Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report.

The lysine methyltransferase 2B (KMT2B) gene product is important for epigenetic modifications associated with active gene transcription in normal development and in maintaining proper neural function. Pathogenic variants in KMT2B have been associated with childhood-onset Dystonia-28 and Intellectual developmental disorder, autosomal dominant 68 (MRD 68) for cases of neurodevelopmental impairment without dystonia (DYT28; OMIM 617284 and MRD68; OMIM 619934, respectively). Since its first description in 2016, approximately one hundred KMT2B genetic variants have been reported with heterogeneous phenotypes, including atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotypes. KMT2B-related disorders share many overlapping phenotypic characteristics with other neurodevelopmental disorders and delayed dystonia, that can appear later in childhood, often delaying clinical diagnosis. Furthermore, conventional genetic testing may not always provide actionable information (e.g., gene panel selection based on early clinical presentation or variants of uncertain significance), which prevents patients and families from obtaining early access to treatments and support. Herein, we describe the early diagnosis of KMT2B-related neurodevelopmental disorder by DNA methylation episignature testing in a 4-year-old patient without features of dystonia at diagnosis, which is reported to develop in more than 80% of KMT2B-related disorder cases. The proband, a 4-year-old female of Jewish-Israeli descent, presented with speech delay, microcephaly, poor weight gain, attention-deficit and hyperactivity disorder, dysmorphism, intellectual disabilities and joint hyperlaxity, but presented no signs of dystonia at initial evaluation. Episignature screening in this pre-symptomatic patient enabled accurate genetic diagnosis and timely and actionable intervention earlier in the natural history of Childhood-onset Dystonia-28.

Feasibility and benefits of home initiation of subcutaneous apomorphine infusion for patients with Parkinson's disease: the APOKADO study.

Continuous subcutaneous apomorphine infusion (CSAI) is used to treat patients with Parkinson's disease (PD) who are experiencing motor fluctuations. However, the need to initiate this treatment during a hospital stay may restrict patients' access to it. To assess the feasibility and benefits of initiating CSAI in the patient's own home. A French prospective multicenter longitudinal observational study (APOKADO) among patients with PD who required subcutaneous apomorphine, comparing in-hospital versus home initiation. Clinical status was assessed according to the Hoehn and Yahr score), the Unified Parkinson's Disease Rating Scale Part III, and the Montreal Cognitive Assessment. We assessed patients' quality of life with the 8-item Parkinson's Disease Questionnaire, rated the improvement in their clinical status on the 7-point Clinical Global Impression-Improvement scale, recorded adverse events, and ran a cost-benefit analysis. 145 patients with motor fluctuations were included in 29 centers (office and hospital). Of these, 106 (74%) were initiated onto CSAI at home, and 38 (26%) in hospital. At inclusion, the two groups were comparable for all demographic and PD characteristics. After 6 months, quality of life, adverse events and early dropout rates were similarly rare-across the two groups. Patients in the home group improved more quickly their quality of life and became more autonomous in managing the device than those in the hospital group, and their care costed less. This study shows that home (versus in-hospital) initiation of CSAI is feasible, improves patients' quality of life more quickly, with the same level of tolerance. It is also less expensive. This finding should make it easier for patients to access this treatment in the future.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Central nervous system complications associated with immune checkpoint inhibitors.

OBJECTIVE: To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI). METHODS: Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI). RESULTS: We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053). CONCLUSION: Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

Patient-ventilator asynchrony during conventional mechanical ventilation in children.

BACKGROUND: We aimed (1) to describe the characteristics of patient-ventilator asynchrony in a population of critically ill children, (2) to describe the risk factors associated with patient-ventilator asynchrony, and (3) to evaluate the association between patient-ventilator asynchrony and ventilator-free days at day 28. METHODS: In this single-center prospective study, consecutive children admitted to the PICU and mechanically ventilated for at least 24 h were included. Patient-ventilator asynchrony was analyzed by comparing the ventilator pressure curve and the electrical activity of the diaphragm (Edi) signal with (1) a manual analysis and (2) using a standardized fully automated method. RESULTS: Fifty-two patients (median age 6 months) were included in the analysis. Eighteen patients had a very low ventilatory drive (i.e., peak Edi < 2 µV on average), which prevented the calculation of patient-ventilator asynchrony. Children spent 27% (interquartile 22-39%) of the time in conflict with the ventilator. Cycling-off errors and trigger delays contributed to most of this asynchronous time. The automatic algorithm provided a NeuroSync index of 45%, confirming the high prevalence of asynchrony. No association between the severity of asynchrony and ventilator-free days at day 28 or any other clinical secondary outcomes was observed, but the proportion of children with good synchrony was very low. CONCLUSION: Patient-ventilator interaction is poor in children supported by conventional ventilation, with a high frequency of depressed ventilatory drive and a large proportion of time spent in asynchrony. The clinical benefit of strategies to improve patient-ventilator interactions should be evaluated in pediatric critical care.

Evolution of inspiratory diaphragm activity in children over the course of the PICU stay.

PURPOSE: Diaphragm function should be monitored in critically ill patients, as full ventilatory support rapidly induces diaphragm atrophy. Monitoring the electrical activity of the diaphragm (EAdi) may help assess the level of diaphragm activity, but such monitoring results are difficult to interpret because reference values are lacking. The aim of this study was to describe EAdi values in critically ill children during a stay in the pediatric intensive care unit (PICU), from the acute to recovery phases, and to assess the impact of ventilatory support on EAdi. METHODS: This was a prospective longitudinal observational study of children requiring mechanical ventilation for ≥24 h. EAdi was recorded using a validated method in the acute phase, before extubation, after extubation, and before PICU discharge. RESULTS: Fifty-five critically ill children were enrolled in the study. Median maximum inspiratory EAdi (EAdimax) during mechanical ventilation was 3.6 [interquartile range (IQR) 1.2-7.6] µV in the acute phase and 4.8 (IQR 2.0-10.7) µV in the pre-extubation phase. Periods of diaphragm inactivity (with no detectable inspiratory EAdi) were frequent during conventional ventilation, even with a low level of support. EAdimax in spontaneous ventilation was 15.4 (IQR 7.4-20.7) µV shortly after extubation and 12.6 (IQR 8.1-21.3) µV before PICU discharge. The difference in EAdimax between mechanical ventilation and post-extubation periods was significant (p < 0.001). Patients intubated mainly because of a lung pathology exhibited higher EAdi (p < 0.01), with a similar temporal increase. CONCLUSIONS: This is the first systematic description of EAdi evolution in children during their stay in the PICU. In our patient cohort, diaphragm activity was frequently low in conventional ventilation, suggesting that overassistance or oversedation is common in clinical practice. EAdi monitoring appears to be a helpful tool to detect such situations.

Pregnancy during enzyme replacement therapy for late-onset acid maltase deficiency.

We report the case of a female patient who developed Pompe's disease when she was 19. She received enzyme replacement therapy from the age of 35, and after three years of treatment the improvement in her clinical condition was such that she was able to consider having a baby. It was the patient's wishes to continue with her treatment throughout the entirety of her pregnancy. There were no complications, but there was a clear deterioration in motor and respiratory functions. She delivered at term by Caesarean section, and the child was healthy. Six months later, we noted an improvement of her motor and respiratory functions. The child was developing normally.