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Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids

From the Departments of Neurology (J.A.V.G., C.W., L.A.B., Z.K.W.), Radiology (D.F.B.), and Pathology (D.W.D.), Mayo Clinic, Jacksonville, FL.

Address correspondence and reprint requests to Dr Wszolek, Mayo Clinic, Neurology, 4500 San Pablo Rd., Jacksonville, FL 32224 wszolek.zbigniew{at}mayo.edu

Objective: To report a new American family with hereditary diffuse leukoencephalopathy with spheroids (HDLS), including serial, presymptomatic and symptomatic, cranial MRIs from the proband.

Methods: We report clinical and genealogic investigations of an HDLS family, sequential brain MRIs of the proband, and autopsy slides of brain tissue from the proband’s father.

Results: We identified seven affected family members (five deceased). The mean age at symptomatic disease onset was 35 years (range: 20–57), and the mean disease duration was 16 years (range: 3–46). Five affected individuals initially manifested memory disturbance and behavioral changes, whereas two experienced a mood disorder as their presenting symptom. Our proband’s father had been diagnosed clinically with vascular dementia, but his brain autopsy was consistent with HDLS. The proband had a cranial MRI prior to symptom onset, with two subsequent MRIs performed during follow-up. These serial images reveal a progressive, confluent, frontal-predominant leukoencephalopathy with symmetric cortical atrophy.

Conclusions: The proband of our newly identified hereditary diffuse leukoencephalopathy with spheroids (HDLS) kindred had subtle evidence of an incipient leukoencephalopathy on a presymptomatic cranial MRI. Conceivably, MRI may facilitate identifying affected presymptomatic individuals within known HDLS kindreds, increasing the likelihood of isolating the causative genes.

GLOSSARY: DLS = diffuse leukoencephalopathy with spheroids; FLAIR = fluid-attenuated inversion recovery; HDLS = hereditary diffuse leukoencephalopathy with spheroids; LENAS = leukoencephalopathy with neuroaxonal spheroids; LFB = Luxol fast blue; NAL = neuroaxonal leukodystrophy; POLD = pigmentary type of orthochromatic leukodystrophy.

C.W. is supported by the Swiss National Science Foundation, Parkinson Switzerland, and the Robert and Clarice Smith Fellowship program. Z.K.W., J.A.V.G., and D.W.D. are supported by the Morris K. Udall Center of Excellence for PD Research (P50-NS40256). D.W.D. is supported by the Mayo Clinic ADRC grant P50-AG16574. Z.K.W. and D.W.D. are supported by the Pacific Alzheimer Research Foundation (PARF) grant C06-01.

Disclosure: The authors report no disclosures.

Received March 31, 2008. Accepted in final form June 12, 2008.

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				C. Wider, J. A. Van Gerpen, S. DeArmond, E. A. Shuster, D. W. Dickson, and Z. K. Wszolek Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): A single entity? Neurology, June 2, 2009; 72(22): 1953 - 1959. [Abstract] [Full Text] [PDF]