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.

Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app.

INTRODUCTION: Friedreich ataxia (FA) is the most common hereditary ataxia in Europe, characterised by progressively worsening movement and speech impairments with a typical onset before the age of 25 years. The symptoms affect the patients' health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app). METHODS AND ANALYSIS: The PROFA Study is a prospective observational study. Patients with FA (n=200) will be recruited at six European study centres (Germany, France and Austria). We will interview patients at baseline in the study centre and subsequently assess the patients' health at home via mobile health app. Patients will self-report ataxia severity, HRQoL, speech and hearing disabilities, coping strategies and well-being, health services usage, adverse health events and productivity losses due to informal care on a daily to monthly basis on the app for 6 months. Our study aims to (1) validate measurements of HRQoL and psychosocial health, (2) assess the usability of the mobile health app, and (3) use descriptive and multivariate statistics to analyse patient-reported and economic outcomes and the interaction effects between these outcomes. Insights into the app's usability could be used for future studies using momentary data assessments to measure outcomes of patients with FA. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of the University Medicine of Greifswald, (BB096/22a, 26 October 2022) and from all local ethics committees of the participating study sites. Findings of the study will be published in peer-reviewed journals, presented at relevant international/national congresses and disseminated to German and French Patient Advocacy Organizations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05943002); Pre-results.

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients.

OBJECTIVE: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. METHODS: Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2-8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes. RESULTS: Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), and fluctuating decreases/increases. All subitems except nose-finger showed moderate-to-strong correlations to activities of daily living, indicating that metric properties-not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG-ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20 to 25%. INTERPRETATION: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023;94:470-485.

Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi).

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.

Real-life gait assessment in degenerative cerebellar ataxia: Toward ecologically valid biomarkers.

OBJECTIVES: With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid motor biomarkers are highly warranted. In this observational study, we aimed to unravel and validate markers of ataxic gait in real life by using wearable sensors. METHODS: We assessed gait characteristics of 43 patients with degenerative cerebellar disease (Scale for the Assessment and Rating of Ataxia [SARA] 9.4 ± 3.9) compared with 35 controls by 3 body-worn inertial sensors in 3 conditions: (1) laboratory-based walking; (2) supervised free walking; (3) real-life walking during everyday living (subgroup n = 21). Movement analysis focused on measures of spatiotemporal step variability and movement smoothness. RESULTS: A set of gait variability measures was identified that allowed us to consistently identify ataxic gait changes in all 3 conditions. Lateral step deviation and a compound measure of spatial step variability categorized patients vs controls with a discrimination accuracy of 0.86 in real life. Both were highly correlated with clinical ataxia severity (effect size ρ = 0.76). These measures allowed detecting group differences even for patients who differed only 1 point in the clinical SARAposture&gait subscore, with highest effect sizes for real-life walking (d = 0.67). CONCLUSIONS: We identified measures of ataxic gait that allowed us not only to capture the gait variability inherent in ataxic gait in real life, but also to demonstrate high sensitivity to small differences in disease severity, with the highest effect sizes in real-life walking. They thus represent promising candidates for motor markers for natural history and treatment trials in ecologically valid contexts. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a set of gait variability measures, even if accessed in real life, correlated with the clinical severity of ataxia in patients with degenerative cerebellar disease.

Standardized Assessment of Hereditary Ataxia Patients in Clinical Studies.

BACKGROUND: Hereditary ataxias are a heterogeneous group of degenerative diseases of the cerebellum, brainstem, and spinal cord. They may present with isolated ataxia or with additional symptoms going beyond cerebellar deficits. There are an increasing number of clinical studies with the goal to define the natural history of these disorders, develop biomarkers, and investigate therapeutic interventions. Especially, early and preclinical disease stages are currently of particular interest. METHODS AND RESULTS: Evidence-based, we review standards for sampling and storage of biomaterials, clinical and neuropsychological assessment, as well as neurophysiology and neuroimaging and recommendations for standardized assessment of ataxia patients in multicenter studies. CONCLUSIONS: DNA, RNA, serum, and, if possible, cerebrospinal fluid samples should be processed following established standards. Clinical assessment in ataxia studies must include use of a validated clinical ataxia scale. There are several validated clinical ataxia scales available. There are no instruments that were specifically designed for assessing neuropsychological and psychiatric symptoms in ataxia disorders. We provide a list of tests that may prove valuable. Quantitative performance tests have the potential to supplement clinical scales. They provide additional objective and quantitative information. Posturography and quantitative movement analysis-despite valid approaches-require standardization before implemented in multicenter studies. Standardization of neurophysiological tools, as required for multicenter interventional trials, is still lacking. Future multicenter neuroimaging studies in ataxias should implement quality assurance measures as defined by the ADNI or other consortia. MRI protocols should allow morphometric analyses.

Spinocerebellar ataxia type 15: diagnostic assessment, frequency, and phenotypic features.

BACKGROUND: To guide time- and cost-efficient analyses of the increasing number of autosomal-dominant spinocerebellar ataxia genes (SCAs), more information about frequency distributions, phenotypic characteristics and optimal diagnostic strategies is warranted. OBJECTIVE: To assess the prevalence and phenotypic spectrum of SCA15 and to confirm multiplex ligation-dependent probe amplification (MLPA) as a robust and efficient strategy for routine molecular diagnosis. METHODS: Fifty-six German SCA families negative for common repeat expansions were screened for ITPR1 deletions by MLPA. Samples with conspicuous MLPA data were additionally assessed by high-density single nucleotide polymorphism (SNP) array to confirm MLPA results and further determine the size of deletions. The phenotype of patients harbouring ITPR1 deletions was characterised by standardised clinical, electrophysiological and imaging assessment. RESULTS: SCA15 accounted for 8.9% (5/56) of SCA families negative for common SCA repeat expansions. All deletions detected by MLPA were confirmed by SNP array. One of the ITPR1 deletions preserved exons 1 and 2 in the 5' prime UTR of the ITPR1 gene. All patients with SCA15 (n=10) presented with slowly progressive cerebellar ataxia and vermal cerebellar atrophy, while clinical and electrophysiological signs of extracerebellar affection were mild and more variable. CONCLUSIONS: SCA15 is the most common non-trinucleotide repeat SCA in Central Europe. Screening for ITPR1 deletions should be considered in patients with slowly progressive SCA, vermal cerebellar atrophy and prominent tremor after excluding common SCA repeat expansions. Promoter and exon 2 of ITPR1 may be preserved from the deletion in some cases of SCA15.

Cardiomyopathy in Friedreich's ataxia-assessment by cardiac MRI.

Cardiomyopathy is an important and frequently life limiting manifestation of Friedreich's ataxia (FA), the most prevalent form of autosomal recessive ataxia. Left ventricular mass is used as primary outcome measure in recent intervention studies but systematic analyses of FA cardiomyopathy are sparse. To assess cardiac hypertrophy by cardiac magnetic resonance imaging (MRI) in vivo, we assessed 41 adult patients with genetically confirmed FA and 33 age- and sex-matched healthy controls by cardiac MRI and echocardiogarphy. Septal hypertrophy and left ventricular mass index were determined by two independent raters. MRI revealed hypertrophy of the interventricular septum in 40% and increased left ventricular mass index in 29% of patients. Interobserver variability was less than 5% for both measures. GAA repeat length had only minor influence on interventricular septum thickness. Left ventricular mass index decreased with age. Severity of ataxia did not correlate with cardiac disease. In echocardiography wall diameter was assessable only in 31 of 41 FA patients with 32% of patients presenting septal hypertrophy and 6% increased left ventricular mass index. We conclude that cardiac hypertrophy is present only in a minority of adult FA patients. If despite this limitation intervention studies use left ventricular mass as outcome measure, MRI is recommended as the most accurate assessment of cardiac anatomy in vivo.