Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): A misdiagnosed disease entity

Abstract

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindred's and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis.

MRI characteristics and scoring in HDLS due to CSF1R gene mutations

“…Current evidence suggests that HDLS initially manifests focally in the WM and becomes confluent. 5,16,26 Our study demonstrates that in some patients, lesions develop deep in the WM, spreading to periventricular and subcortical regions, and finally becoming confluent and generalized. Focal lesions may occur in the early stages of HDLS.…”

“…DISCUSSION Our report describes the MRI pattern of HDLS in patients with CSF1R gene mutations. MRI findings in patients with HDLS have been described previously in 20 reports, 5,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] however, without knowledge of the CSF1R gene mutation carrier status. 4 We developed an HDLS MRI severity scoring system, modified from those devised for X-ALD, Krabbe disease, and MLD.…”

“…Neuropathologically, all had myelin loss and axonal spheroids in cerebral WM, confirming the diagnosis of HDLS. 3,5 MRI characteristics. We categorized the patients into 3 groups: mild (total MRI severity score, 1.0Ϫ6.0 points), moderate (total MRI severity score, 7.0Ϫ15.0 points), and severe disease burden (total MRI severity score, 16.0Ϫ57.0 points).…”

CSF1R mutations link POLD and HDLS as a single disease entity

“…Archival tissue from FTD368 II-1 and II-2, reported previously, 14 was re-evaluated with histologic and immunohistochemical methods as in previous reports. 2,5,8,15 The findings in II-1 and II-2 were essentially the same. For comparison, FTD368 II-2 (figure 2, C and E) was compared with an HDLS case with a documented CSF1R Figure 1 Families with POLD and CSF1R mutations Shown are abbreviated pedigrees of 2 families, family FTD368 (A) and family 5901 (B) affected by pigmented orthochromatic leukodystrophy (POLD) included in this study.…”

“…7,8,[13][14][15][16][17][21][22][23][24][25] The clinical presentation in POLD family FTD368 included symptoms of depression, abnormal behavior, and an inability to function, progressing to dementia in the 3 siblings from the second generation. The proband Figure 3 Functional effects of CSFR1 mutations in cell culture CSF-1 treatment leads to autophosphorylation of wild-type but not mutant CSF1R.…”