CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts.
BACKGROUND
Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a genetically heterogeneous disease characterized by a combination of systemic bone cysts and dementia.


OBJECTIVE
The authors present a neurologic, neuroradiologic, and neuropathologic analysis of a series of PLOSL patients in which the diagnosis has been confirmed by molecular genetic methods.


METHODS
Clinical, neurophysiologic, and imaging follow-up data on eight patients as well as autopsy samples of three patients were analyzed in this study. All eight patients were homozygous for a loss-of-function mutation in the DAP12 gene.


RESULTS
In most patients, the disease debuted with pain in ankles and wrists after strain during the third decade, followed by fractures caused by cystic lesions in the bones of the extremities. Frontal lobe syndrome and dementia began to develop by age 30, leading to death by age 40. Neuroimaging disclosed abnormally high and progressively increasing bicaudate ratios and calcifications in the basal ganglia as well as increased signal intensities of the white matter on T2-weighted MR images even before the appearance of clinical neurologic symptoms. Three patients who had undergone autopsies showed an advanced sclerosing leukoencephalopathy with frontal accentuation, widespread activation of microglia, and microvascular changes.


CONCLUSIONS
Although PLOSL in most patients manifests by bone fractures, some patients do not show any osseous symptoms and signs before the onset of neurologic manifestations. Consequently, patients with frontal-type dementia of unknown origin should be investigated by x-ray of ankles and wrists. The current results suggest early basal ganglia involvement in PLOSL.
Paloneva
J
J
Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.
Autti
T
T
Raininko
R
R
Partanen
J
J
Salonen
O
O
Puranen
M
M
Hakola
P
P
Haltia
M
M
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001845:Bone Cysts / Q000235:genetics / Q000473:pathology*; D003704:Dementia / Q000235:genetics / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D005625:Frontal Lobe / Q000473:pathology*; D006720:Homozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D008060:Lipodystrophy / Q000235:genetics / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins; D017628:Microglia / Q000737:chemistry / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011971:Receptors, Immunologic / Q000235:genetics; D013628:Talus / Q000473:pathology; D000097382:CD68 Molecule
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C110546:TYROBP protein, human