Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brain white matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range of overlapping neurological manifestations possibly associated with variable systemic involvement are found in these disorders making clinical diagnosis challenging. Advances in molecular genetics enabled the identification of the responsible genes of an increasing number of previously undefined forms.
This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of which have an autosomal dominant inheritance. The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinal microangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will be detailed because of the vascular based myelin damage and the recent genetic characterization. Other adult onset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD) due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X-associated tremor/ataxia syndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variants of the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally, palliative, curative and experimental treatment options are here summarized.