Update on leukodystrophies and developing trials

**Background:** Leukodystrophies are a heterogeneous group of rare genetic disorders primarily affecting the white matter of the central nervous system (CNS). Incidence ranges from 1 in 100,000 to 1 in 6,000–7,700 live births in the USA and Europe, and 3 per 100,000 in Asian countries. Metachromatic leukodystrophy (MLD) and X-linked adrenoleukodystrophy (X-ALD) are the most common forms. Leukodystrophies can be classified into demyelinating and hypomyelinating types based on MRI appearance, or by cellular pathophysiology and molecular mechanisms. Inheritance patterns include autosomal recessive (most common), autosomal dominant, X-linked, sporadic, and mitochondrial. Pathophysiology involves defects in oligodendrocytes, astrocytes, axons, microglia, small blood vessels, and various molecular pathways (lysosomal, peroxisomal, mitochondrial, etc.). Clinical manifestations vary by etiology and age of onset, with hypomyelinating forms presenting earlier and demyelinating forms showing motor regression. Common neurological symptoms include motor and cognitive difficulties, pyramidal signs, extrapyramidal movement disorders, seizures, gait abnormalities, peripheral neuropathy, bulbar symptoms, and neurobehavioral abnormalities. Non-neurological manifestations can involve ophthalmological, endocrinological, dental, cutaneous, musculoskeletal, gastrointestinal, and cardiological systems.

**Methods:** This is a narrative review summarizing current knowledge on leukodystrophies, including diagnostic approaches and ongoing clinical trials. The authors synthesized information from published literature and clinical trial registries. Diagnostic workflow includes patient history, comprehensive examination, brain MRI (with specific patterns for different leukodystrophies), biochemical/metabolic tests (e.g., very long-chain fatty acid profiles for X-ALD, leukocyte lysosomal enzyme activity for Krabbe disease and MLD, plasma cholestanol for cerebrotendinous xanthomatosis), and genetic testing (targeted gene panels, whole-exome sequencing [WES], whole-genome sequencing [WGS]). WES has increased diagnostic yield by approximately 10% in recent years. Biomarkers such as psychosine (Krabbe disease), sulfatides (MLD), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) are discussed.

**Key Results:** Currently, no disease-modifying treatments exist for most leukodystrophies; management is mainly symptomatic and palliative, involving a multidisciplinary team. Specific treatments include hematopoietic stem cell transplantation (HSCT) for X-ALD, CTX, Krabbe disease, and MLD; chenodeoxycholic acid for CTX; and growth hormone substitution for 4H syndrome. Gene therapies under investigation include: OTL-200 (Libmeldy) for late juvenile MLD, using ex vivo lentiviral modification of autologous CD34+ hematopoietic stem cells to deliver functional ARSA enzyme; rAAV-Olig001-ASPA for Canavan disease, delivered via neurosurgery to restore ASPA function in oligodendrocytes; and AAV-based therapies for Krabbe disease and Canavan disease. Small-molecule drugs in trials include: ION373 (antisense oligonucleotide targeting GFAP) for Alexander disease (AxD); VK0214 (thyroid beta receptor agonist) for X-ALD; and MIN-102 (Leriglitazone, a PPARγ agonist) for cerebral X-ALD. In the MIN-102 trial, new inflammatory lesions or growth of non-inflammatory lesions occurred exclusively in the placebo group, suggesting potential to slow progression. Preclinical studies of ION373 showed phenotypic benefits in rodent models of AxD. VK0214 demonstrated safety and significant reductions in key lipids in Phase 1 studies.

**Clinical Implications:** Early and accurate diagnosis of leukodystrophies is crucial for appropriate treatment options and participation in clinical trials. The integration of MRI, clinical evaluation, and next-generation sequencing reduces unsolved cases. Newborn screening can enable early diagnosis and treatment. While most leukodystrophies remain incurable, ongoing trials of gene therapies and targeted small molecules offer promise for disease modification. Healthcare professionals should stay updated on these advancements to improve diagnosis, management, and outcomes for patients with leukodystrophies.