Neonatal Brain MRI and Motor Outcome at School Age in Children with Neonatal Encephalopathy: A Review of Personal Experience

The aim of this paper is to review (i) the spectrum of neuromotor function at school age in children who had been born full-term and presented with neonatal encephalopathy (NE) and low Apgar scores and (ii) the relation between the presence/absence of such difficulties and neonatal brain MRI. Motor outcome appears to be mainly related to the severity of basal ganglia and internal capsule involvement. Severe basal ganglia lesions were always associated with the most severe outcome, microcephaly, tetraplegia, and severe global delay, whereas more discrete basal ganglia lesions were associated with athetoid cerebral palsy, with normal cognitive development or minor neuro-motor abnormalities. White matter lesions were associated with abnormal motor outcome only if the internal capsule was involved. Children with moderate white matter changes but normal internal capsule, had normal motor outcome at school age

Detecting early signs in Duchenne muscular dystrophy: comprehensive review and diagnostic implications

Despite the early onset of clinical signs suggestive of Duchenne muscular dystrophy (DMD), a diagnosis is often not made until four years of age or older, with a diagnostic delay of up to two years from the appearance of the first symptoms. As disease-modifying therapies for DMD become available that are ideally started early before irreversible muscle damage occurs, the importance of avoiding diagnostic delay increases. Shortening the time to a definite diagnosis in DMD allows timely genetic counseling and assessment of carrier status, initiation of multidisciplinary standard care, timely initiation of appropriate treatments, and precise genetic mutation characterization to assess suitability for access to drugs targeted at specific mutations while reducing the emotional and psychological family burden of the disease. This comprehensive literature review describes the early signs of impairment in DMD and highlights the bottlenecks related to the different diagnostic steps. In summary, the evidence suggests that the best mitigation strategy for improving the age at diagnosis is to increase awareness of the early symptoms of DMD and encourage early clinical screening with an inexpensive and sensitive serum creatine kinase test in all boys who present signs of developmental delay and specific motor test abnormality at routine pediatrician visits

Complex geometry and kinematics of subsidiary faults within a carbonate-hosted relay ramp

Minor fault geometry and kinematics within relay ramps is strongly related to the stress field perturbations that can be produced when two major fault segments overlap and interact. Here we integrate classical fieldwork and interpretation of a virtual outcrop to investigate the geometry and kinematics of subsidiary faults within a relay ramp along the Tre Monti normal fault in the Central Apennines. Although the Tre Monti fault strikes parallel to the regional extension (NE-SW) it shows predominant dip-slip kinematics, suggesting a NW-SE oriented extension acting at sub-regional scale (1–10 km). Conversely, the slickenlines collected on the front segment of the relay ramp highlight right-lateral kinematics. The subsidiary faults in the relay ramp show a complex geometry (variable attitudes) and slickenlines describe multiple kinematics (left-lateral, dip-slip, right-lateral), independently of their orientation. Our fault slip analysis indicates that a local stress field retrieved from the kinematic inversion of the slickenlines collected on the front segment, and likely promoted by the interaction between the overlapping fault segments that bound the relay zone, can explain most of the geometry and kinematics of the subsidiary faults. Further complexity is added by the temporal interaction with both the regional and sub-regional stress fields

Novel Splicing Mutation in MTM1 Leading to Two Abnormal Transcripts Causes Severe Myotubular Myopathy

Myotubular myopathy; Novel mutation; SplicingMiopatía miotubular; Nueva mutación; EmpalmeMiopatia miotubular; Nova mutació; EmpalmamentX-linked myotubular myopathy (XLMTM) is a severe form of centronuclear myopathy, characterized by generalized weakness and respiratory insufficiency, associated with pathogenic variants in the MTM1 gene. NGS targeted sequencing on the DNA of a three-month-old child affected by XLMTM identified the novel hemizygous MTM1 c.1261-5T>G intronic variant, which interferes with the normal splicing process, generating two different abnormal transcripts simultaneously expressed in the patient’s muscular cells. The first aberrant transcript, induced by the activation of a cryptic splice site in intron 11, includes four intronic nucleotides upstream of exon 12, resulting in a shift in the transcript reading frame and introducing a new premature stop codon in the catalytic domain of the protein (p.Arg421SerfsTer7). The second aberrant MTM1 transcript, due to the lack of recognition of the 3′ acceptor splice site of intron 11 from the spliceosome complex, leads to the complete skipping of exon 12. We expanded the genotypic spectrum of XLMTM underlying the importance of intron–exons boundaries sequencing in male patients affected by XLMTM

Wearable full-body motion tracking of activities of daily living predicts disease trajectory in Duchenne muscular dystrophy

Artificial intelligence has the potential to revolutionize healthcare, yet clinical trials in neurological diseases continue to rely on subjective, semiquantitative and motivation-dependent endpoints for drug development. To overcome this limitation, we collected a digital readout of whole-body movement behavior of patients with Duchenne muscular dystrophy (DMD) (n = 21) and age-matched controls (n = 17). Movement behavior was assessed while the participant engaged in everyday activities using a 17-sensor bodysuit during three clinical visits over the course of 12 months. We first defined new movement behavioral fingerprints capable of distinguishing DMD from controls. Then, we used machine learning algorithms that combined the behavioral fingerprints to make cross-sectional and longitudinal disease course predictions, which outperformed predictions derived from currently used clinical assessments. Finally, using Bayesian optimization, we constructed a behavioral biomarker, termed the KineDMD ethomic biomarker, which is derived from daily-life behavioral data and whose value progresses with age in an S-shaped sigmoid curve form. The biomarker developed in this study, derived from digital readouts of daily-life movement behavior, can predict disease progression in patients with muscular dystrophy and can potentially track the response to therapy

Combination disease-modifying treatment in spinal muscular atrophy: A proposed classification

Spinal muscular atrophyAtròfia muscular espinalAtrofia muscular espinalWe sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA

The visual function assessment: from birth to the follow up

Preterm infants have a high risk to develop visual deficits due to retinopathy of prematurity (ROP), brain lesionsand prematurity per se [1]. The possibility to assess different aspects of visual function can allow early and specific intervention in an attempt to reduce the risk of difficulties in motor coordination, attention and learning at school age. The aim is to identify early signs of visual and motorperceptual deficit in the first years in order to program a specific intervention before school age

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). METHODS: Ambulatory DMD patients who were 657 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. RESULTS: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. INTERPRETATION: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257-271