Spheroids in HDLS resemble to some extent those produced by shear stress in a closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport.

[2] The clinical syndrome in patients with HDLS is not specific and it can be mistaken for Alzheimer's disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.

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).

[3] Persons with HDLS can develop 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).

Additionally, three splice site mutations were identified that caused an in-frame deletion of an exon, an expressed nucleotide sequence, leading to the removal of more than 40 amino acids in the TKD.

[1] Activated or ameboid microglia and macrophages that contain myelin debris, lipid droplets and brown autofluorescent pigment granules are found in the areas with demyelination and axonal spheroids.

[1] In autopsy cases, it has been shown that white matter abnormalities are relatively confined to the cerebrum while avoiding the cerebellum and many of the major fiber tracts of the nervous system.

It is caused by mutations in the genes involved in the same colony stimulating factor (CSF) signaling pathway cascade as identified in HDLS.

Special stains for myelin and axonal pathology show the abnormal changes that are characteristic of HDLS are identified in white matter of the neocortex, basal ganglia, thalamus, midbrain, pons and spinal cord.

[6] With a similar pathology to POLD, HDLS is commonly grouped as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) so as to give these individually under-recognized conditions heightened attention.

HDLS has white matter lesions with abnormalities in myelin sheath around axons, where the causative influences are being continually explored based upon recent genetic findings.

[2] Through the study of numerous kindred, it was found that the disease did not occur among just males or females, but rather was evenly distributed indicative of an autosomal rather than a sex-linked genetic disorder.

A neuropathologist with an interest in HDLS, Dr. Dennis W. Dickson, has identified a number of cases from neuropathology study of brains submitted for investigation of familial adult-onset dementia and movement disorders in New York and later in Florida.