Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life.

Lysosomal storage disorders (LSDs) represent a diverse group of inherited metabolic diseases in which impaired lysosomal function leads to progressive accumulation of undegraded substrates and widespread cellular dysfunction. Although traditionally classified according to the type of stored macromolecule, this substrate-based approach often fails to reflect the underlying molecular mechanisms. Recent advances in genetics and cell biology have prompted a shift toward functional classifications that group disorders by the lysosomal pathway disrupted—namely, enzymatic hydrolytic defects, transporter-related defects, biogenesis and signaling defects, and cross-organelle interaction abnormalities. This framework better captures disease complexity and provides a translational roadmap for precision medicine. The neurological system, with its high metabolic demands and vulnerability to impaired clearance mechanisms, is particularly affected, leading to clinical phenotypes ranging from developmental delay to severe neurodegeneration. Genomic technologies and multi-omics platforms have facilitated earlier diagnoses, revealed atypical variants, and informed the development of tailored therapies such as enzyme replacement, substrate reduction, chaperone-based approaches, and gene therapy. The current review proposes a cellular-pathway-oriented framework for classifying LSDs with neurological features and underscores how such an approach can assist in the development of personalized therapeutic strategies.

Cytoskeletal disorders affecting the nervous system are a diverse group of diseases that display a wide variety of clinical manifestations. Mutations in genes encoding cytoskeletal components disrupt the structural and functional integrity of this complex network, impairing normal development and function of the central and peripheral nervous systems. There are also certain diseases which lead to progressive neurodegeneration, and others which result from an interplay of multiple molecular pathways. This review outlines the primary cytoskeletal disorders affecting the nervous system. To provide a comprehensive overview, these diseases are categorized by their predominantly affected cytoskeletal component—namely microtubules, actin filaments, intermediate filaments, and cytoskeleton-associated proteins. Each category highlights the broader pathophysiological context of the underlying defect rather than an isolated structural disturbance. A deeper understanding of the complex pathophysiology of these disorders may contribute to the discovery of potential therapeutic targets, since current medical management primarily provides symptomatic relief or slows their progression.