Search

Summary: Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. Funding: The Wellcome Trust, the MRC.

Objective: The objective of the study was to determine the significance weights of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) item scores for better evaluation and classification of amyotrophic lateral sclerosis (ALS) status. Methods: We used an analytical hierarchy process (AHP) to determine the weights of the ALSFRS-R item scores based on the opinions of two neurologists. We analyzed data of 51 patients with ALS to group them into four ALS severity classes based on their (i) total ALSFRS-R score and (ii) total weighted ALSFRS-R scores using the proposed weight values. We analyzed the performance differences between the two classification approaches based on the outcomes of these 51 patients. We also used twenty additional patients' data to analyze the accuracies of the total and weighted ALSFRS-R score approaches compared with physicians' actual assessments. Results: The AHP analysis assigned the highest weights to the ALSFRS-R items for respiratory insufficiency, orthopnea, and bed rotation/covering. ALS status classification based on the total and weighted ALSFRS-R scores differed for about 27.5% (confidence interval [CI]: 15.2%–39.8%) of the 51 patients. The classification based on the total weighted ALSFRS-R complied with the actual assessments in 85% (CI: 69.4%–100%) of the patients in the comparison sample; the compliance rate was 60% (CI: 38.5%–81.5%) for the total ALSFRS-R-based classification. Conclusions: Assigning weights to the 12 ALSFRS-R criteria/questions may improve ALSFRS-R's ability to represent ALS severity. This finding requires further investigation.

This consensus statement by a panel of neurology experts aimed to provide a practical and implementable guidance document to assist clinicians with the best clinical practice in terms of diagnosis, treatment, and monitoring of late-onset Pompe disease (LOPD). The participating experts consider the clinical suspicion of LOPD by the physician to be of utmost importance in the prevention of diagnostic and therapeutic delay in LOPD patients. A diagnostic algorithm is proposed to facilitate the diagnosis of LOPD in patients presenting with unexplained proximal/axial weakness (with or without respiratory symptoms) or restrictive respiratory insufficiency with hyperCKemia and/or exercise intolerance as the red flag symptoms/signs that raise the index of suspicion for LOPD diagnosis. The diagnosis is based on the subsequent use of dried blood spot (DBS) assay, and the DBS assay can be confirmed by acid alpha-glucosidase (GAA) tissue analysis in leukocytes, fibroblasts, or muscle fibers and/or genetic mutation analysis. Accordingly, experts consider increased awareness among physicians about potential presenting characteristics with a high index of suspicion for LOPD to be crucial to suspect and consider LOPD in the differential diagnosis, while strongly suggesting the use of a diagnostic algorithm combined with DBS assay and confirmatory tests in the timely diagnosis of LOPD and implementation of best practice patterns.