Autosomal recessive forms of limb-girdle muscular dystrophy are caused by biallelic loss of function variants. Haplosufficient carriers are hypothesized to have sufficient protein expression to maintain normal physical function. This study aims to determine relative protein expression in haplosufficient carriers of 3 subtypes of autosomal recessive LGMD: LGMDR1 (CAPN3, calpain-3), LGMDR9 (FKRP, FKRP), and LGMDR3 (SGCA, α-sarcoglycan). In addition, this study clarifies fukutin-related protein (FKRP) enzymatic functionality in LGMDR9 carriers. Individuals affected with LGMDR1, R9, and R3 and corresponding carriers provided a muscle biopsy following a physical examination. RNA-seq analysis was performed to determine global gene-expression patterns. Gene expression of CAPN3, FKRP, and SGCA were determined using RNA-seq normalized counts, and relative quantification of disease-associated proteins was determined by western blotting. Carriers of LGMDR1 were found to have approximately 25% total calpain-3 expression compared with noncarrier controls, while LGMDR9 carriers had nearly 50% functionality of FKRP. LGMDR3 carriers exhibited α-sarcoglycan and β-sarcoglycan protein levels comparable with controls. Carriers of several autosomal-recessive LGMDs have reduced expression of disease-related proteins compared with noncarrier controls with associated reduced protein functionality. Since these haplosufficient carriers have normal physical strength, this degree of protein expression may represent the threshold to restore haplosufficient status after gene replacement therapy.

Structural neurovascular lesions (SNVLs)-arteriovenous malformations, cavernous malformations, and vein of Galen aneurysmal malformations, among others-have historically been treated using neurosurgical, radiotherapeutic, and endovascular approaches. However, lesion size, location, and presence of high-risk angioarchitectural features preclude many patients from receiving these treatments. Advances in human genetics and cerebrovascular biology have redefined SNVLs as dynamic, genetically driven lesions where sporadic cases are caused by somatic variants. Intriguingly, many SNVL-causing variants are also oncogenic and active drug targets. These data provide the rationale for a genetically driven taxonomy to guide targeted therapeutic selection. In this commentary, we synthesize efforts toward pharmacologic treatments of SNVLs and highlight how variant-specific or pathway-modulating therapies may be investigated, incorporating key considerations in molecular diagnosis, cerebrovascular biology, and molecular and phenotypic outcome measures, in forthcoming clinical trials. Together, these advances support the investigation of pharmacologic treatment strategies in carefully selected patients with SNVLs.

It is a critical time to advance solutions that would mitigate the perceived, potential, and actual risk of discrimination based on neurodegenerative biomarker information. Across neurodegenerative conditions, biomarkers are being evaluated to detect disease pathology before the onset of clinically measurable symptoms. Clinical adoption and research that expands the use of biomarkers raises novel legal questions and exposes potential gaps in existing privacy and antidiscrimination laws. These concerns may be particularly salient for individuals in the earliest disease stages who may still be employed, have yet to complete financial or medico-legal planning (e.g., life insurance), or are considering housing changes. In this article, we evaluate the current landscape of legal protections and propose a strategy for developing a policy agenda that is informed by empirical evidence. We propose an iterative approach that begins with a comprehensive evaluation of the existing landscape of legal protection alongside the development of evidence that identifies priorities and informs policy strategies. Our recommendations aim to build from existing legal mechanisms, identify gaps in legal protections, and prioritize future policy goals that stem from perceived and actual privacy and discrimination risks. We argue that it is essential to understand the goals of new legislative efforts, to comprehensively assess what evidence is needed to prioritize specific domains of discrimination, and to consider unintended consequences of legislative approaches. Absent this, we risk enshrining lackluster protections into law that fail to support access to biomarker testing advancements that align with patient and participants' interests.

Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.