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Hereditary diffuse leukoencephalopathy with spheroids

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Hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare adult onset autosomal dominant disorder characterized by cerebral white matter degeneration with demyelination and axonal spheroids leading to progressive cognitive and motor dysfunction. Spheroids are axonal swellings with discontinuous or absence of myelin sheaths entirely. It is believed that the disease arises from primary disruption of axonal integrity, neuroaxonal damage, and focal axonal spheroids leading to demyelination. Spheroids in HDLS resemble those produced by shear stress in closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport. In addition to trauma, similar axonal spheroids can be found in aged brain, stroke, and in other degenerative diseases.[1] In HDLS, it is uncertain whether demyelination occurs prior to the axonal spheroids or what triggers neurodegeneration after apparently normal brain and white matter development.[2] It is commonly mistaken for Alzheimer's disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.[3]

Classification

HDLS falls under the category of brain white matter diseases called leukoencephalopathies that are characterized by some degree of white matter dysfunction. HDLS specifically 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 Dr. Sundal from Sweden show that a risk allele in Caucasians may be causative because cases identified have thus far been among large Caucasian families.[2]

Epidemiology

An average profile from studies show 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.[4][2] As of 2012, there have been around 15 cases identified with at least 11 sporadic cases of HDLS.[4][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. It was also noticed that the HDLS cases did not skip generations as would be noticed with a recessive inheritance, and as such has been labeled autosomal dominant.[2]

Clinical symptoms & misdiagnoses

"Circuitry of the basal ganglia experiencing Parkinsonism"
Coronal slices of the basal ganglia circuitry marked under Parkinsonism circumstances.

With symptoms of personality changes, behavioral changes, dementia, depression, and epilepsy, HDLS has been commonly misdiagnosed for many other diseases.[5] Dementia or frontotemporal behavioral changes, for example, have commonly steered some clinicians to consider diagnoses such as Alzheimer’s disease when it was actually HDLS. HDLS commonly manifests with neuropsychiatric symptoms, progressing to dementia, and after a few years shows motor dysfunction. Eventually patients become wheelchair-bound or bedridden.[3]

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).[2]

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
Nasu-Hakola
  • Pain and tenderness of ankles/feet/wrist
  • Cystic bone lesions noticeable on radiological films

[2]

Neuropsychiatric symptoms

Many neuropsychiatric symptoms have been identified in genealogical studies. 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).[3]

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). [3]

History

This disease was first described in 1984 by Axelsson et al. in a large Swedish pedigree.[6] Dr. Dennis W. Dickson, who has taken on the pathological study component of investigating HDLS, gained his motivation in the early 90s when he was covering neuropathology in New York on cases that had previously been identified. This curiosity was further heightened in 1997 at the Mayo Clinic when Dr. Zbigniew K. Wszolek came across cases with similar symptoms that at autopsy were shown by Dr. Dickson to have HDLS. Dr. Wszolek established an international consortium in 2005 to identify other families and to send DNA or brain sampled for diagnosis and research at the Mayo Clinic in Florida.[2]

Related disorders in the same disease spectrum as HDLS include Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), and a type of leukodystrophy with pigment-filled macrophages called pigmentary orthochromatic leukodystrophy (POLD).[3] In addition to white matter disease, Nasu-Hakola causes development of bone cysts and is caused by mutations in genes involved in the same colony stimulating factor (CSF) signaling cascade as identified in HDLS.[7]

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 present with 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.[8] Nevertheless, POLD has recently been shown to have the same genetic basis as HDLS.

Pathology

"CT showing a leukoencephalopathy "
An axial CT scan of a patient presenting a leukoencephalopathy, the base disorder to the family of disorders that HDLS falls under.

There is enlargement of the lateral ventricles and marked attenuation of cerebral white matter.[9] The loss of white matter is caused by myelin loss. These changes are associated with diffuse gliosis, moderate loss of axons and many axonal spheroids.[1]

Macrophages with non-metachromatic lipid granules are common. In severely degenerated areas there are lipid-laden macrophages with an aggregation of membranous cytoplasmic bodies as well as many large, reactive astrocytes filled with glial fibrils.[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. The exception is the corticospinal tracts(pyramidal tracts) in the brainstem and sometimes spinal cord.[2]

The brain pathology of HDLS resembles that of Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy).[10]

Causes

The cause of HDLS appears to be due to mutations in the colony stimulating factor 1 receptor (CSF1R).[5]

The mutations are concentrated in tyrosine kinase domain (TKD) of the protein. Mutations were mainly found in exons 12-22 of the intracellular TKD, including 10 missense mutations and a single codon deletion. Additionally, three splice site mutations were identified that caused an in-frame deletion of an exon leading to the removal of more than 40 amino acids in the TKD.[5]

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.[11] 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.

Research

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.[11]

Clinical and genealogic studies

"High magnification of glial lesions"
A micrograph of cellular lesions as seen following H&E Staining. White matter is shown in light pink and grey matter is shown in darked purple with cell bodies. The lesion can be noticed in reddish pink showing nuclear atypia.

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).[2]

Neuroimaging

Standard MRI scans have been performed on 1.5 Tesla scanners with 5 mm thickness and 5 mm spacing to screen for white matter lesions in identified families. If signal intensities of the MRI scans are higher in white matter regions than in grey matter regions, the patient is considered to be at risk for HDLS, although a number of other disorders can also produce white matter changes and the findings are not diagnostic without genetic testing or pathologic confirmation.[2]

Pathology

Paraffin blocks from autopsies and glass slides from brain biopsies were performed on identified probands by the Florida location of the Mayo Clinic where sections of the neocortex, hippocampus, hypothalamus, basal ganglia, thalamus, midbrain, pons, cerebellum, and spinal cord were examined.[2][12] In addition to routine histologic methods (H&E staining)samples were evaluated with immunohistochemistry for ubiquitin among several other techniques to characterize white matter pathology.[9] 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.[3]

See also

References

  1. ^ a b c 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.
  2. ^ a b c d e f g h i j k l 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
  3. ^ a b c d e f 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
  4. ^ a b 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
  5. ^ a b c 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.
  6. ^ Axelsson, R., Roytta, M., Sourander, P., Akesson, H. O., & Andersen, O. (1984). Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand Suppl, 314, 1-65.
  7. ^ Paloneva, J., Mandelin, J., Kiialainen, A., Böhling, T., Prudlo, J., Hakola, P., . . . Peltonen, L. (2003). DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. The Journal of experimental medicine, 198(4), 669-675.
  8. ^ Knaap, Marjo S., & Valk, Jaap. (2005). Pigmentary Orthochromatic Leukodystrophy Magnetic Resonance of Myelination and Myelin Disorders (pp. 557-558): Springer Berlin Heidelberg.
  9. ^ a b Baba, Y., Ghetti, B., Baker, M. C., Uitti, R. J., Hutton, M. L., Yamaguchi, K., . . . Wszolek, Z. K. (2006). Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred. Acta Neuropathol, 111(4), 300-311. doi: 10.1007/s00401-006-0046-z
  10. ^ Hancock, N., Poon, M., Taylor, B., & McLean, C. (2003). Hereditary diffuse leucoencephalopathy with spheroids. J Neurol Neurosurg Psychiatry, 74(9), 1345-1347.
  11. ^ a b Kinoshita, M., Yoshida, K., Oyanagi, K., Hashimoto, T., & Ikeda, S. (2012). Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: Case report. Journal of the Neurological Sciences, 318(1-2), 115-118. doi: 10.1016/j.jns.2012.03.012
  12. ^ Van Gerpen, J. A., Wider, C., Broderick, D. F., Dickson, D. W., Brown, L. A., & Wszolek, Z. K. (2008). Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids. Neurology, 71(12), 925-929. doi: 10.1212/01.wnl.0000325916.30701.21
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