Expanding the clinical and genetic heterogeneity of SPAX5

Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations

Next-generation sequencing approach to hyperCKemia: A 2-year cohort study

Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition

Il ruolo dell'Imaging nelle Paraparesi Spastiche Ereditarie ad esordio in età pediatrica: applicazioni attuali nella diagnostica e prospettive future

Le paraparesi spastiche ereditarie (HSP) sono un gruppo clinicamente e geneticamente eterogeneo di disordini neurodegenerativi con una prevalenza di due-cinque casi per 100.000 individui al mondo. La patologia è causata da una progressiva compromissione del sistema corticospinale e delle colonne dorsali del midollo spinale che si manifesta con spasticità degli arti inferiori, disfunzione vescicale, alterazione della sensibilità vibratoria e debolezza muscolare. Sebbene sia relativamente facile, in appropriati contesti di pratica clinica, ottenere diagnosi cliniche probabili o possibili di HSP, l’elevata eterogeneità genetica e i diversi modelli di ereditarietà associati a questo gruppo di disturbi rendono impegnativa la diagnosi molecolare. La Next generation Sequencing (NGS), con la sua tecnologia innovativa, rappresenta al momento attuale, l’approccio più appropriato in termini di rapidità e convenienza per identificare le varianti causative di questi disordini. La nostra casistica è rappresentata da 32 casi di HSP ad esordio in età pediatrica di cui abbiamo analizzato le caratteristiche cliniche, genetiche e neuroradiologiche. Il campione è costituito da 14 pazienti di sesso maschile e 18 di sesso femminile (range d’età attuale 5-28 anni). L’età all’esordio della malattia è in media di 5.34 ± 5.1. L’età della diagnosi in media 10.5 ± 5.7; il tempo di diagnosi è calcolato in base ai mesi o anni intercorsi tra i primi sintomi di malattia che hanno richiesto una valutazione neurologica e la conferma con la diagnosi molecolare ed è in media 5.26 ± 0.5 anni. Tra questi SPAST/SPG4 rappresenta il gene più mutato del nostro campione e presenta un pattern autosomico dominante (AD) con caratteristiche di RM encefalo. Per quanto riguarda le forme a trasmissione autosomico recessiva, 8 pazienti presentano varianti patogenetiche nel gene KIAA1840/SPG11 seguiti in frequenza dal gruppo di pazienti che presentano mutazioni patogenetiche nel gene AP4S1/SPG52. Il reperto neuroradiologico di maggior riscontro è rappresentato dall’alterazione di segnale a livello della sostanza bianca (22/32). Tale reperto assume caratteristiche eterogenee nei diversi sottogruppi HSP e talvolta (5/22) rappresenta l’unica alterazione neruroradiologica. Il secondo reperto di più frequente riscontro è caratterizzato da un assottigliamento del corpo calloso (17/32) e più frequentemente riguarda le forme di SPG11 (8/8) e SPG52 (6/6). Il sottotipo SPG11, come già noto in letteratura ed è la forma caratterizzata da reperti di imaging più tipici. Il cosiddetto “ear of the lynxs”, che ritroviamo in tutti i pazienti del nostro studio e l’assottigliamento del corpo calloso sono ormai considerati patognomonici di questa forma. Il presente studio intende contribuire ad accrescere la conoscenza delle relazioni tra genotipo-fenotipo e coinvolgimento anatomico nelle HSP. In primo luogo, attraverso una correlazione delle caratteristiche genotipiche e fenotipiche, legate al coinvolgimento del primo motoneurone, del cervelletto e del Sistema nervoso periferico (principali sistemi coinvolti nelle HSP) con il dato anatomico. In secondo luogo verificando se è possibile delineare dei pattern specifici di imaging cerebrale per sottotipo di HSP da utilizzare come indizio diagnostico. Il fine ultimo di questo lavoro è quindi quello di contribuire, attraverso l’analisi del nostro campione geneticamente eterogeneo, nella revisione della flowchart diagnostica delle Paraparesi spastiche ereditarie ad esordio in età pediatrica per dimostrare il ruolo fondamentale dell’imaging nel processo di diagnosi precoce

Sleep and headache

The interaction between sleep and headache or migraine is powerful and an elevated comorbidity between these 2 disorders has been reported in either adults or children. This comobidity is linked to common neurophysiological and neuroanatomical substrates that are genetically based strongly. The first reports on this relationship were related to the prevalence of parasomnias and sleep-disordered breathing in headache but recent research has expanded the comorbidity to several other sleep disorders, such as restless legs syndrome, periodic limb movements during sleep, and narcolepsy. The assessment of children with headache should always include an accurate anamnesis for the presence of sleep problems either in the child or in the relatives; no correct approach for treating children and adolescents is possible without an integrated method of evaluation and managemen

Demand Dynamics With Socially Evolving Preferences

this paper witnessed at a seminar the horror of most colleagues when Werner Hildebrand, presenting some further development on his theory of demand (Hildebrand (1994)) provocatively suggested more or less that "preferences and choices are matters for psychiatrists and not for economists", while the task of the latter should be primarily to establish some statistical conditions under which basic propositions of economic theory -- such as downward sloping demand curves etc. -- hold in the aggregate, in presence of heterogeneous, and possibly "irrational" consumers. In a nutshell, the provocation highlights, first of all, a major divide cutting across the economic discipline -- as well as other social sciences --, namely, how seriously should one take standard utility theory (with or without its more recent refinements) and the associated "rational" theory of decision making as the foundation of a descriptive theory of demand? (Another major problem concerns the aggregate properties of diverse demand schedules, no matter how constructed: we shall come to that below.) Needless to say, the majority of the economic profession seems to take that type of microeconomic foundations of decisions very seriously indeed, entrenched as they are with deep ("anthropological") views on the nature of "rationality" and self-seeking behaviours, passed through successive generations via conventional teaching tools such as "indi#erence curves" and the like, and further justified by their purported role in bridging descriptive and normative analyses (welfare theorems, etc.). However, admittedly minority views in economics (but nearly "mainstream" in other social disciplines) claim that classic decision theory has little to o#er by way of the interpretation of what people actually do and that o..

Data Fairy in Engineering Land: The Magic of Data Analysis as a Sociotechnical Process in Engineering Companies

In the era of digitalization, manufacturing companies expect their growing access to data to lead to improvements and innovations. Manufacturing engineers will have to collaborate with data scientists to analyse the ever-increasing volume of data. This process of adopting data science techniques into an engineering organisation is a sociotechnical process fraught with challenges. This paper uses a participant observation case study to to investigate and discuss the sociotechnical nature of the adoption data science technology into an engineering organisation. In the case study, a young data scientist / statistician interacted with experienced production engineers in a global automotive organisation to mutual satisfaction. However, the case study highlights the mis-aligned expectations between engineers and data scientists and knowledge in what is necessary to successfully benefit from manufacturing process data. The results reveal that the engineers had an initially romantic and idealistic view on how data scientists can bring value out of dispersed and complex information residing in the multi-site manufacturing organisation’s datasets in a “magic” way. Conversely, the data scientist had not enough engineering and contextual understanding to ask the right questions. The case reveals important shortcomings in the sociotechnical processes that undergo changes as digitalisation is brought into mature engineering organisations and points to a lack of knowledge on multiple levels of the data analysis process and the ethical implications this could have

Longitudinal Analysis of PUL 2.0 Domains in Ambulant and Non-Ambulant Duchenne Muscular Dystrophy Patients: How do they Change in Relation to Functional Ability?

Background: The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. Methods: The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, =250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: 5 years. Results: At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51-1.05) for the total score, -0.5 (-0.66-0.39) for the shoulder domain, -0.6 (-0.74-0.5) for the elbow domain and -0.1 (-0.20-0.06) for the distal domain. At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29-2.60) for the total score, -1.30 (-1.47-1.09) for the shoulder domain, -1.30 (-1.45-1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain. Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p < 0.001). Conclusion: There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials