Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (Nasu–Hakola Disease)

75.1 Clinical Features

and Laboratory Findings

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also called Nasu–Hakola disease, was described in the early 1970s by Nasu et al. (Japan) and Hakola (Finland).

The disorder was recognized as a combination of abnormalities in the nervous system and adipose tis- sue in the skeleton. Initially most cases were reported from Japan and Finland, but over the years the disease has been reported on a more global scale, with papers from other Nordic countries, Italy, and Belgium to North America and South Africa. There is no doubt that other countries will follow. The disease has an autosomal recessive mode of inheritance. Patients are often born of consanguineous parents.

The initial development of patients is normal. The first symptoms develop in the second or third decade of life and are mainly related to the skeletal abnor- malities. The disorder affects especially the distal parts of the long cancellous bones, metacarpals, metatarsals, and phalanges. The first symptoms are painful wrists and ankles, distortions and fractures, either occurring spontaneously or induced by minor trauma. In the third decade a slowly progressive de- mentia starts to develop, with the characteristics of a prefrontal psychological syndrome, including per- sonality changes, euphoria, loss of social inhibitions, memory loss, and confabulations. Gradually other symptoms appear. Seizures enter the clinical picture, in addition to gait disturbances, paraplegia, chor- eiform movements, myoclonia, and urinary inconti- nence. In the last phase of the disorder, cortical in- volvement becomes manifest with manifestations such as aphasia, agraphia, acalculia, and alexia. Bul- bar symptoms may develop as well. The prognosis is poor; the average life expectancy is 40 years. Howev- er, patients with a slower and more benign disease course have also been reported.

Laboratory findings may include an increased alkaline phosphatase level. Skeletal X-rays reveal multiple cystic lesions symmetrically located in the metatarsal areas of long bones, the phalanges, metacarpals, and metatarsals. Biopsy of the bone shows the characteristic histological membranocys- tic changes – lesions that can also be found in subcu- taneous adipose layers. DNA confirmation of the diagnosis is possible.

75.2 Pathology

On gross inspection, the brain shows atrophy of vari- able severity, especially in the frontal and temporal regions. The large cerebral arteries at the base of the brain appear normal. On coronal sectioning, the ven- tricles are enlarged, again predominantly in the frontal and temporal lobes. There is a decrease in white matter volume. The white matter appears gray- ish and is of rubbery consistency. The basal ganglia and thalami are smaller than normal. The globus pal- lidus shows a brownish discoloration and contains deposits of sandy material.

Microscopy shows a diffuse, symmetrical myelin pallor and marked astrofibrillary gliosis of the cere- bral white matter, predominantly in the frontal and temporal region, but also in the corpus callosum, in- ternal capsule, and sometimes cerebellar white mat- ter. The arcuate fibers are better spared in the tempo- ral than in the frontal regions. There is little su- danophilic material in perivascular macrophages, al- though sometimes sudanophilic material is more prominent and diffusely scattered in the affected white matter. No metachromatic material is found.

There are no signs of inflammation. Signs of axonal degeneration may be seen within the cerebral hemi- spheric white matter, basal ganglia, cerebellum, and brain stem, with axonal loss, fragmentation, and pres- ence of spheroid bodies. Electron microscopy of these axonal spheroids reveals a compact collection of cell organelles, including degenerated mitochondria, neurofilaments, and vesicles with patchy dense mate- rial. The presence of these axonal spheroids may sug- gest a link to leukoencephalopathies with axonal spheroids. The cerebral cortex is usually intact. The thalamus is rarely seriously affected. In the globus pallidus and putamen, basophilic calcospherites and moderate neuronal loss are seen. There are changes in the blood vessels (small arterioles and capillaries), most prominently in the white matter. The vessels have plump endothelium. The basement membranes of these blood vessels are thickened and often multi- plied, related to concentric deposition of collagen IV.

Immunohistochemically extravasation of plasma constituents can be demonstrated.

Peripheral nerves may be affected and axonal de- generation has been reported.

In addition to the brain, adipose tissue and bone marrow are of interest. In adipose tissue and fatty

Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy

(Nasu–Hakola Disease)

bone marrow, membranocystic lesions are found.

Convoluted membranous structures lie scattered or conglomerated among mature fat cells. The mem- branes, which are mainly eosinophilic but partly ba- sophilic, form irregular cystic cavities containing pale, homogeneous material. Ultrastructurally, the membranes consist of undulating bands composed of numerous minute tubular structures, arranged per- pendicularly to the inner surface of the cavity. The cavity is filled with a lightly osmiophilic amorphous substance. The outer zone of the bands shows tubular crypts with microvesicles. The tubulovesicular struc- ture of the membranocystic lesions arises at the lipid–cytoplasmic interface of degenerated fat cells and enters the interstitium to form the lesion, concur- rent with the collapse of fat cells. There are also mem- branocystic structures with thinner membranes without tubular structures. Membranocystic struc- tures are not specific for PLOSL. They can be induced by several forms of chronic circulatory insufficiency and trauma.

75.3 Chemical Pathology

Lipid analysis of brains of patients with PLOSL has re- vealed large amounts of free fatty acids, but no cho- lesterol esters. Within the white matter, total lipid, cholesterol, and cerebroside content are mildly to se- riously decreased.

75.4 Pathogenetic Considerations

One gene for PLOSL is TYROBP, also called DAP12, located on chromosome 19q13.1. The gene encodes TYRO protein tyrosine kinase binding protein (TYROBP), also called DAP12. TYROBP is an adaptor molecule that couples a variety of cell surface recep- tors expressed by myeloid cells, including natural killer cells, and plays a major role in the transduction of cell activation signals. It is expressed by a wide va- riety of myeloid cells and also by microglia and osteo- clasts.On the plasma membrane of these cells,TYROBP associates with activating receptors recognizing major histocompatibility complex class I molecules.

More recently, TREM2 has been identified as the second PLOLS gene. The gene is located on chromo- some 6p21.2. The protein TREM2 belongs to the im- munoglobulin superfamily and forms a receptor sig- naling complex with TYROBP. Its pattern of expres- sion closely follows the pattern of TYROBP. It triggers activation of immune responses in macrophages and monocyte-derived dendritic cells. PLOSL forms an example of a disease in which mutations in two differ- ent subunits of a multisubunit receptor complex re- sult in an identical phenotypic appearance.

The TYROBP-mediated signaling pathway plays an important role in human brain and bone tissue. The pathogenesis of the disease has still to be clarified.

The precise biochemical and structural steps leading to the histopathology of the disease are not yet under- stood. Patients with PLOSL have no defects in cell- mediated immunity, suggesting a remarkable capaci- ty of the human immune system to compensate for the inactive TYROBP-mediated activation pathway.

The characteristic bone cysts may reflect chronic dys- function of osteoclasts.

75.5 Magnetic Resonance Imaging

The combined findings of X-rays of the skeleton and CT and MRI of the brain are diagnostic. X-rays of the long bones, phalanges, and metacarpal and metatarsal bones show the typical cystic changes, in many cases with evidence of earlier fractures. CT shows calcification of the basal ganglia, especially in the putamen and caudate nucleus (Figs. 75.1 and 75.2), sometimes also in the globus pallidus, rarely in the dentate nucleus (Fig. 75.2). The abnormalities in the white matter are better demonstrated on MRI.

MRI shows bilateral, symmetric, cerebral white matter abnormalities with a high signal intensity on T

-weighted and FLAIR images (Figs. 75.2–75.4). The

Fig. 75.1. Female PLOSL patient, 38 years old. The CT scan

demonstrates the calcium deposits in the basal ganglia. Cour-

tesy of Dr.Y. Ueki, Dr. N. Kohara, Dr. H. Fukuyama, and Dr.Y. Miki,

Departments of Neurology and Brain Pathophysiology, Facul-

ty of Medicine, Kyoto University, Kyoto, Japan

signal change is often mild and ill demarcated. The temporal lobe tends to be better preserved (Figs. 75.3 and 75.4). The U fibers also tend to be spared (Figs. 75.2–75.4). On T

-weighted, but more conspicu- ously on gradient-recalled-echo images, the basal ganglia appear too dark in comparison with average normal findings in this age group (Figs. 75.3 and

75.4). There is progressive cerebral atrophy with widening of the ventricles and subarachnoid spaces (Figs. 75.3 and 75.4). The atrophy may dominate in the frontal area. Perfusion studies have been per- formed with SPECT and PET with evidence of hypo- perfusion in the frontal and temporal lobes.

Fig. 75.2. Male PLOSL patient, 29 years old. The CT scan demonstrates the calcium deposits in the caudate nucleus and dentate nucleus. The MRI reveals abnormalities in the periven- tricular and deep white matter, sparing the U fibers. The hilus of the dentate nucleus and deep cerebellar white matter is affected as well.

From Malandrini et al. (1996),

with permission

Fig. 75.3. A 32-year-old man with PLOSL.The T

-weighted im- ages reveal diffuse, ill-defined signal abnormalities in the cere- bral white matter, relatively sparing the U fibers and temporal white matter. There is some cerebral and cerebellar atrophy with moderate widening of CSF spaces. Note the low signal

intensity of the putamen and globus pallidus, related to calci-

um deposits, as evident on the CT scan (not shown). Courtesy

of Dr. T. Autti, Department of Radiology, Helsinki University

Central Hospital, Helsinki, Finland

Fig. 75.4. Brother of the patient shown in Fig. 75.3, also suffer- ing from PLOSL, 32 years old. Despite being the same age at MRI, this patient has much more severe cerebral atrophy and also some cerebellar atrophy. Note again the low signal inten-

sity of the basal ganglia on these T

-weighted images. Cour-

tesy of Dr. T. Autti, Department of Radiology, Helsinki Universi-

ty Central Hospital, Helsinki, Finland