Leukodystrophies and genetic
leukoencephalopathies comprise a growing group of inherited white matter disorders. Diagnostic rates have improved with increased utilization of next generation sequencing. As treatment options continue to advance for leukodystrophies, so will candidacy for inclusion in the United States' newborn Recommended Universal Screening Panel as was achieved for
X-linked adrenoleukodystrophy. Stem cell
therapies have become standard of care for selected leukodystrophies. However,
transplantation-related risks remain high and outcomes are not fully satisfactory. Transduction of autologous hematopoietic stem cells with lentiviral vectors, referred to as ex vivo gene therapy, circumvents some, but not all, of the risks of traditional
transplantation and has recently been demonstrated to be safe and efficective in clinical studies of
X-linked adrenoleukodystrophy and
metachromatic leukodystrophy. Gene therapy, through direct infusion of adeno-associated virus vectors, has emerged as a safer alternative for many monogenetic pediatric
neurological disorders. Numerous preclinical studies have shown safety and efficacy of adeno-associated virus gene therapy in leukodystrophies allowing expanded access treatment for
Canavan disease prior to initiation of a clinical trial. For inherited white matter disorders resulting from overexpression of a
protein, such as
Pelizaeus-Merzbacher disease, emerging
RNA therapies have shown success in preclinical studies and promise for rapid translation to the clinic. Lastly, small molecule and
protein therapies remain a long-term treatment option for a number of leukodystrophies, including intrathecal
enzyme replacement therapy for
metachromatic leukodystrophy. Herein we review recent advances in diagnosis and treatment of inherited white matter disorders.