Type I Alexander disease: Update and validation of the clinical evolution-based classification.

BACKGROUND AND OBJECTIVES: Alexander disease (AxD) is a rare progressive leukodystrophy caused by autosomal dominant mutations in the Glial Fibrillary Acidic Protein (GFAP) gene. Three main disease classifications are currently in use, the traditional one defined by the age of onset, and two other based on clinical features at onset and brain MRI findings. Recently, we proposed a new classification, which is based on taking into consideration not only the presenting features, but also data related to the clinical course. In this study, we tried to apply this modified classification system to the cases of pediatric-onset AxD described in literature. METHODS: A literature review was conducted in PubMed for articles published between 1949 to date. Articles that reported no patient's medical history and the articles about Adult-onset AxD were excluded. We included patients with a confirmed diagnosis of pediatric-onset AxD and of whom information about age and symptoms at onset, developmental milestones and loss of motor and language skills was available. RESULTS: Clinical data from 205 patients affected with pediatric-onset AxD were retrospectively reviewed. Among these, we identified 65 patients, of whom we had enough information about the clinical course and developmental milestones, and we assessed their disease evolutionary trajectories over time. DISCUSSION: Our results confirm that patients with Type I AxD might be classified into four subgroups (Ia, Ib, Ic, Id) basing on follow up data. In fact, despite the great variability of phenotypes in AxD, there are some shared trajectories of the disease evolution over time.

Brainstem Chipmunk Sign: A Diagnostic Imaging Clue across All Subtypes of Alexander Disease.

BACKGROUND AND PURPOSE: While classic brain MR imaging features of Alexander disease have been well-documented, lesional patterns can overlap with other leukodystrophies, especially in the early stages of the disease or in milder phenotypes. We aimed to assess the utility of a new neuroimaging sign to help increase the diagnostic specificity of Alexander disease. MATERIALS AND METHODS: A peculiar bilateral symmetric hyperintense signal on T2-weighted images affecting the medulla oblongata was identified in an index patient with type I Alexander disease. Subsequently, 5 observers performed a systematic MR imaging review for this pattern by examining 55 subjects with Alexander disease and 74 subjects with other leukodystrophies. Interobserver agreement was assessed by the κ index. Sensitivity, specificity, and receiver operating characteristic curves were determined. RESULTS: The identified pattern was present in 87% of subjects with Alexander disease and 14% of those without Alexander disease leukodystrophy (P < .001), 3 with vanishing white matter, 4 with adult polyglucosan body disease, and 3 others. It was found equally in both type I and type II Alexander disease (28/32, 88% versus 18/21, 86%; P = .851) and in subjects with unusual disease features (2/2). Sensitivity (87.3%; 95% CI, 76.0%-93.7%), specificity (86.5%; 95% CI, 76.9%-92.5%), and interobserver agreement (κ index = 0.82) were high. CONCLUSIONS: The identified pattern in the medulla oblongata, called the chipmunk sign due to its resemblance to the face of this rodent, is extremely common in subjects with Alexander disease and represents a diagnostic tool that can aid in early diagnosis, especially in subjects with otherwise atypical MR imaging findings and/or clinical features.

Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review.

Introduction: The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life. Methods: We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials. Results: We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints. Discussion: We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

Unraveling diagnostic uncertainty in transition phase from relapsing-remitting to secondary progressive multiple sclerosis.

BACKGROUND: Clinicians struggle to timely diagnose secondary-progressive multiple sclerosis (SP-MS), with a 'transition phase' period of diagnostic uncertainty. We aimed at defining clinical markers predicting evolution to SP-MS. METHODS: We reviewed 210 newly diagnosed MS patients experiencing at least one confirmed disability worsening (CDW). CDWs were classified as disability worsening either due to incomplete recovery following relapse (r-CDW), or independent of relapse activity (nr-CDW). Logistic regression and Cox regression models were used to evaluate variables at CDW associated with SP-MS diagnosis. RESULTS: On CDW, higher EDSS (OR: 2.73, p=0.002) and nr-CDW (OR: 2.63, p=0.03) were associated with conversion to SP-MS over the follow-up. In addition, the risk of SP-MS was higher in patients with EDSS>3.0 at CDW (HR: 2.26, p<0.001), and with time to second CDW <24 months (HR: 0.98, p<0.001), compared with patients that experienced a CDW but did not receive SP-MS diagnosis (AUC: 0.95, Sensitivity: 0.83, Specificity: 0.96). CONCLUSION: At their first CDW, patients with higher EDSS, experiencing CDW without relapse and developing a further CDW within 2 years are at higher risk of SP-MS conversion. This provides proxies for conversion to SP-MS since first episode of CDW.