An Integrated clinical pathway for diagnosis, treatment and care of rare diseases: model, operating procedures, and results of the project TRANSLATE-NAMSE funded by the German Federal Joint Committee.

BACKGROUND: Diagnosis, treatment, and care of patients with rare diseases require multidisciplinary cooperation between medical and paramedical specialities and with patients and families. Innovative genetic diagnostics, whole exome and whole genome sequencing (WES, WGS) has enlarged the diagnostic toolkit but also increased the complexity of the endeavour. Structured multidisciplinary clinical pathways (CPW) can guide diagnosis, treatment, and care of patients with rare diseases, link scientific evidence to clinical practice and optimise clinical outcomes whilst maximising clinical efficiency. RESULTS: In contrast to the common approach of appending disease-specific CPWs to disease-specific guidelines, we suggest a generic CPW manoeuvring the patient along the way of finding the correct diagnosis by applying the best diagnostic strategy into an appropriate system of treatment and care. Available guidelines can be integrated into the generic CPW in the course of its application. The approach also applies to situations where a diagnosis remains unsolved. The backbone of the generic CPW is a set of multidisciplinary structured case conferences projecting and evaluating diagnostic and/or therapeutic steps, enforcing to integrate best scientific evidence with clinical experience. The generic CPW is stated as a flowchart and a checklist which can be used to record and document parsimoniously the structure, process and results of a patient's pathway, but also as a data model for research. It was applied in a multicentre setting with 587 cases each with a presumptive diagnosis of a rare disease. In 369 cases (62.8%) a diagnosis could be confirmed, and multidisciplinary treatment and/or care was initiated. The median process time from first contact until confirmation of diagnosis by WES was 109 days and much shorter than diagnostic delays reported in the literature. Application of the CPW is illustrated by two case reports. CONCLUSIONS: Our model is a tool to change the diagnostic odyssey into an organised and trackable route. It can also be used to inform patients and families about the stages of their individual route, to update health care providers only partially involved or attending specialised treatment and care, like the patient's or family's primary physician, and finally to train novices in the field.

Type 1 Plasminogen Deficiency With Pulmonary Involvement: Novel Treatment and Novel Mutation.

Type 1 plasminogen deficiency is a rare genetic disorder. Type 1 plasminogen deficiency is characterized by fibrin-rich pseudomembrane formation on mucosal surfaces, particularly the conjunctiva. Tracheobronchial tree involvement is a less common reported manifestation of type 1 plasminogen deficiency. Pseudomembranes in the tracheobronchial tree may result in respiratory compromise and ultimately fail if not recognized and treated. Currently, there is no specific replacement therapy approved for the treatment of congenital plasminogen deficiency. In the present paper, we report that type 1 plasminogen deficiency with novel frameshift mutation and pulmonary involvement was treated initially with systemic fresh frozen plasma followed by pulmonary lavage with fresh frozen plasma and tissue plasminogen activator.

Late attentional processes potentially compensate for early perceptual multisensory integration deficits in children with autism: evidence from evoked potentials.

Sensory processing deficits and altered long-range connectivity putatively underlie Multisensory Integration (MSI) deficits in Autism Spectrum Disorder (ASD). The present study set out to investigate non-social MSI stimuli and their electrophysiological correlates in young neurotypical adolescents and adolescents with ASD. We report robust MSI effects at behavioural and electrophysiological levels. Both groups demonstrated normal behavioural MSI. However, at the neurophysiological level, the ASD group showed less MSI-related reduction of the visual P100 latency, greater MSI-related slowing of the auditory P200 and an overall temporally delayed and spatially constrained onset of MSI. Given the task design and patient sample, and the age of our participants, we argue that electro-cortical indices of MSI deficits in ASD: (a) can be detected in early-adolescent ASD, (b) occur at early stages of perceptual processing, (c) can possibly be compensated by later attentional processes, (d) thus leading to normal MSI at the behavioural level.

Is reaction time variability consistent across sensory modalities? Insights from latent variable analysis of single-trial P3b latencies.

Recent years have witnessed a steep increase in cognitive, differential and clinical neuroscience research on the neural basis of intra-subject variability of reaction times. Most theoretical accounts make the implicit assumption that individual differences in intra-subject variability are consistent across sensory modalities, but this remains largely untested. The present EEG study aims to fill this gap by analyzing, for the first time, stimulus- and response-locked single-trial P3bs across visual and auditory sensory modalities, and employing an innovative supra-task latent variables approach. We found unidimensionality of intra-subject variability variables across modalities as well as high correlations between the latency jitter of stimulus- and response-locked P3bs. These findings support the hypothesis that intra-subject variability represents a unitary construct, and that the processes underlying that generalises not only across different cognitive tasks, but also across different sensory modalities.

Cortical post-movement and sensory processing disentangled by temporary deafferentation.

Motor system calibration depends crucially on the adjustment to the consequences of a movement, which often occur when the movement itself is already completed. The mechanisms by which reafferent feedback information is compared to the programmed movement remain unclear. In the current study, the hypothesis of a short term memory trace in the motor cortex which outlasts quick movements and is generated independently from reafferent feedback was challenged by temporal deafferentation. Post-movement cortical potentials were recorded by high-resolution EEG during a reaction time task which required speeded unilateral right-hand or left-hand button presses. We analysed lateralized motor N700 (motor post-imperative negative variation), a post-movement component, under temporary deafferentation achieved through application of a blood pressure tourniquet in ten healthy adult subjects. Motor N700 persisted under deafferentation in the absence of reafferent tactile and proprioceptive feedback input into the sensorimotor cortex, which was abolished under deafferentation. Source analysis pointed towards continuing activation in the pre-/primary motor cortex. Thus, motor post-processing can be dissociated from reafferent sensory feedback. Motor cortex activation outlasts quick movements for about a second also in the absence of a reafferent signal. Continuing motor cortex activation could act as an internal motor model in motor learning and allow better adjustment of movements according to the evaluation of their consequences.