Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases.

BACKGROUND: In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts. METHODS: An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented. RESULTS: 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy. CONCLUSIONS: This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

Assessment of Bioenergetic Deficits in Patients With Parkinson Disease and Progressive Supranuclear Palsy Using 31P-MRSI.

BACKGROUND: Bioenergetic disturbance, mainly caused by mitochondrial dysfunction, is an established pathophysiological phenomenon in neurodegenerative movement disorders. The in vivo assessment of brain energy metabolism by 31phosphorus magnetic resonance spectroscopy imaging could provide pathophysiological insights and serve in the differential diagnosis of parkinsonian disorders. In this study, we investigated such aspects of the underlying pathophysiology in patients with idiopathic Parkinson's disease (PwPD) and progressive supranuclear palsy (PwPSP). METHODS: In total, 30 PwPD, 16 PwPSP, and 25 healthy control subjects (HCs) underwent a clinical examination, structural magnetic resonance imaging, and 31phosphorus magnetic resonance spectroscopy imaging of the forebrain and basal ganglia in a cross-sectional study. RESULTS: High-energy phosphate metabolites were remarkably decreased in PwPD, particularly in the basal ganglia (-42% compared with healthy controls and -43% compared with PwPSP, p<.0001). This result was not confounded by morphometric brain differences. In contrast, PwPSP had normal levels of high-energy energy metabolites. Thus, the combination of morphometric and metabolic neuroimaging was able to discriminate PwPD from PwPSP with an accuracy of up to 0.93 [95%-CI: 0.91, 0.94]. DISCUSSION: Our study shows that mitochondrial dysfunction and bioenergetic depletion contribute to idiopathic Parkinson's disease pathophysiology but not to progressive supranuclear palsy. Combined morphometric and metabolic imaging could serve as an accompanying diagnostic biomarker in the neuroimaging-guided differential diagnosis of these parkinsonian disorders.

Non-motor phenotype of dopa-responsive dystonia and quality of life assessment.

BACKGROUND: Dopa-responsive dystonia (DRD) is a young-onset neurometabolic disorder often presenting with a combination of parkinsonism and dystonia. The pathophysiology includes an impairment of dopaminergic and serotonergic neurotransmission. Uncontrolled reports suggest an increased frequency of neuropsychiatric abnormalities and sleep impairment. METHODS: In 23 GCH1 mutation-positive DRD patients and 26 healthy controls, non-motor features and their effect on the quality of life (QoL) were assessed. Six patients underwent polysomnography (PSG). RESULTS: Depressive and anxiety symptoms were not more common among DRD patients. Average sleep quality was similar across groups. This was also true for self-reported mean sleep onset (27.5 vs. 27.1 min) and total sleep time (6.5 vs. 6.6 h). Upon PSG, the number of spontaneous arousals was increased in four patients. QoL was impaired with respect to physical health. Sleep impairment and depressive but not anxiety symptoms were associated with lower QoL. CONCLUSION: The present results do not confirm the clinical impression and biologically plausible assumption of an increased frequency of non-motor symptoms in DRD. The impairment of QoL is associated with a decline of the physical condition only but not with other factors.

Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families.

The purpose of the study was to delineate clinical and electrophysiological characteristics as well as laryngoscopical and transcranial ultrasound (TCS) findings in THAP1 mutation carriers (MutC). According to recent genetic studies, DYT6 (THAP1) gene mutations are an important cause of primary early-onset dystonia. In contrast to DYT1 mutations, THAP1 mutations are associated with primary early-onset segmental or generalised dystonia frequently involving the craniocervical region and the larynx. Blood samples from twelve individuals of three German families with DYT6 positive index cases were obtained to test for THAP1 mutations. Eight THAP1 MutC were identified. Of these, six (three symptomatic and three asymptomatic) THAP1 MutC could be clinically evaluated. Laryngoscopy was performed to evaluate laryngeal dysfunction in patients. Brainstem echogenicity was investigated in all MutC using TCS. Two of the patients had undergone bilateral pallidal DBS. In all three symptomatic MutC, early-onset laryngeal dystonia was a prominent feature. Laryngeal assessment demonstrated adductor-type dystonia in all of them. On clinical examination, the three asymptomatic MutC also showed subtle signs of focal or segmental dystonia. TCS revealed increased substantia nigra (SN) hyperechogenicity in all MutC. Intraoperative microelectrode recordings under general anesthesia in two of the patients showed no difference between THAP1 and previously operated DYT1 MutC. The presence of spasmodic dysphonia in patients with young-onset segmental or generalised dystonia is a hallmark of DYT6 dystonia. SN hyperechogenicity on TCS may represent an endophenotype in these patients. Pallidal DBS in two patients was unsatisfactory.