With symptoms of personality changes, behavioral changes, dementia, depression, and epilepsy, HDLS has been commonly misdiagnosed for a number of other diseases. Dementia or frontotemporal behavioral changes, for example, have commonly steered some clinicians to mistakenly consider diagnoses such as Alzheimer’s disease, frontotemporal dementia or atypical Parkinsonism. The presence of white matter changes has led to misdiagnosis of multiple sclerosis. HDLS commonly manifests with neuropsychiatric symptoms, progressing to dementia, and after a few years shows motor dysfunction. Eventually patients become wheelchair-bound or bedridden. White matter degeneration is associated with and makes differential diagnoses out of other adult onset leukodystrophies such as metachromatic leukodystrophy (MLD), Krabbe disease (globoid cell leukodystrophy), and X-linked adrenoleukodystrophy (X-ADL). Disease Exclusive Trait MLD Accumulation of metachromatic material in white matter Krabbe Disease Presence of globoid cells derived from microglia which have multiple nuclei X-ALD Predominant parieto-occipital white matter abnormality Vanishing White Matter (VWM) Disease *Increased white matter rarefaction *Cystic degeneration *Sparse dysmorphic astrocytes *Scanty astogliosis *Increased macroglia around cavity regions and lesser areas *Foamy oligodendrocytosis Nasu-Hakola *Pain and tenderness of ankles/feet/wrist *Cystic bone lesions noticeable on radiological films Neuropsychiatric symptoms Many neuropsychiatric symptoms have been identified in clinical studies of HDLS patients. These include severe depression and anxiety that have been identified in about 70% of HDLS families, verging on suicidal tendencies and substance abuse such as alcoholism. Additionally, patients may exhibit disorientation, confusion, agitation, irritability, aggressiveness, an altered mental state, the loss of the ability to execute learned movements (apraxia), or the inability to speak (mutism). Motor impairment Persons with HDLS can suffer from tremors, decreased body movement, unsteadiness (Parkinsonism, muscles on one side of the body in constant contraction (spastic hemiparesis), impairment in motor and sensory function in the lower extremities (paraparesis), paralysis resulting in partial or total loss of all extremities and torso (tetraparesis), and the lack of voluntary coordination of muscle movements (ataxia).
Hereditary diffuse leukoencephalopathy with spheroids
Powassan encephalitis
Toxic leukoencephalopathy
Autoimmune encephalitis
Transmissible spongiform encephalopathy
Progressive multifocal leukoencephalopathy
Malignant multiple sclerosis
Variant Creutzfeldt–Jakob disease