients with amyloidosis (87% in ankle and 73% in thigh). It was not detected in any of the control groups. A small fiber neuropathy was encountered in 100% of amyloidosis patients, in 80% of MGUS, and in 78% of ONC. Amyloid burden was higher in ATTRv, followed by AL and ATTRwt. The ultrastructural examination allowed the identification of the precursor protein by immunotyping in most of the cases. INTERPRETATION: Skin biopsy is a minimally invasive test with optimal sensitivity for amyloid. It allows amyloid typing by electron microscope to identify the precursor protein. The diagnostic work up of systemic amyloidosis should include a skin biopsy.

Impact of the COVID-19 pandemic on clinical autonomic practice in Europe A survey of the European Academy of Neurology (EAN) and the European Federation of Autonomic Societies (EFAS).

OBJECTIVE: To investigate the impact of the coronavirus-disease-2019 (COVID-19) pandemic on European clinical autonomic practice. METHODS: Eighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021. RESULTS: Forty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every-third center reported major adverse events due to postponed examinations or visits. The most frequent newly-diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension, and recurrent vasovagal syncope, deemed likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new-onset of orthostatic intolerance, but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly-diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently POTS and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50-100% recovery rates at follow-up. CONCLUSIONS: Cardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, while the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints.

Clinical autonomic nervous system laboratories in Europe: A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies: A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies.

BACKGROUND AND PURPOSE: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. METHODS: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. RESULTS: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). CONCLUSIONS: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies.

Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.

Impairment of sleep homeostasis in cervical dystonia patients.

Alterations in brain plasticity seem to play a role in the pathophysiology of cervical dystonia (CD). Since evidences indicate that sleep regulates brain plasticity, we hypothesized that an alteration in sleep homeostatic mechanisms may be involved in the pathogenesis of CD. We explored sleep in control subjects (CTL) and CD patients before (Tpre-BoNT) and after (Tpost-BoNT) botulinum toxin (BoNT) treatment. A physiological slow wave activity (SWA) power decrease throughout the night was observed in CTL but not in CD at Tpre-BoNT. BoNT restored the physiological SWA decrease in CD at Tpost-BoNT. Furthermore, in the first part of the night, CD at Tpost-BNT showed a frontal increase and parietal decrease in SWA power compared to CD at Tpre-BoNT, with a SWA distribution comparable to that observed in CTL. Our data highlighted a pathophysiological relationship between SWA during sleep and CD and provided novel insight into the transient central plastic effect of BoNT.

Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson's disease.

The proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.

Searching food during the night: the role of video-polysomnography in the characterization of the night eating syndrome.

OBJECTIVES: To describe the video-polysomnographic (VPSG) features of the night eating syndrome (NES), exploring the existence of potential subtypes. METHODS: In this study, 20 consecutive patients with NES according to the most recent diagnostic criteria underwent an overnight VPSG. None of them presented with a sleep-related eating disorder (SRED). VPSG recordings were reviewed identifying all eating episodes. For each episode, eating latency (time delay from awakening to food intake), eating duration (time between eating onset to eating offset) and sleep latency after eating offset (time delay from eating offset to sleep) were calculated. Total episode duration was considered as the time between awakening and sleep latency after eating offset. RESULTS: Ten patients fulfilled the A1 core criterion for NES (evening hyperphagia with consumption of at least 25% of the daily caloric intake after the evening meal); within this group, eight patients also fulfilled the A2 criterion (at least two episodes of nocturnal eating per week) and were thus included in the evening hyperphagia (EH) subgroup. The remaining 10 patients satisfied only the A2 core criterion for NES, constituting the nocturnal ingestion (NI) subgroup. We recorded 20 eating episodes, seven in the EH group and 13 in the NI group. In the EH subgroup, three eating episodes occurred before sleep onset, one after an awakening from non-rapid eye movement (NREM) stage 1 sleep, two from NREM stage 2 and one from REM sleep. All 13 NI episodes occurred after an awakening from sleep (1 from NREM stage 1 sleep, 8 from NREM stage 2 and four from NREM stage 3). In EH patients, eating latency, total episode duration and sleep latency after eating offset were significantly longer than in NI patients. CONCLUSION: Our VPSG data from a case series of 20 patients referred to our center for nocturnal eating indicate potential different NES subtypes. This distinction may have an impact on patients' treatment and follow-up.

Restless legs syndrome, periodic limb movements during sleep and cardiovascular risk.

Multiple mechanisms may modulate an association between restless legs syndrome/Willis-Ekbom disease (RLS/WED) and cardiovascular disease (CVD), including chronic sleep deprivation, intermittent, periodic limb movements in sleep (PLMS)-related autonomic fluctuations and possible autonomic dysfunction intrinsically associated with RLS per se. The purpose of this paper is to review the existing RLS/WED literature focusing on the pathophysiologic evidence for possible associations between RLS/WED and PLMS with CVD and events (CVE). Specific intrinsic dysautonomic aspects of the disease, which may contribute to generating CVD, are separately discussed. The association between RLS/WED and both CV risk factors and CVD still remains elusive. Although several shared pathophysiological causes could explain these possible relationships, the emerging body of literature focusing on these disorders remains controversial. Not only longitudinal population-based studies and meta-analyses, but also more animal models and therapeutic interventions are needed in order to build a sufficiently robust body of evidence on this topic.

Autonomic impairment as a potential biomarker in idiopathic REM-sleep-behavior disorder.

Autonomic dysfunction is common in REM-sleep behavior disorder (RBD). Several studies have demonstrated abnormalities in heart rate variability, cardiac scintigraphy, and cardiovascular autonomic reflex testing. In addition, the type and severity of these abnormalities may correlate with rate of phenoconversion from idiopathic RBD (iRBD) to manifest neurodegenerative disease. This article summarizes the current literature on autonomic impairment in iRBD, with specific focus on the role of autonomic impairment as a potential biomarker of disease progression. REM sleep physiology and relevant anatomy is also discussed in relation to the central autonomic network and autonomic neurodegeneration.

Nightmare disorder and REM sleep behavior disorder in inflammatory arthritis: Possibility beyond neurodegeneration.

OBJECTIVES: To investigate the prevalence of REM sleep behavior disorder (RBD) in patients with inflammatory arthritis (IA) to ascertain if RBD could be an internal red flag signaling a fluctuating state of inflammation based on the theory of "protoconsciousness". MATERIALS & METHODS: One hundred and three patients with a confirmed diagnosis of IA were consecutively recruited. The patients underwent general (IA activity, functional status, laboratory tests) and neurological evaluations. A neurologist investigated RBD and REM sleep parasomnias in a semi-structured interview. Sleep quality was assessed with the Pittsburgh Sleep Quality Index, while the risk of obstructive sleep apnea syndrome (OSAS) was evaluated with the Berlin questionnaire. Beck Depression Inventory II and State-Trait Anxiety Inventory investigated depression and anxiety. RESULTS: Patients had a mean age of 53.7 ± 14.6 years, 65% were women; 57.3% were in a clinically active phase of IA. Two women fulfilled ICSD-3 criteria for RBD appearing 11 years after and 20 years before IA onset respectively. 31 patients scored positive for nightmare disorder (ND), 8 for recurrent isolated sleep paralysis. 65 (63.1%) patients reported poor sleep quality and 25 (24.3%) resulted at high risk for OSAS. 32 (31.0%) patients scored positively for depression or anxiety. CONCLUSIONS: The prevalence of RBD in patients with IA did not differ from that in the general population, whereas ND presented a 2-fold increased prevalence. Whether RBD can be considered a red flag signaling an internal danger remains an open question, while ND may be a new player in this intriguing relation.

REM sleep without atonia with REM sleep-related motor events: broadening the spectrum of REM sleep behavior disorder.

Study Objectives: To assess the presence of increased REM-related motor activity during sleep, by questionnaires for REM sleep behavior disorder (RBD), in participants with "isolated" REM sleep without atonia (RWA). Participants and Methods: Two hundred forty-nine patients were consecutively enrolled, with age ≥18 years, sharing bedroom with a roommate, and without a severe health, neurological, or cognitive problem. Motor activity during sleep was assessed by means of the RBD Screening Questionnaire (RBDSQ) and the RBD questionnaire-Hong Kong (RBDQ-HK). A video-polysomnographic recording was obtained and the REM Atonia Index was computed. Thirteen participants were diagnosed to have RBD while the remaining 236 were subdivided into two subgroups: 34 participants with "low" (<0.8) and 202 participants with "high" Atonia Index (≥0.8). Results: RBDSQ and RBDQ-HK were both higher in participants with low Atonia Index than in those with high Atonia Index, as well as number of drugs taken and number of comorbidities. No effect of antidepressant use was found on Atonia Index and a multiple-regression analysis showed that Atonia Index was significantly (inversely) correlated only with the behavioral score obtained with the RBDQ-HK. Conclusions: Our study shows that individuals with isolated RWA have an increased motor activity/behavioral pattern during sleep, although this activity does not allow us to diagnose RBD. Our findings broaden the spectrum of RBD and the condition that we have identified should be better characterized in order to understand its eventual development into fully blown RBD or not.

Severe Chronic Abuse of Zolpidem in Refractory Insomnia.

ABSTRACT: Zolpidem is an imidazopyridine nonbenzodiazepine hypnotic drug with a high affinity to the α1 subunit of the gamma amino butyric acid A receptor It is the first pharmacological option in the short-term management of sleep-onset insomnia. Initially considered a safer drug compared to benzodiazepines because of lower liability for abuse and dependence, recently, an increasing body of reports has questioned zolpidem's proneness to misuse. In this report, we describe a case of serious zolpidem abuse requiring pharmacological washout during hospitalization because of previous withdrawal seizures in a patient with chronic sleep-onset and maintenance insomnia.

REM sleep behavior disorder, autonomic dysfunction and synuclein-related neurodegeneration: where do we stand?

INTRODUCTION: From newfound parasomnia to a marker of future synucleinopathy, since its first description in 1986, REM sleep behavior disorder (RBD) has been systematically tackled from virtually many viewpoints in basic, translational, and clinical studies. The time delay between RBD and synucleinopathy onset offers an exceptional window for observation and design of neuroprotective trials. In the last few years, research has focused on characterizing possible differences within RBD patients in order to draw potential profiles more or less susceptible to further neurodegeneration. Attention has been drawn towards autonomic dysfunction in RBD as one of such variables. OVERVIEW: In this review, REM sleep physiology and relevant brain anatomy is briefly mentioned and integrated with neuroanatomical and physiological concepts regarding the central autonomic network. A detailed summary of works showing the presence of autonomic dysfunction in RBD is provided, and clinical and electrophysiological features of RBD in synucleinopathies are discussed. A short overview of RBD in other neurodegenerative diseases is also provided.

Sleep-Related Rhythmic Movement Disorder and Obstructive Sleep Apnea in Five Adult Patients.

ABSTRACT: Sleep-related rhythmic movements (SRRMs) are typical in infancy and childhood, where they usually occur at the wake-to-sleep transition. However, they have rarely been observed in adults, where they can be idiopathic or associated with other sleep disorders including sleep apnea. We report a case series of 5 adults with sleep-related rhythmic movement disorder, 4 of whom had a previous history of SRRMs in childhood. SRRMs mostly occurred in consolidated sleep, in association with pathological respiratory events, predominantly longer ones, especially during stage R sleep, and recovered in 1 patient with continuous positive airway pressure therapy. We hypothesize that sleep apneas may act as a trigger of rhythmic motor events through a respiratory-related arousal mechanism in genetically predisposed subjects.

Hypnic jerks are an underestimated sleep motor phenomenon in patients with parkinsonism. A video-polysomnographic and neurophysiological study.

INTRODUCTION: Hypnic jerks (HJs) are sudden contractions of one or more body segments occurring mostly at sleep onset. They are highly sporadic and affect all ages and both sexes with prevalence between 60% and 70% in the general population. STUDY OBJECTIVES: This study describes the frequency and the neurophysiological characteristics of HJs in a population of patients with parkinsonism by means of nocturnal video-polysomnographic recordings. METHODS: This is a prospective cohort study and is reported following the STROBE guidelines. We analyzed the clinical and video-polysomnographic data of the first 66 consecutive patients recruited in the ongoing prospective study "Bologna motor and non-motor Prospective study on Parkinsonism at onset" (BoProPark). Each patient underwent a full neurological workup including a whole-night video- polysomnography. Neurophysiological characteristics including the propagation patterns of the HJs were studied with an extended muscle montage polysomnography. RESULTS: We recorded a total of 62 HJs in 16 patients out of 66 (24%). Sleep parameters were not statistically different between patients with and without HJs. All HJs were spontaneous and occurred randomly throughout the night. Electromyographic analysis showed that muscle activity arose from different muscles with no prevalence of one over the other and without any ordered propagation. No recurring motor pattern of the jerks was detected. DISCUSSION AND CONCLUSIONS: Our findings demonstrated that HJs are a frequent, underestimated, sleep-related motor phenomenon in patients with parkinsonism. As they may represent a further cause of sleep disruption and insomnia, HJs should be actively examined. Neurophysiological analysis suggests a subcortical origin of HJs as shown previously for a healthy subject.

Neuroimaging in Restless Legs Syndrome.

Neuroimaging studies are of crucial relevance in defining the pathophysiology of restless legs syndrome (RLS). MRI studies showed no structural brain lesions and confirmed a central iron deficiency. Structural and functional studies showed an involvement of the thalamus, sensorimotor cortical areas, and cerebellum in RLS and assessed neurotransmission abnormalities in the dopaminergic and opiate systems. Finally, glutamatergic hyperactivity has been proposed as a cause of disrupted and shortened sleep in RLS. Differences among the results of the studies make it difficult to draw any definitive conclusions, thus, suggesting the need for future research.

A patient with PMP22-related hereditary neuropathy and DBH-gene-related dysautonomia.

Recurrent focal neuropathy with liability to pressure palsies is a relatively frequent autosomal-dominant demyelinating neuropathy linked to peripheral myelin protein 22 (PMP22) gene deletions. The combination of PMP22 gene mutations with other genetic variants is known to cause a more severe phenotype than expected. We present the case of a patient with severe orthostatic hypotension since 12 years of age, who inherited a PMP22 gene deletion from his father. Genetic double trouble was suspected because of selective sympathetic autonomic disturbances. Through exome-sequencing analysis, we identified two novel mutations in the dopamine beta hydroxylase gene. Moreover, with interactome analysis, we excluded a further influence on the origin of the disease by variants in other genes. This case increases the number of unique patients presenting with dopamine-ß-hydroxylase deficiency and of cases with genetically proven double trouble. Finding the right, complete diagnosis is crucial to obtain adequate medical care and appropriate genetic counseling.