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).
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).
This determination has based upon genetic studies of 14 HDLS families confirming mutations in this gene. The CSF1 receptor protein primarily functions in regulation, survival, proliferation, and differentiation of microglial cells. The mechanism of microglial dysfunction due to mutations in CSF1R to the myelin loss and axonal spheroid formation remains unknown. Further research is needed to better understand disease pathogenesis.
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. The exception is the corticospinal tracts(pyramidal tracts) in the brainstem and sometimes spinal cord.
The brain pathology of HDLS resembles that of Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy).
Research as of 2012 includes investigations of microglial function. This work would further clarify whether the disease is primarily a defect in microglia function. For such a study, microglial cells from HDLS kindred can be cultured from autopsy brain and analyzed in comparison to normal microglial cells on the basis of differences in mutation occurrences and growth factor expression.
Nasu-Hakola disease appears to be caused by mutations in the TYRO protein tyrosine kinase-binding protein (TYROBP - also known as DAP12) or the triggering receptor expressed on myeloid cells 2 (TREM2) protein. While different gene mutations occur within the pathway for Nasu-Hakola and HDLS, both are characterized by white matter degeneration with axonal spheroids. Current researchers in the field believe that more in depth analysis and comparison of the two genetic abnormalities in these disorders could lead to a better understanding of the disease mechanisms in these rare disorders. POLD exhibits noninflammatory demyelination of axons with initial symptoms of euphoria, apathy, headache, and executive dysfunction. While HDLS is autosomal dominant, some families with POLD have features that suggest autosomal recessive inheritance. Nevertheless, POLD has recently been shown to have the same genetic basis as HDLS.
To gain a better understanding of the disease, researchers have retrospectively reviewed medical records of probands and others who were assessed through clinical examinations or questionnaires. Blood samples are collected from the families of the probands for genetic testing. These family members are assessed using their standard medical history, on their progression of Parkinson's like symptoms (Unified Parkinson's Disease Rating Scale), and on their progression of cognitive impairment such as dementia (Folstein Test).
HDLS falls under the category of brain white matter diseases called leukoencephalopathies that are characterized by some degree of white matter dysfunction. 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. Studies by Sundal and colleagues from Sweden showed that a risk allele in Caucasians may be causative because cases identified have thus far been among large Caucasian families.
An average clinical profile from published studies shows that the median onset age for HDLS patients is 44.3 years with a mean disease duration of 5.8 years and mean age of death at 53.2 years. As of 2012, there have been around 15 cases identified with at least 11 sporadic cases of HDLS. HDLS cases have been located in Germany, Norway, Sweden, and the United States, showing an international distribution focusing between Northern Europe and the United States.
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. It was also observed that the HDLS cases did not skip generations as it would occur with a recessive inheritance, and as such has been labeled autosomal dominant.
Lin, W. L., Wszolek, Z. K., & Dickson, D. W. (2010). Hereditary diffuse leukoencephalopathy with spheroids: ultrastructural and immunoelectron microscopic studies. Int J Clin Exp Pathol, 3(7), 665-674.
Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
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Rademakers, R., Baker, M., Nicholson, A., Rutherford, N., Finch, N., Soto-Ortolaza, A., . . . Wszolek, Z. (2012). Mutations in the colony stimulating factor 1 receptor (CSF1R) cause hereditary diffuse leukoencephalopathy with spheroids. Movement Disorders, 27, S399-S400.
Wider, C., Van Gerpen, J. A., DeArmond, S., Shuster, E. A., Dickson, D. W., & Wszolek, Z. K. (2009). Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): a single entity? Neurology, 72(22), 1953–1959. doi:10.1212/WNL.0b013e3181a826c0 /wiki/Doi_(identifier)
Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
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Rademakers, R., Baker, M., Nicholson, A., Rutherford, N., Finch, N., Soto-Ortolaza, A., . . . Wszolek, Z. (2012). Mutations in the colony stimulating factor 1 receptor (CSF1R) cause hereditary diffuse leukoencephalopathy with spheroids. Movement Disorders, 27, S399-S400.
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Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
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Wider, C., Van Gerpen, J. A., DeArmond, S., Shuster, E. A., Dickson, D. W., & Wszolek, Z. K. (2009). Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): a single entity? Neurology, 72(22), 1953–1959. doi:10.1212/WNL.0b013e3181a826c0 /wiki/Doi_(identifier)
Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
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Sundal, C., Van Gerpen, J. A., Nicholson, A. M., Wider, C., Shuster, E. A., Aasly, J., . . . Wszolek, Z. K. (2012). MRI characteristics and scoring in HDLS due to CSF1R gene mutations. Neurology, 79(6), 566-574. doi:10.1212/WNL.0b013e318263575a /wiki/Doi_(identifier)
Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)
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Sundal, C., Lash, J., Aasly, J., Oygarden, S., Roeber, S., Kretzschman, H., . . . Wszolek, Z. K. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci, 314(1-2), 130-137. doi:10.1016/j.jns.2011.10.006 /wiki/Doi_(identifier)