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Keywords:

  • parkinsonism;
  • leucoencephalopathy;
  • genetics

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with progressive behavioral, cognitive, and motor symptoms.[1, 2] Mutations in the colony-stimulating factor 1 receptor gene (CSF1R) recently were shown to cause the disorder.[1] There is phenotypic heterogeneity, and misdiagnosis is possible.[2] We describe a patient with HDLS resulting from a CSF1R mutation presenting with features of parkinsonism.

Clinical History and Examination (see Video)

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information

A 41-year-old man presented with a 4-month history of progressive word-finding difficulty, reduced verbal fluency, social withdrawal, and bifrontal headaches. He reported being “slowed up” with impaired right-arm dexterity. He had no relevant medical history or recognized family history of neurological illness. He did not smoke or take illicit drugs.

There was cognitive impairment (26/30 in the Montreal Cognitive Assessment and 80/100 in the Addenbrooke Cognitive Exam [ACE], losing points for constructional skills, delayed recall, and verbal fluency). There was a striking reduction in phonemic verbal fluency. Speech was nonfluent and palilalic. There was hypomimia, hypophonia, and apraxia of eyelid opening. Downward saccades were mildly hypometric. Tongue movements were slow, jaw jerk was brisk, and pout and palmomontal reflexes were present. There was axial rigidity, bilateral mild limb rigidity, moderately severe bradykinesia in the arms, and micrographia. There was mild postural arm tremor, but no resting tremor. Left-arm ideomotor apraxia was noted. Limb reflexes were brisk without clonus, and plantar responses were flexor. Gait was slow and broad based, and there was mild postural instability.

Investigations

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information

Cranial MRI scan (see Fig. 1) showed cerebral atrophy and bilateral, confluent, frontal white matter hyperintensity on fluid attenuated inversion recovery (FLAIR) and T2-weighted sequences containing patchy areas of restricted diffusion, which persisted on a repeat scan 3 months later.

image

Figure 1. FLAIR imaging (top) showed generalized atrophy and signal abnormality in the deep white matter of both hempisheres, predominantly in the frontal and parietal lobes, with relative sparing of the temporal and occipital lobes. Diffusion-weighted imaging and ADC sequences (bottom) showed patchy areas of restricted diffusion within the abnormal areas of white matter hyperintensity.

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The MRI findings prompted a search for causes of cerebral vasculopathy. Intracranial magnetic resonance angiogram was normal. Inflammatory markers were normal, and there was no serological evidence of vasculitis. Other negative or normal results included the following: human immunodeficiency virus and treponemal serology; cerebrospinal fluid protein, glucose, cell count, oligoclonal bands and JC (john cunningham) virus polymerase chain reaction (PCR); C.A.D.A.S.I.L. (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and M.E.L.A.S. (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) genetics; and plasma white cell and lysosomal enzymes and very-long-chain fatty acids.

A heterozygous mutation in exon 18 of the CSF1R gene (c.2381T>C p.1794T) was found, confirming the diagnosis of HDLS. This mutation is pathogenic and was described in the seminal article.[1] Family members were offered genetic counseling.

Discussion

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information

Elements of clinical presentation with progressive, predominantly frontal, cognitive decline, and features of Parkinsonism (with levator inhibition, impaired vertical saccades, axial rigidity, symmetric bradykinesia, and postural instability) were suggestive of PSP. However, the abnormal MRI appearances prompted investigation for causes of leucoencephalopathy. The restricted diffusion on MRI, together with the complaint of headaches, made cerebral vasculitis an important consideration. However, restricted diffusion on MRI persisting 3 months later is not the result of acute infarction; this MRI feature, probably caused by high-grade intramyelinic edema, has been reported in HDLS[3] and in other leukodystrophies.[4] Parkinsonism has been described in HDLS[5] and, as with our patient, is unresponsive to levodopa. It is likely that HDLS is under-recognized. The recent discovery of the genetic cause[1] obviates the need for brain biopsy and allows swift diagnosis of a disorder previously often diagnosed at postmortem. We highlight another cause of “atypical” parkinsonism with features of PSP.[6] HDLS should be considered in cases of atypical parkinsonism with cognitive decline and appropriate cranial MRI appearances, even in the absence of an obvious family history of similar illness.

Author Roles

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

A.M.: 1C, 3A, 3B

L.W.: 3B

M.F.: 1B, 3B

S.O.R.: 1A, 1B, 3B

Disclosures

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: S.O.R. reports receiving an honorarium from Abbott (advisory board) and a speaker's honorarium from Lundbeck. The authors declare that there are no additional disclosures to report.

References

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information

Supporting Information

  1. Top of page
  2. Clinical History and Examination (see Video)
  3. Investigations
  4. Discussion
  5. Author Roles
  6. Disclosures
  7. References
  8. Supporting Information
FilenameFormatSizeDescription
mdc312033-sup-0001-VideoS1.mpgvideo/mpg49929K

A video accompanying this article is available in the supporting information here.

Video. Videotaped examination shows features of facial impassivity, frontalis overactivity, and hypophonia. Speech is hesitant and nonfluent, with palilalia. There is severe impairment of phonemic verbal fluency. Blink frequency is reduced and there is has apraxia of eyelid opening. Vertical downward saccades are hypometric. There is severe bradykinesia in the upper limbs, worse on the left side. There is a mild postural finger tremor in the right hand. There is micrographia. His posture is erect. Gait is stiff, slow, and broad based.

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