Leukoencephalopathy, Hereditary Diffuse, With Spheroids

A number sign (#) is used with this entry because hereditary diffuse leukoencephalopathy with spheroids (HDLS) is caused by heterozygous mutation in the CSF1R gene (164770) on chromosome 5q32.

Description

Hereditary diffuse leukoencephalopathy with spheroids is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes (summary by Rademakers et al., 2012).

Clinical Features

Lanska et al. (1994) presented clinical and pathologic information on 2 large multigenerational families with a form of autosomal dominant adult-onset dementia termed progressive subcortical gliosis. Affected individuals presented in the fifth or sixth decade of life with personality change and degeneration of social ability which later developed into a profound dementia with mutism, dysphagia, and extrapyramidal signs. The presentation was similar to that of Pick disease. Autopsies were done on 7 affected individuals. These showed moderately severe atrophy with preferential involvement of the frontal and temporal lobes but without the knife edge pattern characteristic of Pick disease. The most striking microscopic finding was a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts (U fibers) at the junction of cortical lamina VI and the subcortical white matter, and in the subpial cerebral cortex (lamina I). There was also laminar spongiosis, particularly in laminae II and III similar to that observed in Pick disease and Alzheimer disease, but different from the pancortical spongiform change in Creutzfeldt-Jakob disease which is usually most prominent in deeper layers. Neuronal inclusions and amyloid deposits, which are pathologic hallmarks of Alzheimer disease and Pick disease, were uniformly absent. One of the families reported by Lanska et al. (1994) was found by Goedert et al. (1999) to have a mutation in the MAPT gene (157140.0006), thus confirming a diagnosis of MAPT-related frontotemporal dementia (FTD; 600274).

Knopman et al. (1996) reported 3 sisters who developed progressive frontotemporal dementia between 40 and 70 years of age. Two presented with depression, abnormal behavior, and mild memory difficulties, ultimately resulting in an inability to function. None had prominent motor dysfunction. Neuropathologic examination of 2 sisters who died showed atrophy of the frontal and temporal lobes as well as white matter degeneration affecting the subcortical white matter and deep white matter without neuronal loss. There was extensive demyelination, loss of white matter axons, and gliosis. Abundant lipofuscin granules in microglia, macrophages, and astrocytes were also noted. Neurofibrillary tangles and senile plaques were not found in either case. The clinical and pathologic findings were consistent with a diagnosis of orthochromatic leukodystrophy. Nicholson et al. (2013) reported another affected member of the family described by Knopman et al. (1996), a daughter of 1 of the affected sisters. This patient developed symptoms of frontotemporal dementia at age 51. Brain imaging showed frontal atrophy and white matter hyperintensities throughout the frontal lobes, which worsened over time. Reevaluation of the neuropathology from the deceased affected family members showed the presence of axonal spheroids in areas with early white matter changes, consistent with HDLS.

Van der Knaap et al. (2000) reported a father and daughter with adult-onset deterioration of frontal lobe function, spasticity, ataxia, and mild extrapyramidal signs. MRI showed cerebral atrophy and patchy white matter changes. Postmortem examination showed leukoencephalopathy with numerous neuroaxonal spheroids. The frontal and frontoparietal lobes were most affected.

Baba et al. (2006) reported a kindred in which 6 individuals had dementia, depression, and frontal lobe signs variably associated with parkinsonism, apraxia, and seizures. The mean age at onset was 54 years. Postmortem examination of the brains showed loss of myelinated fibers, bizarre astrocytosis, white matter gliosis, and axonal spheroids. Inheritance was autosomal dominant. Molecular analysis excluded mutations in the MAPT gene and in several genes involved in leukoencephalopathy with white matter disease (603896).

Swerdlow et al. (2009) reported a multigenerational family with frontotemporal dementia associated with subcortical gliosis inherited in an autosomal dominant pattern. Age at onset ranged from the forties to sixties in affected individuals. The phenotype was characterized mainly by progressive behavioral changes, disorientation, frontal release signs, and memory loss. Later symptoms and signs included dementia, mutism, and incontinence. Some individuals developed parkinsonism. Neuropathologic studies showed frontotemporal cortical atrophy, ventriculomegaly, neuronal loss, hypertrophic astrogliosis in the superficial and deep white matter, loss of axons, dystrophic axons, and axonal spheroids containing neurofilaments. Immunohistochemical studies did not identify tau, ubiquitin, or prion (PRNP; 176640) inclusions. Swerdlow et al. (2009) noted that the disorder shared some characteristics with leukoencephalopathy with neuroaxonal spheroids, as described by van der Knaap et al. (2000) and Baba et al. (2006).

Rademakers et al. (2012) reported 14 families with HDLS, including those reported previously by Swerdlow et al. (2009) and Baba et al. (2006). Clinical features of 24 affected individuals showed that the mean age at onset was 47.2 years (range, 18-78 years), with a mean age of death at 57.2 years (range, 40-84 years). One patient was described in detail. He developed mild depression and forgetfulness at age 50 years. Two years later, he had a flat affect, inappropriate behavior, poor concentration, executive dysfunction, restless legs syndrome, and insomnia. There was psychomotor slowing, and ideomotor and constructional apraxia. He had a slow, shuffling gait, postural instability, rigidity, and bradykinesia. Brain imaging showed hyperintense foci in both the frontal and parietal lobes, involving the periventricular, deep and subcortical white matter, but sparing the subcortical U fibers. At the end of his illness, he was mute and in a vegetative state; death occurred at age 55 years. Neuropathologic examination showed myelin loss, axonal spheroids containing neurofilaments, astrocytes, gliosis, and ballooned neurons. There was inter- and intrafamilial variability, with different ages at onset and death, as well as variable clinical features. Antemortem clinical diagnoses in mutation carriers included frontotemporal dementia (FTD; 600275), corticobasal syndrome, Alzheimer disease (AD; 104300), multiple sclerosis (MS; 126200), atypical cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310), and Parkinson disease (PD; 168600).

Konno et al. (2014) reported 7 Japanese patients with HDLS. The age at onset ranged from 36 to 55 years (mean of 44 years), and all patients presented with cognitive impairment followed by behavioral and personality changes. Later features included parkinsonism, including bradykinesia and gait disturbance, pyramidal signs, and seizures (2 patients). Six of the 7 patients progressed to being wheelchair-bound and having severe dementia with communication problems within 5 years after onset. Three patients had a family history of a similar disorder, consistent with autosomal dominant inheritance. Neuropathologic studies of several patients showed diffuse loss of myelin sheaths and axons in the white matter, as well as severe gliosis prominent in the frontal lobe. Scattered axonal spheroids that were immunoreactive for phosphorylated neurofilaments were present in the white matter lesions. In addition, there was abnormal appearance of activated microglia.

Neuroradiologic Findings

Sundal et al. (2012) reviewed 20 brain MRI scans of 15 patients from 9 HDLS families, all of Caucasian descent with genetically confirmed disease, and assigned a severity score based on the lesion load. The mean age at onset was 44.3 years and the mean age at death was 53.2 years. All patients had a progressive clinical course, except 1, who had mild disease burden on initial MRI. At onset, 14 of 15 patients had localized white matter lesions (WML) with deep, subcortical, and periventricular involvement, whereas 1 more severely affected patient had generalized WML. All lesions were bilateral, but asymmetric, and predominantly in the frontal/parietal regions. There was cortical atrophy and involvement of the corpus callosum, but gray matter pathology and brainstem atrophy were absent; corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Indicators of rapid disease progression included onset before age 45 years, female sex, WML extending beyond the frontal regions, an MRI severity score greater than 15 points, and deletion mutations. Sundal et al. (2012) concluded that recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments.

Konno et al. (2014) reported the neuroradiologic features of 7 Japanese patients with HDLS. Brain MRI showed T2-weighted bilateral hyperintensities in the white matter with frontal predominance, as well as thinning of the corpus callosum. The changes were progressive, and included brain atrophy. CT scans of 5 patients showed spotty calcifications in the affected white matter, which were confirmed by histology in 1 patient.

Inheritance

The transmission pattern of HDLS in the families reported by Rademakers et al. (2012) was consistent with autosomal dominant inheritance.

Molecular Genetics

By linkage analysis followed by whole-exome sequencing of the family with HDLS reported by Swerdlow et al. (2009), Rademakers et al. (2012) identified a heterozygous mutation in the CSF1R gene (164770.0001). Sequencing of this gene in 13 additional probands with HDLS identified a different heterozygous mutation in each (see, e.g., 164770.0002-164770.0005). The mutations cosegregated with the disorder in all families for which DNA from multiple affected individuals was available, including the family reported by Baba et al. (2006). In vitro functional expression studies of some of the missense mutations indicated that the mutant proteins did not show autophosphorylation, suggesting a defect in kinase activity that likely also affects downstream targets. The mutant proteins probably also act in a dominant-negative manner, since CSF1R assembles into homodimers. Overall, the findings indicated that a defect in microglial signaling and function resulting from CSF1R mutations can cause central nervous system degeneration.

In 7 Japanese probands with HDLS, Konno et al. (2014) identified 6 different heterozygous mutations in the CSF1R gene (see, e.g., 164770.0004; 164770.0006-164770.0008). Two of the mutations resulted in truncated proteins, indicating that haploinsufficiency is sufficient to cause the disorder. In vitro functional expression studies in HEK293 cells showed that none of the mutant CSF1R proteins, including those caused by missense mutations, were able to autophosphorylate. However, coexpression of the mutants with wildtype did not suppress wildtype autophosphorylation, indicating that the mutations do not act in a dominant-negative manner.

In affected members of a family (FTD368) with a clinicopathologic diagnosis of pigmented orthochromatic leukodystrophy (POLD), originally reported by Knopman et al. (1996), Nicholson et al. (2013) identified a heterozygous missense mutation in the CSF1R gene (R728H; 164770.0009). In vitro functional expression studies in HeLa cells showed that the mutation abrogated CSF1R autophosphorylation, which would inhibit downstream signaling. The findings indicated that POLD and HDLS are a single disease entity, and Nicholson et al. (2013) suggested the term 'adult-onset leukodystrophy with axonal spheroids and pigmented glia' (ALSP).

History

Khoubesserian et al. (1985) reported a 70-year-old man with dementia who had 2 brothers who had died at age 59 with dementia. Pick disease (172700) and Alzheimer disease (AD; 104300) were ruled out by cerebral biopsy and normal levels of neurotransmitters in the biopsy tissue and CSF. These and histologic changes suggested that this may be the disorder reported by Neumann (1949) and designated 'subcortical gliosis' (Neumann and Cohn, 1967). This was the first familial observation.